18F-Labeling of Arenes and Heteroarenes for Applications in Positron

Jan 11, 2016 - Since her appointment in Oxford, she holds a Tutorial Fellowship at Merton College Oxford where she teaches organic and biological chem...
39 downloads 9 Views 8MB Size
Review pubs.acs.org/CR

18

F‑Labeling of Arenes and Heteroarenes for Applications in Positron Emission Tomography

Sean Preshlock, Matthew Tredwell, and Véronique Gouverneur* Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom ABSTRACT: Diverse radiochemistry is an essential component of nuclear medicine; this includes imaging techniques such as positron emission tomography (PET). As such, PET can track diseases at an early stage of development, help patient care planning through personalized medicine and support drug discovery programs. Fluorine-18 is the most frequently used radioisotope in PET radiopharmaceuticals for both clinical and preclinical research. Its physical and nuclear characteristics (97% β+ decay, 109.8 min half-life, 635 keV positron energy) and high specific activity make it an attractive nuclide for labeling and molecular imaging. Arenes and heteroarenes are privileged candidates for 18F-incorporation as they are metabolically robust and therefore widely used by medicinal chemists and radiochemists alike. For many years, the range of (hetero)arenes amenable to 18F-fluorination was limited by the lack of chemically diverse precursors, and of radiochemical methods allowing 18Fincorporation in high selectivity and efficiency (radiochemical yield and purity, specific activity, and radio-scalability). The appearance of late-stage fluorination reactions catalyzed by transition metal or small organic molecules (organocatalysis) has encouraged much research on the use of these activation manifolds for 18F-fluorination. In this piece, we review all of the reactions known to date to install the 18F substituent and other key 18F-motifs (e.g., CF3, CHF2, OCF3, SCF3, OCHF2) of medicinal relevance onto (hetero)arenes. The field has changed significantly in the past five years, and the current trend suggests that the radiochemical space available for PET applications will expand rapidly in the near future. 4.4.4. Cu-Mediated 18F-Fluorination of Aryliodonium Salts 4.5. 18F-Fluorination of Iodonium Ylides 4.6. 18F-Fluorination of Triarylsulfonium Salts and Diaryl Sulfoxides 4.7. Oxidative 18F-Fluorination of Phenols and Anilines 4.8. Electrochemical 18F-Fluorination of Arenes 4.9. 18F-Fluorination of Preformed Aryl Palladium and Aryl Nickel Complexes 4.10. Pd-Mediated 18F-Fluorination of Aryl Triflates 4.11. Cu-Mediated 18F-Fluorination of Arylboronate Esters 5. 18F-Trifluoromethylation and 18F-Difluoromethylation of (Hetero)arenes 5.1. Synthesis of [18F]Aryl−CF3 via Halogen Exchange 5.2. 18 F-Fluorodecarboxylation with [ 18 F]Selectfluor Bis(triflate) 5.3. Cross-Coupling of Aryl Iodides and Aryl Boronic Acids with [18F]CuCF3 18 6. F-Labeling of Aryl−SCF3, −OCF3, and −OCHF2 with [18F]Fluoride 7. Conclusion and Perspective

CONTENTS 1. Introduction 2. Synthesis of 18F-Reagents 2.1. Electrophilic and Radical 18F-Sources 2.2. Nucleophilic 18F-Sources 18 3. F-Fluorination of (Hetero)arenes Using an “[18F] F+” Source 3.1. 18F-Fluorination through C−H Functionalization 3.2. 18F-Fluorination of Organometallic Reagents 3.3. Ag-Mediated 18F-Fluorination of Aryl Stannanes and Aryl Boranes 4. 18F-Fluorination of (Hetero)arenes Using an [18F] F¯ Source 4.1. The Balz−Schiemann and Wallach Reactions 4.2. Nucleophilic Aromatic Substitution (SNAr) 4.2.1. Prosthetic Groups 4.2.2. Alternative Drying and Elution Techniques Applied with SNAr 4.2.3. Application to PET Radiotracers 4.3. SNAr of Heteroarenes with 18F-Fluoride 4.3.1. 18F-Labeling of Pyridines 4.3.2. 18F-Labeling of 1,3-Thiazoles 4.3.3. 18F-Labeling of Purines 4.4. 18F-Fluorination of Di(hetero)aryliodonium Salts 4.4.1. Chemoselectivity and Mechanism 4.4.2. Synthesis of 18F-Labeled Heteroarenes 4.4.3. Applications to PET Ligands © 2016 American Chemical Society

720 720 721 722 722 722 723 724 724 724 725 726 727 728 728 728 731 732 732 732 736 736

737 738 741 742 742 743 745 746 747 747 750 750 753 754

Special Issue: 2015 Fluorine Chemistry Received: August 20, 2015 Published: January 11, 2016 719

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

Associated Content Special Issue Paper Author Information Corresponding Author Notes Biographies Acknowledgments References

radiopharmaceuticals and radioligands. Beyond the context of nuclear imaging, the multiple benefits of fluorine substitution on ADME profiling (absorption, distribution, metabolism, excretion) have enhanced the efficacy of agrochemicals and pharmaceutical drugs.26−30 Precise fluorine substitution using a range of fluorine-containing motifs has also served the purpose of modulating conformational and stereoelectronic properties, and favorably influences parameters such as polarity, lipophilicity, or the pKa values of neighboring Brønsted acid/base centers. For PET imaging, 18F-labeling could therefore be considered as a multifunctional operation because the 18F-tag serves its primary positron emitting function, and can be introduced at a specific position to improve radiotracer performance. Such advances require diverse radiochemical transformations allowing for precision 18F-radiochemistry with a range of 18F-containing motifs. This Review discusses all methods available to date for 18F-incorporation onto arenes and heteroarenes (for recent reviews covering some aspects of 18Fincorporation onto arenes, see also refs 31−36). These include direct 18F-fluorination strategies as well as protocols to install onto these aromatic ring systems a range of 18F-labeled motifs that have proved significant in medicinal chemistry or radiotracer design. Arenes and heteroarenes remain privileged structural motifs of great importance for both medicinal chemistry and for radiochemists, because they are metabolically robust and do not easily undergo defluorination processes possible with alkyl fluoride. In the context of PET imaging, in vivo defluorination should be avoided due to complications resulting from the propensity of 18F-fluoride to accumulate within the bones. Selected applications to radiotracer and radiopharmaceutical development are provided for 18F-radiochemistry disclosed prior to 2010; for methods that appeared after 2010, we provide a fuller picture of the downstream applications reported to date. Radiofluorination methods using either electrophilic or nucleophilic 18F-reagents are discussed.

754 754 754 754 754 754 755 755

1. INTRODUCTION Functional molecular imaging has facilitated the diagnosis and management of illnesses such as cancer, heart diseases, and brain disorders. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are subfields of nuclear imaging that emerged from the combined efforts of national laboratories, academia, and industries.1−5 These sophisticated imaging techniques have required the development of particle accelerators that produce radionuclides, synthetic protocols to access radiopharmaceuticals, and instrumentation to detect radiation emitted from the radionuclides that accumulate in the human body. PET and SPECT provide quantitative information at the molecular and cellular level, so these techniques help clinicians to monitor chemical and biological processes. In terms of diagnosis, these imaging modalities provide information that cannot be obtained using structural imaging technologies such as X-ray or computed tomography, or that would require invasive procedures such as biopsy or surgery. As a result, PET and SPECT can identify disease state at an early stage of development, often before symptoms occur or abnormalities can be detected with other tests. PET stands out due to its better image resolution and the benefits gained from the advances made in hardware for quantification.6−8 Combined with CT, PET has been widely used in oncology,9−11 cardiology,12−14 and for the characterization of early stage neurological disorders.15−18 PET also plays an important role in drug development as an in vivo pharmacological imaging tool.19−23 A major advantage of PET is that detection of radioactivity can be highly sensitive with the quantity of radiotracer needed for intraveneous injection being as little as 10−6−10−8 grams; PET studies are therefore tracer experiments allowing the investigation of biological systems not perturbed by mass effect. The positron emitting radioisotope 18F has distinct advantages over alternative nonmetallic radioisotopes (e.g., 11C, 13N, 15O); it has a clean positron emission profile consisting of 97% positron (β+) emission and 3% electron capture (EC) with both modes of decay yielding stable oxygen18, and its maximal positron energy of 0.63 MeV (maximal positron range of 2.4 mm in water)24 is favorable for image resolution (Table 1).25 These advantageous characteristics have encouraged radiochemists to invest much effort in the production of 18F-labeled

2. SYNTHESIS OF 18F-REAGENTS The radionuclide 18F is made available to chemists either as an aqueous solution of 18F-fluoride ([18F]F−) or as gaseous [18F]F2. Selected methods available to produce the radioisotope Table 2. Selected Nuclear Reactions for the Production of 18 F nuclear reaction target product specific activity (GBq/μmol)

109.8

decay mode 97% β+ 3% EC

max beta energy (MeV)

average beta energy (MeV)

max positron range in water (mm)

theoretical max specific activity (GBq/μmol)

0.630

0.25

2.4

6.3 × 104

18

20

Ne(d,α)18F Ne (200 μmol of F2) [18F]F2 0.04−0.40

18

O(p,n)18F O2, Kr (50 μmol of F2) [18F]F2 0.35−2.00

18

O(p,n)18F H218O

[18F]fluoride 4 × 104

F are presented in Table 2.37−40 The nuclear reactions Ne(d,α)18F and 18O(p,n)18F, carried out from the gas targets 20 Ne (200 μmol of F2) and 18O2 (50 μmol of F2), respectively, produce carrier-added [18F]fluorine gas ([18F]F2, which contains both [18F] and [19F] isotopes) with relatively low specific activity.41 The specific activity measures the extent to which an 18F-labeled compound is contaminated with the non radioactive isotopic compound; it is usually expressed as the ratio of radioactivity relative to the mass or molar amount of the compound (e.g., Bq/g or Bq/mol), and is subject to radioactive decay. The maximum theoretical specific activity 18 20

Table 1. Physical Characteristics of 18F halflife (min)

20

720

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

(activity/mol) is defined as ASmax = ln 2NA/t1/2, where NA is the Avogadro constant and t1/2 (half-life) is the time for the number of parent nuclei to drop to 1/2 of its original value. In practice, the maximum specific activity is never attainable as contamination with the stable isotope through radionuclide production, solvents, and chemical impurities is unavoidable.42−44 Today, the nuclear reaction 18O(p,n)18F has superseded 20Ne(d,α)18F for routine production of [18F]F2. Alternatively, this reagent can be obtained from [18F]CH3F and [19F]F2 by atomization in an electric discharge. This “posttarget” synthesis first reported by Bergman and Solin provides [18F]F2 with higher specific activities that can reach up to 55 GBq/μmol.45 For most purposes, no-carrier-added (n.c.a.) 18Ffluoride is preferentially used for 18F-labeling because this reagent currently produced with the 18O(p,n)18F nuclear reaction is easier to handle and made available with specific activity up to 4 × 104 GBq/μmol42 (n.c.a. refers to a preparation of a radioactive isotope essentially free from stable isotopes of the element in question).46 Medical cyclotrons can easily generate proton energies of 16 MeV, and up to 50−100 GBq of n.c.a. 18F-fluoride can be produced within 30−60 min. For incorporation into radiotracers or radiopharmaceuticals, the half-life of 18F (109.8 min) imposes a time constraint less demanding than for other nonmetallic radioisotopes 11C, 13N, or 15O (half-life of 20.3 min, 9.97 min, and 122 s, respectively). In addition, relatively long imaging times are possible, as well as production-distribution to (pre)clinical PET centers that are not equipped with an on-site cyclotron. 2.1. Electrophilic and Radical

Figure 1. (a) Selection of electrophilic 18F-fluorinating reagents derived from [18F]F2. (b) Radiosynthesis of [18F]AcOF. (c) Carrier added synthesis of [18F]XeF2 from [18F]fluoride. (d) Radiosynthesis of [18F]NFSI. (e) Radiosynthesis of [18F]Selectfluor bis(triflate).

18

F-Sources

The fluorination of nucleophilic and radical entities is an important reactivity manifold that has allowed the preparation of an impressive number of fluorine-containing molecules with applications in material sciences, the pharmaceutical, and agrochemical sectors. The most common source of 18F for electrophilic and/or radical fluorination is [18F]F2. This reagent can be used directly or derivatized into less reactive 18F sources. These secondary reagents include [18F]XeF2, O-18F-fluorinated reagents such as hypofluorite reagents and perchloryl fluoride, and more recently a range of N-18F-fluorinated reagents (Figure 1a). Xenon 18F-difluoride is accessible by reacting [18F]F2 and xenon on a sealed nickel reactor at 390 °C for 40 min47−49 or through isotopic exchange with [ 18 F]HF and XeF 2 .50 Alternatively, XeF2 can be labeled by direct treatment with cyclotron-produced [18F]fluoride ion in dichloromethane at room temperature, or in acetonitrile at elevated temperature.51−53 Specifically, the reaction of [18F]fluoride ion with XeF2 in acetonitrile at 90 °C for 10 min followed by separation from the reaction mixture by distillation at 110 °C can generate [18F]XeF2 on a multi-mCi scale (Figure 1b). The [18F]O-F reagent trifluoromethyl [18F]hypofluorite was produced by reacting cesium fluoride, F2, and carbonyl fluoride with targetbound 18F in the target chamber for 35 min at 100 °C.54 The preparation of acetyl [18F]hypofluorite, an alternative O-F type secondary reagent with significantly milder reactivity than [18F]F2, relies on a two-stage process consisting first of passing [18F]F2 gas through a stationary phase with bound complexes of acetic acid and alkali metal acetate, followed by eluting [18F]AcOF from the stationary phase. The reaction is quantitative with one-half of 18F transferred to the electrophilic agent [18F]AcOF and the other half released as [18F]HF·AcOK (Figure 1c).55 Similarly, gaseous perchloryl fluoride [18F]FClO3 is generated by passing [18F]F2 through a stationary phase with

KClO3 at 90 °C. Similar to [18F]AcOF, 50% of the radioactivity is transferred to the reagent because an equimolar amount of [18F]KF is simultaneously produced.56 Attempts were made to access n.c.a. [18F]FClO3 reacting first [18F]fluoride with fuming sulfuric acid. The resulting 18F-labeled hypofluorous sulfuric anhydride was treated with KClO4 to afford [18F]FClO3, albeit in very low RCY.57 The perchlorate salts required to produce 18 F-labeled perchloryl fluoride pose a threat of explosion in organic solvents, a property that has not encouraged widespread use of the methodology. In fact, O-F reagents are not commonly used for late-stage fluorination as they still are very reactive, presenting handling difficulties, and are not compatible with most functionalized precursors. N-Fluoro reagents have emerged as incredibly useful alternative “F+” sources for the selective fluorination of a range of complex molecules;58 to date, a selection of N-F reagents have been considered for 18Flabeling. [18F]N-Fluoropyridinium triflate59 and [18F]1-fluoro2-pyridone60 were prepared by direct fluorination with [18F]F2 of N-trimethylsilylpyridinium triflate in acetonitrile and 2((trimethylsilyl)oxy)pyridine in CFCl3, respectively. These reactions generate [18F]FSiMe3 as the other radioactive product. Various N-fluoro-N-alkylsulfonamides were 18Flabeled upon treatment of the corresponding parent sulfonamides with [18F]F2 in CFCl3 with RCY reaching ca. 40%.61 None of these reagents has been the subject of extensive studies to assess their value as “18F+” reagents. The syntheses of N-fluoro-bis-trifluoromethanesulfonimide and N-fluoro-orthobenzenesulfonimide were attempted, but the resulting 18Flabeled species were found to be unsuitable for subsequent fluorinations.62 In 2007, N-[18F]fluorobenzenesulfonimide 721

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

Figure 2. Diagram of commonly used technique for the purification and drying of aqueous [18F]fluoride with an ion-exchange resin.

pathways. The high solvation energy of fluoride in water (439 kJ mol−1) is circumvented through azeotropic distillation with acetonitrile, a process that minimizes the amount of water present and provides a more reactive [18F]fluoride ion.70 This residue is subsequently dissolved in a polar aprotic solvent prior to use for 18F-labeling. These operations have been automated into a reliable process producing ready-to-use high specific activity [18F]fluoride. High specific activity (>100 GBq/μmol) is required for biological studies involving low target concentration.71 Various modifications to improve these standard protocols have been examined such as the use of ionic liquid media72−74 or the effect of additives such as alcohols,75−77 but these modifications have not been widely adopted by the PET community. Latent [18F]fluoride sources have also been considered; acyl [18F]fluorides were prepared from acetic or propionic anhydride and [18F]fluoride, and subsequently treated with a solution of tetraethylammonium bicarbonate to release [18F]fluoride in acetonitrile or other polar organic solvents employed for 18F-radiofluorination. This mode of generating [18F]fluoride from anhydrous gaseous acyl [18F]fluorides could be beneficial for water-sensitive transformations.78 More recently, 2-pyridinesulfonyl fluoride (PyFluor) was reported to be an inexpensive, thermally stable deoxyfluorination reagent that fluorinates a broad range of aliphatic alcohols without substantial competitive elimination. The [18F]PyFluor was prepared by reacting 2-pyridinesulfonyl chloride with [18F]KF/K222 at 80 °C for 5 min in 88% radiochemical conversion (RCC) (Figure 3). This reagent allowed for the deoxyradiofluorination of a tetrahydro-2Hpyran-2-ol in acetonitrile at 80 °C and in the presence of the strong base MTBD (7-methyl-1,5,7-triazabicyclo(4.4.0)dec-5ene). After 20 min, the desired 2-fluoro tetrahydro-2H-pyran was obtained with 15% RCC.79

([18F]NFSI) was successfully prepared from sodium dibenzenesulfonimide with the maximum RCY of 50%, and this reagent was found to be competent for the 18F-fluorination of silyl enol ethers, allylsilanes, and aldehydes (Figure 1d).63,64 Among the series of N-F fluorinating reagents, 1-chloromethyl-4-fluoro-1,4diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), Selectfluor bis(tetrafluoroborate), is arguably the most commonly used “F +” reagent for electrophilic fluorination in academic laboratories and for research-based medicinal chemistry, and it is therefore surprising that this reagent was not selected for 18 F-labeling studies until 2010.65 For 18F-incorporation, Selectfluor bis(triflate) was selected in preference to Selectfluor bis(tetrafluoroborate) to avoid isotopic exchange. A suitable protocol for the preparation of [18F]Selectfluor bis(triflate) consists of bubbling [18F]F2 through a 0.02 M solution of 1chloromethyl-4-aza-1-diazoniabicyclo[2.2.2]octane triflate and 1 equiv of lithium triflate in anhydrous CH3CN at −10 °C; instantaneous fluorination affords a crude stock solution that can be used without purification (Figure 1e). Starting material and [18F]LiF are present in the stock solution, but these compounds do not interfere with subsequent 18F-labeling. All of these secondary reagents are prepared from [18F]F2 and are therefore available in low specific activity, 55 GBq/μmol at best. 2.2. Nucleophilic

18

F-Sources

18

The [ F]fluoride ion used in SNAr reactions is most commonly produced in cyclotrons by the nuclear reaction 18O(p,n)18F by proton bombardment of [18O]water. This delivers aqueous [18F]fluoride, which must be activated before it becomes sufficiently nucleophilic. This is achieved with a multistep process starting by trapping the [18F]fluoride on an ionexchange column and subsequently eluting with an MeCN/ H2O solution containing a countercation (Figure 2).66,67 Tetraalkylammonium ions,68 or potassium ions complexed with the aminopolyether cryptand Kryptofix 2.2.2 (K222),69 are typically added as fluoride counterions. Large soft metals such as rubidium or cesium have also been employed for this purpose. For these cations, carbonate or hydrogen carbonate is selected as first choice counterions due to their nonnucleophilic and relatively nonbasic nature, two advantageous properties preventing competitive substitution and elimination

3.

18

F-FLUORINATION OF (HETERO)ARENES USING AN “[18F]F+” SOURCE

3.1.

18

F-Fluorination through C−H Functionalization

The direct electrophilic fluorination of aromatic compounds with F2 gas yields complex product mixtures due to the potent 722

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

electrophilic fluorodemercuration.92−94 This methodology was adopted for the regioselective radiolabeling of 6-[18F]fluoro-LDOPA from a protected N-(trifluoroacetyl)-3,4-dimethoxy-6trifluoroacetoxy-mercurio-L-phenylalanine ethyl ester precursor using the electrophilic reagent [18F]AcOF.95 Decay-corrected RCY for 6-[18F]fluoro-L-DOPA are 11−12% using this methodology, with the final product after purification containing less than 20 ppb of mercury (Figure 5).96,97 Fluorodemercuration has also been applied to access 4[18F]fluoro-L-m-tyrosine98 and 6-[18F]fluorometaraminol.99 Arylstannanes,100 arylsilanes,101,102 and arylpentafluorosilicates103 are competent substrates for electrophilic radiofluorodemetalation reactions with [18F]F2. Coenen and Moerlein conducted a comparative reactivity study for a series of group IV organometallic reagents with [18 F]F 2 or [18F]AcOF, and found an order of decreasing RCY of [18F]ArF from ArSnMe3 > ArGeMe3 > ArSiMe3 (Figure 6).104 Fluorodestannylation105,106 and fluorodesilylation107

Figure 3. Radiosynthesis of [18F]PyFluor and its use as a deoxyradiofluorination reagent.

oxidizing strength of fluorine.80,81 Nonetheless, [18F]F2 has been used for the radiosynthesis of complex radiotracers such as 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine (6-[18F]fluoroL-DOPA) by tempering its reactivity with low temperatures and by dilution in neon gas.82 Chirakal et al. reported that 0.5% [18F]F2 in neon gas reacts directly with L-DOPA in a solution of HF at −65 °C to produce a mixture of 2-, 5-, and 6-[18F]fluoroL-DOPA. The solvent and Lewis acid additives affect both RCYs and regioisomer distributions.83,84 With addition of BF3 to HF solvent, 0.3 GBq of 6-[18F]fluoro-L-DOPA could be produced from 3.7 GBq of [18F]F2 with a specific activity of 8.1 × 10−3 GBq/μmol after HPLC purification. The direct electrophilic radiofluorination of L-DOPA can also be accomplished with milder electrophilic fluorinating reagents such as [18F]XeF285 and [18F]AcOF.86−89 As expected, poor regioselectivity is observed in these reactions with the 2- and 5regioisomers produced in addition to the desired 6-[18F]fluoroDOPA (Figure 4).

Figure 6. Fluorodemetalation of group IV organometallic reagents.

methods allow for the regiospecific radiosynthesis of PET radiotracers such as 6-[18F]fluoro-L-DOPA (Figure 7)108 and 2-

Figure 4. Radiosynthesis of 6-[18F]fluoro-DOPA from [18F]AcOF.

3.2.

18

F-Fluorination of Organometallic Reagents

Electrophilic [18F]perchloryl fluoride reacts regioselectively with functionalized aryl lithium reagents to form [18F]fluoroarenes.56,90 N-[18F]Fluoro-N-alkylsulfonamides61,91 react similarly with aryl lithium or aryl Grignard reagents, and N[18F]fluoropyridinium triflate60 has been shown to react with aryl Grignard reagents to produce [18F]fluoroarenes by ipso fluorodemetalation. Fluoroarenes are also within reach by

Figure 7. Radiosynthesis of 6-[18F]fluoro-L-DOPA by electrophilic fluorodestannylation.

[18F]fluoro-L-tyrosine.109,110 Radiotracers such as (1R,2S)-4[18F]fluorometaraminol111 and 6-[18F]fluoro-L-DOPA (Figure

Figure 5. Radiosynthesis of 6-[18F]fluoro-L-DOPA by fluorodemercuration. 723

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

Figure 8. Electrophilic synthesis of 6-[18F]fluoro-L-DOPA using post-target produced [18F]F2.

Figure 9. Silver-mediated radiosynthesis of 6-[18F]fluoro-L-DOPA.

8)112 can be labeled in moderate SA by electrophilic fluorodestannylation using post-target produced [18F]F2. 3.3. Ag-Mediated Aryl Boranes

18

Figure 10. Radiosynthesis of [18F]fluoroarenes by thermal fluorodediazonation.

F-Fluorination of Aryl Stannanes and

Selectfluor has proven itself a versatile fluorinating reagent for the synthesis of fluoroarenes from aryl stannane and aryl boronic ester precursors in the presence of silver113,114 or copper complexes.115,116 The electrophilic radiofluorination of electron-rich aryl stannanes via the N−F reagent [18F]Selectfluor bis(triflate) was accomplished by Solin, Luthra, and Gouverneur.65 A number of electron-rich aryl stannanes reacted with [18F]Selectfluor bis(triflate) in the presence of 2 equiv of AgOTf in acetone with a reaction time of 20 min. 4[18F]Fluoroveratrole was made in 18% RCY according to this procedure, and 4-[18F]fluorophenol was labeled in 14% RCY via fluorodestannylation of the unprotected stannane precursor. Optimization for the radiosynthesis of 6-[18F]fluoro-L-DOPA found the neopentyl glycol boronate ester precursor was superior to the corresponding aryl stannane, and 6-[18F]fluoroL-DOPA was synthesized in 19% RCY with a specific activity of 2.6 GBq/μmol after deprotection (Figure 9).117

4.

counterions rapidly incorporate [18F]fluoride via a halogen exchange reaction to produce [18F]Ar−N2BFCl3 that can produce [18F]fluoroarenes via thermal decomposition.120 However, such reactions lose up to 75% of [18F]fluoride as gaseous [18F]BFCl2 leading to low RCYs. Higher RCYs and specific activity could be obtained by modified n.c.a. Balz− Schiemann decomposition reactions utilizing diazonium anions, which would not undergo isotopic exchange (Figure 11).121 For example, the diazonium 2,4,6-triisopropylbenzenesulfonate precursor could produce 4-[18F]fluorotoluene in a decaycorrected RCY of 39% under optimized conditions.

18

F-FLUORINATION OF (HETERO)ARENES USING AN [18F]F¯ SOURCE

Figure 11. Radiosynthesis of [18F]fluoroarenes via a n.c.a. Balz− Schiemann.

4.1. The Balz−Schiemann and Wallach Reactions

Early reports of the radiosynthesis of electron-rich and neutral [18F]fluoroarenes from [18F]fluoride were based on the Balz− Schiemann reaction118 and preceded via fluorodediazonation of aryldiazonium [18F]tetrafluoroborates (Figure 10).119 The reaction suffers from a maximum theoretical RCY of 25% and low specific activity due to competing incorporation of unlabeled fluoride from the monolabeled [18F]tetrafluoroborate counterion. Diazonium salts with BCl4¯

This methodology has been used for the synthesis of a number of aromatic amino acids122 including racemic 3- and 4[18F]fluorophenylalanines;123−125 fluoroheteroarenes such as 5and 6-[18F]fluorotryptophan126 are also within reach via thermal decomposition of the corresponding (hetero)aryldiazonium [18F]tetrafluoroborate precursors followed by deprotection. These early syntheses used [18 F]fluoride produced by nuclear reactions, which have since been 724

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

superseded by more efficient methods. Initially, the [18F]Ar− N2BF4 salts used for radiolabeling of phenylalanines and tryptophans utilized [18F]LiBF4 made by the 19F(n,2n)18F reaction from LiBF4. However, higher specific activity is obtained with [18F]fluoride from a water target, which is coprecipitated with a preformed Ar−N2BF4 complex, followed by drying and pyrolysis (Figure 12).

tion of the resulting aryl diazonium salts in the presence of [18F]fluoride yields [18F]fluoroarenes (Figure 14).

Figure 14. Thermal decomposition of 1-aryl-3,3-dialkyltriazenes.

The decomposition of triazenes has been used to radiolabel [18F]haloperidol with specific activity sufficient for PET imaging of dopamine receptors in man.134 The use of halogenated solvents is beneficial for the synthesis of radiolabeled arenes by inhibiting competing protodediazoniation.135 For the labeling of [ 18 F]spiperone from the corresponding diethyltriazene, reactions in MeCN gave the desired target in 0.5% RCY, while reactions under identical conditions but in Cl3CCN produced [18F]spiperone in 4% RCY (Figure 15). Chlorinated solvents have also found use in Figure 12. Radiosynthesis of 5- and 6-[18F]fluorotryptophan by fluorodediazonation.

5-[18F]Fluoro-DOPA can be prepared from [18F]5-(2′,2′dicarbethoxy-2′-acetamidoethyl)-2,3-dimethoxybenzyldiazonium fluoroborate precursor followed by deprotection (Figure 13).127 The reaction yielded the desired product in very low

Figure 15. Radiosynthesis of [18F]spiperone with Cl3CCN solvent.

Wallach reactions for the radiosynthesis of a protected 3[18F]fluoro-α-methylphenylalanine136 (Figure 16) and for the labeling of triazenes bound to a polymer resin solid support.137 Figure 13. Radiosynthesis of 5-[18F]fluoro-DOPA by fluorodediazoniation.

specific activity and utilized [18F]fluoride produced from [6Li]Li2CO3 by the nuclear reaction sequence 6Li(n,4He)3H and 16O(3H,n)18F. The enantiopure 5-[18F]fluoro-L-DOPA has been synthesized by the Balz−Schiemann reaction starting from the racemic diazonium tetrafluoroborate precursor in a decaycorrected 24% RCY after chiral HPLC separation and purification.128 The reaction utilized [18F]fluoride produced by the modern 18O(p,n)18F, and isotopic exchange with the 5(2′,2′-dicarbethoxy-2′acetamidoethyl)-2,3-dimethoxybenzyldiazonium fluoroborate precursor occurred in the target water solution. Thermal decomposition in xylene at 120 °C followed by hydrolysis gave racemic 5-[18F]fluoro-DOPA in an overall decay-corrected RCY of 54% prior to chiral HPLC purification. Another strategy for the synthesis of [18F]fluoroarenes is to form the aryldiazonium salts in situ from 1-aryl-3,3-dialkyltriazenes in the presence of strong acid, a process referred to as the Wallach reaction.129−133 Triazenes are stable relative to diazonium salts and dissociate into the diazonium and corresponding amine after protonation. Thermal decomposi-

Figure 16. Radiosynthesis of protected [18F]-3-fluoro-α-methylphenylalanine.

The Balz−Schiemann and Wallach methodologies have not been widely adopted and have been eclipsed by the development of nucleophilic radiofluorination reactions, which involve more stable functional groups amenable to ipso fluorination. 4.2. Nucleophilic Aromatic Substitution (SNAr)

The introduction of [18F]fluoride into [18F]fluoroarenes by SNAr of electron-deficient aryl precursors is a widely practiced method for the synthesis of radiotracers for PET imaging.31,138 The reaction is only viable for activated arenes with strong inductively withdrawing groups or resonance withdrawing groups positioned ortho or para to the group that is to be displaced.139 These restrictions limit the reaction scope or require post labeling functional group manipulations to access 725

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

Table 4. Radiosynthesis of meta-Substituted [18F]Fluoroarenes via SNAr

[18F]fluoroarenes not directly viable by SNAr. An order of reactivity for electron-withdrawing groups commonly used to activate leaving groups for nucleophilic displacement is p-NO2 > p-CF3 ≈ p-CN > p-CHO > p-Ac > m-NO2. The leaving groups, which have been most successfully employed for displacement by [18F]fluoride, are the nitro and trimethylammonium groups. Halides have also been used as leaving groups for the introduction of [18F]fluoride via halogen exchange but are typically not as effective.140−142 Reaction conditions used for SNAr commonly require heating to high temperatures in polar aprotic solvents. Molten salts have been used as reaction solvents as an alternative to the more conventional polar aprotic solvents used for nucleophilic aromatic fluorination reactions.143 With favorable substitution patterns, the reactions can occur under very mild conditions. A rare example of a room temperature SNAr reaction is the radiosynthesis of 2-chloro-1[18F]fluoro-4-nitrobenzene, which can be prepared in 71−76% RCY in MeCN with a reaction time of 25 min from the corresponding aryltrimethylammonium triflate.144 A potential competing side reaction observed with aryltrimethylammonium salts is the formation of [18F]fluoromethane.145 The group of DiMagno looked at the relative product distribution of fluoroarenes to fluoromethane for a series of 4-substituted trimethylanilinium triflates when reacted with unlabeled TBAF. Their results showed that substrates substituted with groups with large Hammet σ constants favored the formation of fluoroarenes, while substrates with substituents with low Hammet σ constants give fluoromethane as the major product (Table 3).146

RCY %

a

EWG

LG

thermal

microwave

NO2 CN Br Br CF3 NO2

NO2 NO2 F NMe3I NMe3I NMe3I

21 20 9 3 1 4

47 46 19 17 12 8

NMP = N-methyl-2-pyrrolidone.

Figure 17. Radiosynthesis of 4-[18F]acetophenones via SNAr.

despite Ar−NO2 precursors generally giving higher RCYs than comparable Ar−halo precursors, illustrated with the labeling of [18F]PK 14105 (Figure 18).149

Table 3. Electronic Effects in Fluorodeamination Reaction of Trimethylanilinium Triflates

−R

σp-

reaction time (min)

ArF:CH3F

NO2 CHO CN COPh CO2Me Br H Me OMe

1.27 1.03 1.00 0.84 0.64 0.25 0 −0.17 −0.26

1 1 1 1 2 10 10 10 30

>99:1 >99:1 99:1 99:1 96:4 2:98 I. Unlabeled fluoride has been shown in certain examples to lead to higher [18F]fluoride incorporation than −NO2 or −NMe3X precursors; however, the reaction is not practiced as the desired radiolabeled product is inseparable from the isotopomer precursor (Figure 17).148 Notably, halides are selectively displaced by [18F]fluoride in p-nitrohaloarenes, 726

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

(SPE) cartridge by loading them with long alkyl chain quaternary ammonium salts.162 The modified support was prepared by adding a solution of n-tetradecyl-trimethylammonium bicarbonate or similar ammonium salts in MeCN to a copolymer sorbent and allowing to dry. The modified support was then added into a SPE cartridge between two frits. The modified support was shown to be capable of quantitatively trapping [18F]fluoride from an aqueous solution. The [18F]fluoride could then be eluted from the cartridge with dried MeCN, with recovery of more than 90% of the activity. The [18F]fluoride solutions were sufficiently nucleophilic to radiolabel several aromatic precursors via SNAr with high RCYs without any evaporation event occurring. Lemaire et al. developed a method for eluting [18F]fluoride from an ion-exchange resin using a variety of organic bases.161 A trace amount of cosolvent containing acidic protons was required, and by adding between 3100 and 25 000 ppm water to a dry acetonitrile solution with appropriate organic base, [18F]fluoride was eluted nearly quantitatively, and the residual activity remaining on the support was less than 3% of the starting radioactivity. Similar effects could be obtained when the trace amounts of water cosolvent were replaced with MeOH or i PrOH. A number of organic bases were screened (Figure 21);

Figure 19. Common 18F-labeled prosthetic groups.

labeled peptides and heterocycles through well-established multicomponent coupling reactions such as those of Ugi, Biginelli, Groebke, and Passerini.158 Automated procedures have been developed for the rapid multistep radiosynthesis of [18F]fluorobenzyl halide derivatives, an important [18F]fluorinated alkylating reagent not amenable to direct SNAr due to the benzyl halides reactivity with nucleophiles.159,160 Labeling of the ortho or para-forymylN,N,N-trimethylbenzenaminium trifluormethanesulfonate in DMSO at 140 °C led to the corresponding [ 18 F]fluorobenzaldehyde in decay-corrected RCYs of 69% ± 3% (n = 3) and 73% ± 4% (n = 15), respectively. A sodium borohydride reduction of the aldehyde followed by halogenation with the appropriate acid enabled access of 2- and 4[18F]fluorobenzyl chlorides, bromides, and iodides in decaycorrected RCYs ranging from 12% to 63% (Figure 20).

Figure 21. [18F]Fluoride elution with organic base.

however, only bases with pKa values of around 30 were capable of eluting [18F]fluoride from the ion-exchange resin in nearly quantitative yield. These mixtures could be used directly without the need for further azeotropic drying for the synthesis of [18F]fluoroarenes via SNAr. It has also been demonstrated that MeCN solutions of KOH/K222 can also elute [18F]fluoride from ion-exchange resins without the need for further azeotropic drying.163 Another alternative to azeotropic distillation is the electrodeposition of [18F]fluoride onto carbon electrodes from aqueous solutions and resolvation into organic solvents.164−167 This methodology was used for the radiosynthesis of [18F]flumazenil from the corresponding nitro precursor.168 A novel method utilizing TiO2 nanoparticles and aqueous [18F]fluoride solutions delivered directly from the cyclotron with no prior purification steps has been developed for SNAr reactions on tosylated precursors.169 The TiO2 catalyst is thought to play multiple roles in the proposed reaction mechanism. First, active sites on the TiO2 nanoparticles desolvate the [18F]fluoride anion, increasing its nucleophilicity (Figure 22a). In addition, the TiO2 nanoparticles are hypothesized to coordinate to the oxygen atoms on the sulfonyl moiety of the tosylated precursor (Figure 22b). TBAB then serves as a phase transfer catalyst to shuttle the activated [18F]fluoride to surface bound tosylated precursor, followed by a nucleophilic substitution reaction (Figure 22c and d). The reaction was carried out on a number of aromatic substrates

Figure 20. Multistep synthesis of 2- and 4-[18F]fluorobenzyl chlorides, bromides, and iodides.

4.2.2. Alternative Drying and Elution Techniques Applied with SNAr. As detailed in section 2.2, the [18F]fluoride ion used in SNAr reactions is produced by the nuclear reaction 18O(p,n)18F by proton bombardment of [18O]water. This delivers aqueous [18F]fluoride, which must be activated prior to use; the [18F]fluoride is therefore trapped on an ion-exchange column and subsequently eluted with an MeCN/H2O solution containing a countercation, most commonly Cs or K base with a cryptand or a tetraalkylammonium salt, and azeotropically dried. This procedure is timeconsuming and results in loss of activity by radioactive decay and by surface adsorption. Also, the automation required to azeotropically dry the [18F]fluoride remotely imposes constraints onto the miniaturization of PET equipment.161 Several methodologies have been designed to avoid the need for azeotropic drying and have been applied in the synthesis of radiolabeled [18F]fluoroarenes. Aerts and co-workers describe a procedure for modifying a commercial solid-phase extraction 727

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

Figure 24. Radiosynthesis of [18F]MFBG and [18F]PFBG. Figure 22. Proposed mechanism for TiO2-catalyzed radiofluorination.

catalyzed alkylation of 4-[18F]fluorocatechol,175 a preformed Ni(II)complex with a chiral inductor,176 and enantioselective alkylation with a chiral phase-transfer catalyst.177−179 These multistep procedures have been automated and allow for rapid synthesis times and production of 6-[18F]fluoro-L-DOPA on the curie level (Figure 26).180,181 An additional strategy for the synthesis of 6-[18F]fluoro-LDOPA is via isotope exchange of an unlabeled precursor with an activating aldehyde para to the fluoro substituent.182 Following isotope exchange, 6-[18F]fluoro-L-DOPA is formed after a Baeyer−Villiger oxidation with mCPBA and hydrolysis with HBr (Figure 27). Because of isotopic dilution from unlabeled starting material, this method does not produce high SA 6-[18F]fluoro-L-DOPA unlike the other nucleophilic methods previously covered in this section. However, recent studies comparing high SA 6-[18F]fluoro-L-DOPA and low SA 6-[18F]fluoro-L-DOPA found no difference in uptake in an in vivo model for neuroendocrine tumors183 or in biodistribution and imaging properties in a Parkinson’s rat model.184 A number of aryl amino acids have been synthesized via similar reaction sequences such as L-3-[18F]fluoro-α-methyltyrosine185 and 6[18F]fluoro-L-meta-tyrosine (Figure 28).186 4-[18F]Fluoro-Ltryptophan was synthesized by a similar sequence involving isotopic exchange, reductive decarbonylation, and hydrolysis.187

(Figure 23) and utilized small amounts of aqueous [18F]fluoride solution (approximately 10 μL diluted in an additional 30 μL of MeCN).

Figure 23. TiO2-catalyzed radiofluorination of [18F]fluoroarenes.

4.3. SNAr of Heteroarenes with

4.2.3. Application to PET Radiotracers. The accessibility of the −NO2, −halo, and −NMe3+ precursors used in SNAr and their relative stability as compared to precursors used in other methods for radiosynthesis of [18F]arenes has encouraged radiochemists to apply this methodology to the production of a large number of radiotracers and radiopharmaceuticals. For molecules lacking the required substitution patterns allowing for direct SNAr with [18F]fluoride, elegant post labeling transformations have been implemented. For example, [ 18 F]MFBG and [ 18 F]PFBG can be made from the corresponding cyano-N,N,N-trimethylbenzenaminium triflate, after reduction of the nitrile to the benzylamine and subsequent guanylation.170 The much higher RCYs for [18F]PFBG (41% ± 12% (n = 5), as compared to [18F]MFBG (11% ± 2% (n = 12), is a result of the more favorable substitution pattern on the benzonitrile starting material (Figure 24). Electron-rich catecholamines such as 6-[18F]fluorodopamine can be synthesized starting from precursors amenable to SNAr followed by elaborate synthesis of the target molecule (Figure 25).171 Synthesis of chiral electron-rich amino acids such as 6[18F]fluoro-L-DOPA via similar reaction sequences is more difficult due to the added requirement of producing the desired product in high ee.172 Early syntheses produced racemic 6[18F]fluoroDOPA and relied on chiral separation.173,174 Several syntheses have been reported for the radiosynthesis of 6[18F]fluoro-L-DOPA in high ee including an enzymatic

18

F-Fluoride

18

4.3.1. F-Labeling of Pyridines. Pyridine derivatives are the most widely studied heterocycles for the incorporation of [18F]fluoride by SNAr, with the resultant [18F]pyridines having applications directly as radiotracers and as prosthetic groups.188 The comparative popularity of pyridine over other heteroarenes is in part due to the availability of the precursors and the ease of incorporation of [18F]fluoride at C-2 and C-4. The presence of the nitrogen atom promotes nucleophilic aromatic substitution in pyridine relative to benzene, a difference in reactivity due to the lower aromatic stabilization of pyridine and the fact that the intermediate meisenheimer complex gains additional stabilization from the nitrogen atom by both inductive and mesomeric effects.189−191 The magnitude of this activation in pyridine is akin to the addition of a nitro group to benzene.192 4.3.1.1. Scope and Limitations. The first systematic study on the parameters that influence the synthesis of [18F]fluoropyridines examined the effect of the leaving group, reaction conditions, and method of heating on the RCY.193 A series of functionalized pyridines bearing a leaving group in 2position were subjected to [18F]KF/K222 in DMSO at a range of temperatures and times (Table 5). Of the halogenated precursors tested, 2-bromopyridine gives the highest yield under all conditions employed with a maximum of 87% RCY obtained at 180 °C for 20 min. None of the halogenated precursors gives any of the desired 2728

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

Figure 25. Radiosynthesis of [18F]FDA.

Figure 26. Radiosynthesis of 6-[18F]fluoro-L-DOPA by post labeling transformations.

Figure 27. Synthesis of 6-[18F]fluoro-L-DOPA via isotope exchange.

Figure 28. Synthesis of 6-[18F]fluoro-L-meta-tyrosine via isotope exchange.

[18F]fluoropyridine at a temperature of 120 °C at any of the time points examined. 2-Nitropyridine gives 2-[ 18 F]fluoropyridine in 76% RCY after 10 min at 120 °C; increasing either the temperature and/or the time results in only a modest increase in RCY. The RCYs from trimethylammonium triflate precursor are superior to those from the nitropyridine, with an 81% RCY obtainable by heating at 120 °C for 5 min, although an increase in reaction time and/or temperature has a negligible effect on this RCY. Performing a similar study with microwave heating instead of conventional heating results in a very similar reactivity profile of the leaving groups, albeit with reduced reaction times of 1−2 min (Table 6). The efficiency of 18F incorporation into 3-methyl- or 3-methoxy-2-nitropyridines is very similar to that of the parent 2-nitropyridine, demonstrating that these electron-donating groups at position 3 have little effect on the RCY. 194,195 The synthesis of 2-[ 18 F]fluoropyridines by 19F/18F isotope exchange is also a viable

strategy; heating 2-fluoropyridine (0.1 mmol) in DMF at 140 °C for 20 min gives a 90% RCY with a SA of 0.5 GBq/μmol. By decreasing the precursor quantity to 0.001 mmol, the RCY decreases to 20%, but the SA increases to 11.7 GBq/μmol.196 The radiochemical synthesis of 2-, 3-, and 4-[18F]fluoropyridine by nucleophilic aromatic substitution of the corresponding nitro-substituted derivatives, with [18F]KF/K222 in DMSO, with either conventional heating or microwave activation has been undertaken. The nitro leaving group was selected despite earlier studies that indicated the trimethylammonium triflate gave superior RCYs in the 2-position, due to the difficulty in preparation of the 3- and 4-trimethylammonium salts. These data for the synthesis of 2-[18F]fluoropyridine are in accordance with Dollé’s earlier publication, while 4-[18F]fluoropyridine can be accessed under the same conditions as 2[18F]fluoropyridine, albeit with slightly diminished yields. As would be expected, the radiochemical synthesis of 3-[18F]729

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

Table 5. Radiosynthesis of 2-[18F]Fluoropyridines

RCY (%) after x (min) temp (°C)

−X

5

10

20

120

Cl, Br, I NO2 NMe3OTf Cl Br I NO2 NMe3OTf Cl Br I NO2 NMe3OTf

0 11 81 1 1 0 52 89 11 56 2 77 88

0 76 87 3 16 0 85 89 28 60 5 88 91

0 82 91 23 25 1 92 90 57 87 19 89 92

150

180

Figure 29. Radiosynthesis of activated 3-[18F]fluoropyridines. 18

F-fluoride. The group of Dollé has reported a number of 2[18F]fluoropyridine-based prosthetic groups such as 2-bromoN-[3,(2-[18F]fluoropyridin-3-yloxy)propyl]acetamide ([18F]FPyBrA), 200 1-[3-(2-[ 18 F]fluoropyridin-3-yloxy)propyl]pyrrole-2,5-dione ([18F]FPyME),201 and 2-[18F]fluoro-3-pent4-yn-1-yloxypyridine ([18F]FPyKYNE)202−204 for the labeling of oligonucleotides, peptides, and proteins (Figure 30). The

Table 6. Radiosynthesis of 2-, 3-, and 4-[18F]Fluoropyridines

Figure 30. Common fluoropyridyl motif.

18

F prosthetic groups bearing the 2-[18F]-

pendant functional groups for attachment to the target of interest are α-bromo ketone, pyrrole-2,5-dione, and an alkyne, respectively. Simultaneously with Dollé’s report of 2-[18F]fluoro-3-pent-4-yn-1-yloxypyridine, Inkster and co-workers reported the structurally similar 2-[18F]fluoro-3-hex-5-yn-1yloxypyridine.205,206 Both groups demonstrate that both the nitro and the trimethylammonium triflate are the optimal leaving groups for these valuable prosthetic groups. The inherent reactivity of pyridine toward nucleophilic aromatic substitution allows the synthesis of activated esters in a single step. N,N,N-Trimethyl-5-((2,3,5,6-tetrafluorophenoxy)carbonyl)pyridine-2-aminium trifluoro-methanesulfonate in the presence of [18F]TBAF at 40 °C in t-BuOH/MeCN (4:1) gives a 50% RCY of 6-[18F]fluoronicotinic acid 2,3,5,6tetrafluorophenyl ester in 10 min (Figure 31).207 2-Ethynyl-6[18F]fluoropyridine can be synthesized in 27% RCY from 2bromo-6-ethynylpyridine, with [18F]KF/K222 in DMSO at 130 °C. This prosthetic group will undergo a Cu(I)-catalyzed cycloaddition “click” reaction with pHLIP (pH low insertion peptide) analogues bearing azide functional groups.208 To complement the more widely used prosthetic groups, 2-bromo6-[18F]fluoropyridine has been shown to undergo palladiummediated cross-coupling with primary and secondary amines, boronic acids, and an aminocarbonylation with carbon monoxide and primary amines, which demonstrates the versatility of this prosthetic group in radiochemistry.209

fluoropyridine is more challenging, with only trace product being formed under microwave irradiation. Subjecting 3bromopyridine to these SNAr conditions fails to yield any of the desired product.197 To access meta-[18F]fluorinated pyridine derivatives, it has been shown that the presence of an additional electron-withdrawing group in the 2-position is required to sufficiently activate the pyridine moiety to attack by [18F]fluoride.198,199 Langer and co-workers synthesized 5bromopyridines activated at the 2-position by cyano, nitro, or carboxamide. Subjecting the nitro derivative to [18F]KF/K222 in DMSO at 150 °C for 20 min does not yield the desired 2-nitro5-[18F]fluoropyridine, but gave 2-[18F]fluoro-5-bromopyridine in 85% RCY, whereby the nitro group is chemoselectively displaced (Figure 29). However, 5-bromo-2-pyridinecarboxamide and 5-bromo-2-pyridinecarbonitrile both give the desired product whereby bromide is selectively displaced. The cyano substrate is somewhat more reactive than the carboxyamide with the former giving 5-[18F]fluoro-2-pyridinecarbonitrile in 92% RCY ([18F]KF/K222, DMSO, 150 °C, 5 min), while the latter requires higher temperature and a longer reaction time to achieve a 62% RCY ([18F]KF/K222, DMSO, 180 °C, 20 min). 4.3.1.2. 2-[18F]Fluoropyridyl-Based Prosthetic Groups. The relatively facile synthesis of 2-[18F]fluoropyridyl motifs makes these compounds useful 18F prosthetic groups for the indirect labeling of molecules that are unsuitable for direct labeling with 730

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

Figure 31. Selected applications of the 2-[18F]fluoropyridyl-based prosthetic group.

4.3.1.3. PET Ligands with a 18F-Labeled Fluoropyridyl Motif. Nicotinic acetylcholine receptors (nAChR) are proposed to play key roles in the central nervous system, in particular for Parkinson’s disease and Alzheimer’s disease (AD), tobacco dependency and schizophrenia, in addition to numerous other disorders; this has promoted much research into selective radioligands to study these receptors.210−212 The earliest published data on use of SNAr for labeling on heteroarenes with [18F]fluoride are by Knust and co-workers, who report the synthesis of 2-[18F]fluoro- and 6-[18F]fluoro-nicotinic acid diethylamide by displacement of a chloride leaving group.213−215 The reaction conditions are extremely harsh, with 2-chloro- or 6-chloro-nicotinic acid diethyl amide with [18F]KF being heated to 250 °C in an acetamide melt, for approximately 30 min in a sealed bulb. Higher temperatures and longer reactions times led to lower RCYs presumed to be the result of decomposition. A RCY of 40% of 2-[18F]fluoronicotinic acid diethylamide can be obtained under these conditions. Ballinger and co-workers developed a synthetic route to 2-[18F]fluoro- and to 6-[18F]fluoronicotine by means of bromide displacement with [18F]CsF in DMSO at 210 °C.216 The high specificity of Epibatidine (exo-2-(2′-chloro-5′pyridinyl)-7-azabicyclo[2.2.1]heptane) for nAChRs, an alkaloid isolated from the skin of a species of Epipedobates anthonyi, has made it a popular candidate for radiolabeling studies.217 The presence of the pyridine ring in the parent Epibatidine structure allows for a straightforward route to synthesize 18F analogues, and has been adopted by numerous groups. Horti and coworkers opted to use exo-2-(2′-bromo-5′-pyridinyl)-7azabicyclo[2.2.1]heptane to access the desired 18F analogues by displacement of bromide with [18F]KF/K222, in 10% RCY and SA greater than 74 GBq/μmol (Figure 32a).218−220 A similar route employs a Boc-protecting group on the secondary amine and a trimethylammonium group, with the 18F fluorination proceeding in high RCY (70%) (Figure 32b).221,222 The effect of the leaving group and the reaction conditions on the synthesis of [18F]norchlorofluoroepibatidine reveals that for the Boc protected precursor, bromide is superior to nitro, with the iodo derivative performing the worst (Figure 32c).223 The acute toxicity profile of Epibatidine has driven the development of several related 18F derivatives with an improved safety profile.224−230

Figure 32. Radiosynthesis of [18F]norchlorofluoroepibatidine.

A further class of nicotinic acetylcholine radioligands are those based on a 3-[2-azetidinylmethoxy]pyridine core, whereby 18F is incorporated into a 2 position of a pyridine ring by SNAr.231−237 A [18F]fluoropyridinyl derivative of cytosine has been investigated as a radioligand for nicotinic receptors.238 AD is a neurodegenerative brain disease that remains challenging to diagnose. The development of radiotracers that are able to target amyloid plaques is a major avenue of research, as the accumulation of amyloid plaques in the human brain is considered a characteristic hallmark of Alzheimer’s disease.239 Fluoroazabenzoxazoles have shown promise as PET tracers for amyloid plaques; four fluorinated derivatives that have high binding affinity in human AD brain cortical homogenates as well as moderate lipophilicities were identified as potential candidates. In each case, the fluorinated motif is a 2fluoropyridyl system, which allows for facile access to the 18F derivatives by SNAr with [18F]fluoride. 2-Chloropyridyl precursors were selected due to their ease of synthesis; in addition, the authors suggest that HPLC separation of the precursor and product is more facile when compared to the more reactive nitro precursors.240 Structurally similar benzofurans, benzothiazoles, and benzoxazoles presenting the 2[18F]fluoropyridine motif have also been examined as potential radiotracers for AD.241 2-[18F]Fluoroquinolin-8-ol is also proposed as an imaging agent for AD (Figure 33).242,243 The [18F]fluoropyridyl motif, synthesized by nucleophilic substitution, has also found application in PET radiotracers for mGluR5, 2 4 4 5-HT 1 A , 2 4 5 monoamine oxidase, 2 4 6 , 2 4 7 TSPO,248,249 dopamine transporter (DAT),250 and melanoma.251,252 4.3.2. 18F-Labeling of 1,3-Thiazoles. 1,3-Thiazole is activated toward nucleophilic aromatic substitution in the 2position due to the ability of the nitrogen atom to stabilize the negative charge upon attack of a nucleophile. 1,3-Thiazole is found in many natural products and is regarded as an isostere for benzene and pyridine.253 Siméon proposed accessing 2[18F]fluoro-1,3-thiazoles by displacement of halides at the 2position with [18F]fluoride.254,255 Treatment of 2-bromo-1,3thiazole to [18F]KF/K222 under microwave radiation (35 W, 731

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

Figure 33. Radiosynthesis of 2-[18F]fluoroquinolin-8-ol via nucleophilic halogen exchange.

at 60 °C gave the desired product in 92−98% RCY. This transformation is very sensitive to the identity and the quantity of potassium salt used to generate [18F]KF and allowed for the isolation of a 2-[18F]fluoropurine nucleoside with SA up to 148 GBq/μmol.260

130 °C) for 10 min yields the desired product in 95% RCY. With the ultimate aim of synthesizing an 18F mGluR5 inhibitor, the effect of the halogen leaving on the efficiency of the fluorination was tested on 2-halo-4-(phenylethynyl)thiazoles under their microwave conditions. The iodo-substituted precursor gives an isolated decay-corrected 2% RCY, while the chloro and bromo precursors give RCYs of 14.5% and 14%, respectively (Figure 34). The benefits of microwave heating versus conventional heating have been investigated, with improved RCYs being found in some cases with the use of microwaves.

4.4.

18

F-Fluorination of Di(hetero)aryliodonium Salts

Diaryliodonium salts are air- and moisture-stable compounds first synthesized in 1894. The aryl substituents serve as highly labile leaving groups and make them versatile arylating agents that can react with a variety of nucleophiles. Numerous synthetic routes are currently available for their preparation; a common strategy consists of an initial oxidation of an aryl iodide to an iodine(III) species with an inorganic oxidant under acidic conditions. The aryliodine(III) intermediate then undergoes ligand exchange with an arene or an organometallic reagent to obtain the diaryliodonium salt. A subsequent anion exchange step is often necessary. Alternatively, preformed inorganic iodine(III) reagents can be employed.261 Numerous variants have been reported expanding the range of diaryliodonium precursors for further functional manipulation inclusive of fluorination. 4.4.1. Chemoselectivity and Mechanism. Diaryliodonium salts react with nucleophilic [18F]fluoride to extrude [18F]fluoroarenes and iodoarenes.262,263 Both electron-poor and electron-rich [18F]fluoroarenes can be radiosynthesized via this methodology offering an advantage over SNAr reactions, which rely on traditional leaving groups and are only viable with activated electron-deficient aromatic substrates. The 18Ffluorination of unsymmetrical diaryliodonium salts occurs at the more electron-deficient aromatic (Figure 36). Addition of [18F]fluoride to (4-bromophenyl)phenyliodonium triflate forms 4-[ 18F]fluorobromobenzene in a 7:3 ratio with [ 18 F]fluorobenzene in a combined RCY of 95%. Conversely, reactions performed under identical conditions with (4methoxyphenyl)phenyliodonium triflate form [ 18 F]-

Figure 34. Radiosynthesis of 2-[18F]fluoro-1,3-thiazoles by halogen exchange.

4.3.3. 18F-Labeling of Purines. Purines can be labeled in the 6-position by nucleophilic displacement of the trimethylammonium group with [18F]KF and [18F]KHF2. 6-[18F]Fluoropurine and 6-[18F]fluoro-9-β-D-ribofuranosylpurine can be synthesized upon heating of the corresponding trimethylammonium precursor in DMF with carrier added [18F]KF. For the synthesis of 6-[18F]fluoro-9-β-D-ribofuranosylpurine, the RCY from carrier added synthesis was 64%, while the n.c.a. synthesis gave 35% RCY.256 6-[18F]Fluoropenciclovir, a radiotracer for imaging the reporter gene HSV1-tk, can also be synthesized in a single step in 45−55% RCY (Figure 35).257

Figure 35. Radiosynthesis of 6-[18F]Fluoropenciclovir.

Nucleophilic displacement of a chloride leaving group gives access to both 6-[18F]fluoro-9-benzylpurine and 2-[18F]fluoro9-benzylpurine with the use of fluorinating agent [18F]AgF with carrier added AgF.258 The synthesis of 2-[18F]fluoroadenosine, from the corresponding iodo and fluoro precursors, under identical conditions gives 5% RCY (carrier-added) and 2,4,6-trimethyl > 2bromo > 2-methyl > 2-ethyl ≈ 2-iso-propyl > hydrogen > 2methoxy. The inability of the 2-methoxy group to impart an ortho-directing effect in (2-methoxyphenyl)phenyliodonium tosylate suggests that the directing ability of various substituents is not entirely determined by steric bulk. The meta-substituted [18F]fluoroarenes can be synthesized efficiently from the corresponding diaryliodonium tosylates using a microreactor.274 The microfluidic apparatus allowed for reactions in MeCN to be conducted at up to 200 °C. The symmetric bis(3-cyanophenyl)iodonium tosylate gave 3-[18F]fluorobenzonitrile in 55% RCY at 160 °C with a reaction time of just over 3 min. Use of unsymmetrical (3-cyanophenyl)phenyliodonium tosylate gave 3-[18F]fluorobenzonitrile in 25% RCY, but was still highly regioselective for the more electrondeficient ring. RCYs of 3-[18F]fluorobenzonitrile could be increased when the partner aromatic was more electron-rich. A series of unsymmetrical diaryliodonium tosylates were screened with (4-methoxyphenyl)(3-cyanophenyl)iodonium tosylate producing 3-[18F]fluorobenzonitrile in the highest RCY of 93% and (5-methyl-2-thienyl)(3-cyanophenyl)iodonium tosylate producing 3-[18F]fluorobenzonitrile with the greatest regioselectivity of 78:1 3-[18F]fluorobenzonitrile to 2-[18F]fluoro-5-methylthiophene in 79% RCY (Figure 39). [18F]Fluoroarenes with electron-donating substituents in the meta position could be produced selectively with choice of an appropriate auxiliary aryl ring.274 The product selectivity and RCYs are greatly affected by the nature of the substituents in the non-meta-position on the electron-rich ring. 3-[18F]Fluorotoluene was produced in a low RCY of 12% from (3tolyl)phenyliodonium tosylate, while [18F]fluorobenzene was the major product produced in 15% RCY. When similar conditions were applied to (3-methoxyphenyl)phenyliodonium tosylate, 3-[18F]fluoroanisole was produced in the exceptionally high RCY of 87%, while only 6% RCY of [18F]fluorobenzene side product was produced. Use of 2-thienyl as the electron-rich 733

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

Figure 39. Radiosynthesis of meta-substituted electron-poor arenes via unsymmetric diaryliodonium salts.

fluorobenzene and 2-fluoroanisole could be enhanced by addition of 10 mol % of the radical scavenger TEMPO. However, nucleophilic [18F]fluorination of diaryliodonium salts done in microreactors, which store and mix reagents in the dark, gave consistent results without the need for a radical scavenger additive; added TEMPO was found to have no advantageous effect on certain substrates, suggesting the benefit of added TEMPO may be dependent on the structure of the diaryliodonium salt.268 4.4.1.1. Functional Group Tolerance. Diaryliodonium salts can be used to give comparable or higher yields of functionalized [18F]fluoroarenes traditionally made by n.c.a. SNAr reactions with [18F]fluoride.277 4-[18F]Fluorobenzaldehyde is a commonly used labeling synthon for building more elaborate PET radiotracers278,279 has been radiolabeled by SNAr reactions with [18F]fluoride and 4formyl-N,N,N-trimethyl benzenaminium triflate salts in RCY up to 66%.280 4-[18F]Fluorobenzaldehyde could be radiosynthesized in 73% RCY with (4-formylphenyl)(4′-methoxyphenyl)iodonium chloride as precursor under microfluidic conditions, comparable to the best RCYs obtained by SNAr reactions. The meta-substituted analogue 3-[18F]fluorobenzaldehyde has proven extremely difficult to prepare via SNAr.281−283 Chun and Pike showed diaryliodonium salts could be used to prepare 3[18F]fluorobenzaldehyde in 46% RCY from (3-formylphenyl)(2′-thionyl)iodonium chloride. The electron-rich 3-[18F]fluoro4-methoxybenzaldehyde could likewise be prepared in 40% RCY from (3-formyl-4-methoxyphenyl)(2′-thionyl)iodonium tosylate in a microreactor.277 3−6[18F]Fluorobenzaldehyde has also been prepared in 80% RCY from (3-formylphenyl) (phenyl)iodonium bromide under microwave conditions in the presence of 0.5−1 mg of TEMPO as radical scavenger.284 Bromo-4-[18F]fluorobenzene and 4-[18F]fluoroiodobenzene have been used as radiolabeled coupling partners in a number

ring partner led to the target meta-substituted [18F]fluoroarenes in low yields, while use of 4-methoxyphenyl as electron-rich ring partner produced meta-substituted [18F]fluoroarene targets in moderate yields (Figure 40). Diaryliodonium salts are known to be photosensitive275 and are prone to undergo decomposition by homolytic cleavage of the aryl iodine bond generating radicals, which may further degrade the reaction mixtures.276 Yields of 4-methoxy-2-methyl

Figure 40. Radiosynthesis of meta-substituted electron-rich arenes via unsymmetric diaryliodonium salts. 734

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

of Pd-catalyzed C−C coupling reactions285 such as Stille,286−290 Kumada,291 Sonogashira,292 and Suzuki,293 and Pd-catalyzed carbon-heteroatom coupling reactions such as Buchwald− Hartwig amination294,295 and Miyaura C−B borylation.296 Bromo-4-[18F]fluorobenzene has also been used for the in situ preparation of 4-[18F]fluorophenylmagnesium bromide, 4[18F]fluorophenyllithium, and 4-[18F]fluorophenylsodium organometallic reagents and trapping with benzophenone to produce (4-[18F]fluorophenyl)diphenylmethanol in RCY of 43% ± 3%, 48% ± 4%, and 50% ± 4%, respectively.297 Ermert and co-workers conducted a comparative study of existing methodologies for a one-step synthesis of bromo-4-[18F]fluorobenzene.298 They determined the use of diaryliodonium salts to be the optimum precursor with radiosynthesis of bromo-4-[18F]fluorobenzene in 50−60% RCY from the symmetrical bis-(4-bromophenyl)iodonium bromide. Thermal decomposition of 1-piperidyldiazo-4-bromobenzene under a variety of conditions led to the formation of bromo-4[18F]fluorobenzene in much lower RCY of 3−4%. SNAr reactions on 1,4-dibromobenzene or 4-bromonitrobenzene led to low RCYs of bromo-4-[18F]fluorobenzene in 1−2% and ArCF2Br ≈ ArCHFCl > ArSCF2Br > ArOCF2Br. The specific activity of the labeled products was in the range of 0.1 GBq/μmol. Control experiments inform that 19F−18F isotope exchange does not occur on the 18F-labeled product; a representative brominated

18 F-LABELING OF ARYL−SCF3, −OCF3, AND −OCHF2 WITH [18F]FLUORIDE Di- and trifluoromethyl ether, as well as thioether substitution of arenes, is a strategy applied by medicinal chemists to modulate conformation and physicochemical parameters of a drug candidate.408−410 To date, only one method based on halogen exchange 18F-fluorination is available for the 18Flabeling of aryl−SCF3, −OCF3, and − OCHF2.411 The finding that thermal activation at reaction temperature up to 180 °C does not permit 18F-incorporation to label aryl−OCF3 or aryl− SCF3 derivatives from the corresponding aryl−OCF2Br or aryl−SCF2Br precursors encouraged the development of a metal-based strategy relying on the halogenophilicity of Ag(I)

6.

753

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

date, one may take the view that the field of 18F-radiochemistry is still in its infancy as we are far from an ideal situation where, by design, one can label any molecules at a precise position with a functional 18F-motif of choice from a readily accessible precursor. However, the progresses made in the past five years has opened the door to a myriad of opportunities if one keeps bridging the gap between the continuing progress made in modern 19F-fluorine chemistry and the field of radiochemistry. This vision will require research aimed at diversifying the range of 18F sources with a more in depth understanding of the factors that control “F+” and F−-based reactivity.

thioether precursor gave ArSCF3 in the presence of AgOTf (d2DCM, room temperature) in the absence of an external source of fluoride. This Ag(I)-mediated process could account for the low SA measured for the 18F-labeled products. Inductively coupled plasma atomic emission spectrometry (ICP-MS) analysis was performed on representative products purified by a conventional HPLC technique. This analysis indicated that the Ag content was well below any levels of concern.

7. CONCLUSION AND PERSPECTIVE The 18F-fluorination of arenes and heteroarenes remains an important and challenging problem. Until recently, heating and microwave irradiation were the main modes of activation used to induce 18F-aryl bond formation from a range of precursors armed with leaving groups of variable efficacy. Today, this approach, augmented with microfluidic technology, occupies a central position in 18F-labeling, as it is logistically easy to implement. However, the synthesis of the necessary preactivated precursors bearing either a nitro-, ammonium, sulfonium, sulfoxide, iodonium, or iodonium ylide leaving group requires multistep synthesis and, in some cases, may be challenging and time-consuming. This chemistry has been stretched to a point where its scope and limitations are well-defined. The advances made in the past 10 years on late-stage fluorination under transition metal catalysis and organocatalysis have encouraged radiochemists to consider these activation manifolds for 18Ffluorination. These studies were also spurred by the prospect of labeling a much wider range of precursors that are either commercially available or easy to access, as well as addressing some of the well-documented limitations associated with SNArbased radiochemistry. So far, the focus has been on the labeling of (hetero)arenes, although selected studies have appeared that allow 18F-Csp3 formation using readily available precursors that do not require prefunctionalization.64,412−414 Transition metals such as silver, palladium, nickel, and copper have all been successfully applied to induce 18F-aryl bond formation. Some of these processes required the preparation of fairly complex organometallic precursors, while others employ more accessible preactivated (hetero)arenes such as arylstannanes and arylboronic acid or ester derivatives. Both “[18F]F+” and [18F]F− sources have been used in these metal-mediated 18Ffluorinations, with the most impactful developments employing cyclotron-produced [18F]fluoride available in high specific activity. These proof-of-concept transformations will require further optimization to be routinely considered for the synthesis of radiotracers and radiopharmaceuticals necessary for preclinical and clinical studies. With the pressing demand from the pharmaceutical industry for methods allowing for the labeling of fluorine-containing motifs commonly used in drug design, the problem of 18Ffluorination has expanded considerably. Ideally, radiochemists should compose a toolbox of radiofluorination methods presenting with wide functional group tolerance and which is compatible with the most commonly found structural scaffolds in medicinal chemistry. Little progress has been made in this direction with the exception of late-stage 18F-trifluoromethylation using either thermal or metal activation (silver, copper), and of a recently disclosed silver-mediated halogen exchange 18 F-fluorination giving access to 18F-labeled CF3O-, CHF2O-, and CF3S-containing (hetero)arenes. Methodology for the incorporation for the 18F-labeled −SCF3 motif has recently been disclosed for aliphatic substrates as well.415 This Review indicates that, despite the very large body of work published to

ASSOCIATED CONTENT Special Issue Paper

This paper is an additional review for Chem. Rev. 2015, Volume 115, Issue 2, “Fluorine Chemistry”.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

Sean Preshlock was born in San Antonio, TX. He received his B.S. degree in Chemistry from Tulane University. He then completed his Ph.D. work under Prof. Milton R. Smith, III in collaboration with Prof. Robert E. Maleczka, Jr. at Michigan State University. Sean then joined the Gouverneur group working on the fluorination of arenes.

Matthew Tredwell obtained his D.Phil. under the supervision of Prof. V. Gouverneur at the University of Oxford. He then undertook postdoctoral studies with Prof. M. Gaunt at the University of 754

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

(8) Paans, A. M. J.; van Waarde, A.; Elsinga, P. H.; Willemsen, A. T. M.; Vaalburg, W. Positron emission tomography: the conceptual idea using a multidisciplinary approach. Methods 2002, 27, 195−207. (9) (a) Wood, K. A.; Hoskin, P. J.; Saunders, M. I. Positron Emission Tomography in Oncology: A Review. Clin. Oncol. 2007, 19, 237−255. (10) Weber, W. A. Positron Emission Tomography As an Imaging Biomarker. J. Clin. Oncol. 2006, 24, 3282−3292. (11) Oriuchi, N.; Higuchi, T.; Ishikita, T.; Miyakubo, M.; Hanaoka, H.; Iida, Y.; Endo, K. Present role and future prospects of positron emission tomography in clinical oncology. Cancer Sci. 2006, 97, 1291− 1297. (12) Schwaiger, M.; Ziegler, S.; Nekolla, S. G. PET/CT: Challenge for Nuclear Cardiology. J. Nucl. Med. 2005, 46, 1664−1678. (13) Di Carli, M. F.; Dorbala, S.; Meserve, J.; El Fakhri, G.; Sitek, A.; Moore, S. C. Clinical Myocardial Perfusion PET/CT. J. Nucl. Med. 2007, 48, 783−793. (14) deKemp, R. A.; Yoshinaga, K.; Beanlands, S. B. Will 3dimensional PET-CT enable the routine quantification of myocardial blood flow? J. Nucl. Cardiol. 2007, 14, 380−397. (15) Herholz, K.; Heiss, W. D. Positron emission tomography in clinical neurology. Mol. Imaging Biol. 2004, 6, 239−269. (16) Wu, C.; Pike, V. W.; Wang, Y. Amyloid Imaging: From Benchtop to Bedside. Curr. Top. Dev. Biol. 2005, 70, 171−213. (17) Cai, L.; Innis, R. B.; Pike, V. W. Radioligand development for PET imaging of β-amyloid (Aβ)-current status. Curr. Med. Chem. 2007, 14, 19−52. (18) Nordberg, A. PET imaging of amyloid in Alzheimer’s disease. Lancet Neurol. 2004, 3, 519−527. (19) Wang, J. L.; Maurer, L. Positron Emission Tomography: Applications In Drug Discovery and Drug Development. Curr. Top. Med. Chem. 2005, 5, 1053−1075. (20) Aboagye, E. O.; Price, P. M.; Jones, T. In vivo pharmacokinetics and pharmacodynamics in drug development using positron-emission tomography. Drug Discovery Today 2001, 6, 293−302. (21) Gee, D. Neuropharmacology and drug development. Br. Med. Bull. 2003, 65, 169−177. (22) Lever, J. R. PET and SPECT Imaging of the Opioid System: Receptors, Radioligands and Avenues for Drug Discovery and Development. Curr. Pharm. Des. 2007, 13, 33−49. (23) Matthews, P. M.; Rabiner, E. A.; Passchier, J.; Gunn, R. N. Positron emission tomography molecular imaging for drug development. Br. J. Clin. Pharmacol. 2012, 73, 175−186. (24) Levin, C. S.; Hoffman, E. J. Calculation of positron range and its effect on the fundamental limit of positron emission tomography system spatial resolution. Phys. Med. Biol. 1999, 44, 781−799. (25) Miller, P. W.; Long, N. J.; Vilar, R.; Gee, A. D. Synthesis of 11C, 18 F, 15O, and 13N Radiolabels for Positron Emission Tomography. Angew. Chem., Int. Ed. 2008, 47, 8998−9033. (26) Gouverneur, V.; Müller, K. Fluorine in Pharmaceutical and Medicinal Chemistry: From Biophysical Aspects to Clinical Applications; Imperial College Press: London, 2012. (27) Müller, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond Intuition. Science 2007, 317, 1881−1886. (28) Purser, S.; Moore, P. R. Swallow, S.; Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 2008, 37, 320−330. (29) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; Pozo, C. d.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001−2011). Chem. Rev. 2014, 114, 2432−2506. (30) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem. 2015, 58, 8315. (31) Cai, L.; Lu, S.; Pike, V. W. Chemistry with [18F]Fluoride Ion. Eur. J. Org. Chem. 2008, 2008, 2853−2873. (32) Tredwell, M.; Gouverneur, V. 18F Labeling of Arenes. Angew. Chem., Int. Ed. 2012, 51, 11426−11437.

Cambridge, and subsequently with Prof. V. Gouverneur at the University of Oxford. His research interests are broadly in the field of fluorine chemistry, with a particular focus on the use of 18F in PET imaging.

Véronique Gouverneur received her undergraduate degree and Ph.D. in chemistry at the Université Catholique de Louvain (LLN, Belgium) under the mentoring of Prof L. Ghosez. She moved to a postdoctoral position with Prof R. Lerner at the Scripps Research Institute (CA). ̂ de Conférence at the She returned to Europe in 1994 as Maitre University Louis Pasteur in Strasbourg (France). She was appointed University Lecturer at the Chemistry Faculty at the University of Oxford in 1998 with a research program aimed at developing late-stage fluorination methods toward fluorinated analogues of natural products, pharmaceutical drugs, and molecular probes for imaging. Since her appointment in Oxford, she holds a Tutorial Fellowship at Merton College Oxford where she teaches organic and biological chemistry. In 2008, she became Full Professor in Chemistry at the University of Oxford. She is currently holding a Royal Society Wolfson Research Merit Award (2013−2018).

ACKNOWLEDGMENTS We thank H. H. Coenen for helpful discussions in preparation of the manuscript. Financial support was provided by the EPSRC (S.P., M.T.), and the CRUK (M.T.). V.G. holds a Royal Society Wolfson Research Merit Award (2013-2018).

REFERENCES (1) Dobrucki, L. W.; Sinusas, A. J. PET and SPECT in cardiovascular molecular imaging. Nat. Rev. Cardiol. 2010, 7, 38−47. (2) Hicks, R. J.; Hofman, M. S. Is there still a role for SPECT-CT in oncology in the PET-CT era? Nat. Rev. Clin. Oncol. 2012, 9, 712−720. (3) Dierckx, R. A. J. O.; Otte, A.; de Vries, E. F. J.; van Waarde, A.; Leenders, K. L. PET and SPECT in Neurology; Springer: New York, 2014. (4) Piel, M.; Vernaleken, I.; Rö sch, F. Positron Emission Tomography in CNS Drug Discovery and Drug Monitoring. J. Med. Chem. 2014, 57, 9232−9258. (5) Coenen, H. H.; Elsinga, P. H.; Iwata, R.; Kilbourn, M. R.; Pillai, M. R. A.; Rajan, M. G. R.; Wagner, H. N.; Zaknun, J. J. Fluorine-18 radiopharmaceuticals beyond [18F]FDG for use in oncology and neurosciences. Nucl. Med. Biol. 2010, 37, 727−740. (6) (a) Fowler, J. S.; Wolf, A. P. Working against Time: Rapid Radiotracer Synthesis and Imaging the Human Brain. Acc. Chem. Res. 1997, 30, 181−188. (7) Phelps, M. E. Positron emission tomography provides molecular imaging of biological processes. Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 9226−9233. 755

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

(33) Brooks, A. F.; Topczewski, J. J.; Ichiishi, N.; Sanford, M. S.; Scott, P. J. H. Late-stage [18F]fluorination: new solutions to old problems. Chem. Sci. 2014, 5, 4545−4553. (34) Ermert, J. 18F-Labelled Intermediates for Radiosynthesis by Modular Build-Up Reactions: Newer Developments. BioMed Res. Int. 2014, 2014, 1−15. (35) Jacobson, O.; Kiesewetter, D. O.; Chen, X. Fluorine-18 Radiochemistry. Labeling Stategies and Synthetic Routes. Bioconjugate Chem. 2015, 26, 1−18. (36) Campbell, M. G.; Ritter, T. Modern Carbon−Fluorine Bond Forming Reactions for Aryl Fluoride Synthesis. Chem. Rev. 2015, 115, 612−633. (37) Roberts, A. D.; Barnhart, T. E.; Nickles, R. J. Isotope Production for Medical Applications; Springer: Heidelberg, 2005. (38) Strijkmans, K. The isochronous cyclotron: principles and recent developments. Comput. Med. Imag. Graph 2001, 25, 69−78. (39) O’Neil, J. P.; VanBrocklin, H. F. Preparation of fluorine-18 gas from an 11 MeV cyclotron: a target system for the CTI RDS 111 cyclotron. Nucl. Instrum. Methods Phys. Res., Sect. A 1999, 438, 166− 172. (40) Bishop, A.; Satyamurthy, N.; Bida, G.; Phelps, M.; Barrio, J. R. Identification and Quantification of Gaseous Compounds of Fluorine Generated in [18F]F2 Target Systems. Nucl. Med. Biol. 1996, 23, 391− 405. (41) de Goeij, J. J. M.; Bonardi, M. L. How do we define the concepts specific activity, radioactive concentration, carrier, carrier-free and nocarrier-added? J. Radioanal. Nucl. Chem. 2005, 263, 13−18. (42) Füchtner, F.; Preusche, S.; Mading, P.; Zessin, J.; Steinbach, J. Factors affecting the specific activity of [18F]fluoride from a [18O]water target. Nuklearmedizin 2008, 47, 116−119. (43) Berridge, M. S.; Apana, S. M.; Hersh, J. M. Teflon radiolysis as the major source of carrier in fluorine-18. J. Labelled Compd. Radiopharm. 2009, 52, 543−548. (44) Lapi, S. E.; Welch, M. J. A historical perspective on the specific activity of radiopharmaceuticals: What have we learned in the 35 years of the ISRC? Nucl. Med. Biol. 2013, 40, 314−320. (45) Bergman, J.; Solin, O. Fluorine-18-labeled fluorine gas for synthesis of tracer molecules. Nucl. Med. Biol. 1997, 24, 677−683. (46) Van Grieken, R.; de Bruin, M. Nomenclature for Radioanalytical Chemistry. Pure Appl. Chem. 1994, 66, 2513−2526. (47) Sood, S.; Firnau, G.; Garnett, E. S. Radiofluorination with Xenon Difluoride: A New High Yield Synthesis of [18F]2-Fluoro-2deoxy-D-glucose. Int. J. Appl. Radiat. Isot. 1983, 34, 743−745. (48) Shiue, C.-Y.; To, K.-C.; Wolf, A. P. A Rapid Synthesis of 2Deoxy-2-fluoro-D-glucose From Xenon Difluoride Suitable for Labelling with 18F. J. Labelled Compd. Radiopharm. 1983, 20, 157−162. (49) Chirakal, R.; Finau, G.; Schrobilgen, G. J.; Mckay, J.; Garnett, E. S. the Synthesis of [18F]Xenon Difluoride from [18F]Fluorine Gas. Int. J. Appl. Radiat. Isot. 1984, 35, 401−404. (50) Schrobilgen, G.; Firnau, G.; Chirakal, R.; Garnett, E. S. Synthesis of [18F]XeF2, a Novel Agent for the Preparation of 18F-Radiopharmaceuticals. J. Chem. Soc., Chem. Commun. 1981, 198−199. (51) Constantinou, M.; Aigbirhio, F. I.; Smith, R. G.; Ramsden, C. A.; Pike, V. W. Xenon Difluoride Exchnanges Fluoride under Mild Conditions: A Simple Preparation of [18F]Xenon Difluoride for PET and Mechanistic Studies. J. Am. Chem. Soc. 2001, 123, 1780−1781. (52) Vasdev, N.; Pointner, B. E.; Chirakal, R.; Schrobilgen, G. J. On the preparation of fluorine-18 labelled XeF2 and chemical exchange between fluoride ion and XeF2. J. Am. Chem. Soc. 2002, 124, 12863− 12868. (53) Lu, S.; Pike, V. W. Synthesis of [18F]xenon difluoride as a radiolabelling reagent from [18F]fluoride ion in a micro-reactor and at production scale. J. Fluorine Chem. 2010, 131, 1032−1038. (54) Neirinckx, R. D.; Lambrecht, R. M.; Wolf, A. P. Cyclotron Isotopes and Radiopharmaceuticals-XXV An Anhydrous 18F-Fluorination Intermediate: Trifluoromethyl Hypofluorite. Int. J. Appl. Radiat. Isot. 1978, 29, 323−327.

(55) Jewett, D. M.; Potocki, J. F.; Ehrenkaufer, R. E. A Gas-SolidPhase Microchemical Method for the Synthesis of Acetyl Hypofluorite. J. Fluorine Chem. 1984, 24, 477−484. (56) Ehrenkaufer, R. E.; MacGregor, R. R. Synthesis of [18F]Perchloryl Fluoride and its Reactions with Functionalized Aryl Lithiums. Int. J. Appl. Radiat. Isot. 1983, 34, 613−615. (57) Hiller, A.; Ficher, C.; Jordanova, A.; Patt, J. T.; Steinbach, J. Investigations to the synthesis of n.c.a. [18F]FClO3 as electrophilic fluorination agent. Appl. Radiat. Isot. 2008, 66, 152−157. (58) Lal, G. S.; Pez, G. P.; Syvret, R. G. Electrophilic NF Fluorinationg Agents. Chem. Rev. 1996, 96, 1737−1756. (59) Oberdorfer, F.; Hofmann, E.; Maier-Borst, W. Preparation of 18 F-Labelled N-Fluoropyridinium Triflate. J. Labelled Compd. Radiopharm. 1988, 25, 999−1005. (60) Oberdorfer, F.; Hofmann, E.; Maier-Borst, W. Preparation of a New 18F-Labelled precursor: 1-[18F]FLuoro-2-Pyridone. Appl. Radiat. Isot. 1988, 39, 685−688. (61) Satyamurthy, N.; Bida, G. T.; Phelps, M. E.; Barrio, J. R. N[18F]Fluoro-N-alkylsulfonamides: Novel reagent for Mild and Regioselective Radiofluorination. Appl. Radiat. Isot. 1990, 41, 733− 738. (62) Oberdorfer, F.; Dietzel, G. Methodical Study of Direct Fluorination Using [18F]F2 in Presence of Amides and Imides. J. Labelled Compd. Radiopharm. 2003, 46, S216. (63) Teare, H.; Robins, E. G.; Årstad, E.; Luthra, S. K.; Solin, O.; Gouverneur, V. Synthesis and reactivity of [18F]-N-fluorobenzenesulfonimide. Chem. Commun. 2007, 2330−2332. (64) Buckingham, F.; Kirjavainen, A.; Forsback, S.; Kryczmonik, A.; Keller, T.; Newington, I. M.; Glaser, M.; Luthra, S. K.; Solin, O.; Gouverneur, V. Organomediated Enantioselective 18F-Fluorination for PET Application. Angew. Chem., Int. Ed. 2015, 54, 13366−13369. (65) Teare, H.; Robins, E. G.; Kirjavainen, A.; Forsback, S.; Sandford, G.; Solin, O.; Luthra, S. K.; Gouverneur, V. Radiosynthesis and Evaluation of [18F]Selectfuor bis(triflate). Angew. Chem., Int. Ed. 2010, 49, 6821−6824. (66) Coenen, H. H. No-carrier-added 18F-chemistry of radiopharmaceuticals. Synthesis and Application of Isotopically Labeled Compounds; Elsevier: Amsterdam, 1989; pp 433−448. (67) Kilbourn, M. R. Nucl. Sci. Series, NAS-NS3203; National Academy Press: Washington, DC, 1990. (68) Gately, S. J.; Shaughnessy, W. J. Production of 18F-Labeled Compounds with 18F− Produced with a 1-MW Research Reactor. Int. J. Appl. Radiat. Isot. 1982, 33, 1325−1330. (69) Coenen, H. H.; Klatte, B.; Knochel, A.; Schuller, M.; Stocklin, G. Preparation of n.c.a. [17-18F]fluoroheptadecanoic acid in high yields via aminopolyether supported, nucleophilic fluorination. J. Labelled Compd. Radiopharm. 1986, 23, 455−467. (70) Zhan, C.-G.; Dixon, D. A. Hydration of the Fluoride Anion: Structures and Absolute Hydration Free Energy from First-Principles Electronic structure Calculations. J. Phys. Chem. A 2004, 108, 2020− 2029. (71) Lien, V. T.; Riss, P. J. Radiosynthesis of [18F]Trifluoroalkyl Groups: Scope and Limitations. BioMed Res. Int. 2014, 2014, 1−10. (72) Kim, D. W.; Song, C. E.; Chi, D. Y. New Method of Fluorination Using Potassium Fluoride in Ionic Liquid: Significantly Enhanced Reactivity of Fluoride and Improved Selectivity. J. Am. Chem. Soc. 2002, 124, 10278−10279. (73) Kim, D. W.; Choe, Y. S.; Chi, D. Y. A new nucleophilic fluorine18 labeling method for aliphatic mesylates: Reaction in ionic liquids shows tolerance for water. Nucl. Med. Biol. 2003, 30, 345−350. (74) Kim, H. W.; Jeong, J. M.; Lee, Y.-S.; Chi, D. Y.; Chung, K.-H.; Lee, D. S.; Chung, J.-K.; Lee, M. C. Rapid synthesis of [18F]FDG without an evaporation step using an ionic liquid. Appl. Radiat. Isot. 2004, 61, 1241−1246. (75) Kim, D. W.; Ahn, D. S.; Oh, Y.-H.; Lee, S.; Kil, H. S.; Oh, S. J.; Lee, S. J.; Kim, J. S.; Ryu, J. S.; Moon, D. H.; Chi, D. Y. A New Class of SN2 Reactions Catalyzed by Protic Solvents: Facile Fluorination for Isotopic Labeling of Diagnostic Molecules. J. Am. Chem. Soc. 2006, 128, 16394−16397. 756

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

Semiautomated Production of 6-[18F]Fluoro-L-dopa for Human Studies with PET. Appl. Radiat. Isot. 1990, 41, 275−281. (98) Perlmutter, M.; Satyamurthy, N.; Luxen, A.; Phelps, M. E.; Barrio, J. R. Synthesis of 4-[18F]Fluoro-L-m-tyrosine: a Model Analog for the In Vivo Assessment of Central Dopaminergic Function. Appl. Radiat. Isot. 1990, 41, 801−807. (99) Mislankar, S. G.; Gildersleeve, D. L.; Wieland, D. M.; Massin, C. C.; Mulholland, G. K.; Toorongian, S. A. 6-[18F]Fluorometaraminol: A Radiotracer for in Vivo Mapping of Adrenergic Nerves of the Heart. J. Med. Chem. 1988, 31, 362−366. (100) Adam, M. J.; Pate, B. D.; Ruth, T. J.; Berry, J. M.; Hall, L. D. Cleavage of Aryl-Tin Bonds with Elemental Fluorine: Rapid Synthesis of [18F]Fluorobenzene. J. Chem. Soc., Chem. Commun. 1981, 733. (101) Raddo, P. D.; Diksic, M.; Jolly, D. The 18F Radiofluorination of Arylsilanes. J. Chem. Soc., Chem. Commun. 1984, 159−160. (102) Speranza, M.; Shiue, C.-Y.; Wolf, A. P.; Wilbur, D. S.; Angelini, G. Electrophilic Radiofluorination of Aryltrimethylsilanes as a General Route to 18F-Labeled Aryl Fluorides. J. Fluorine Chem. 1985, 30, 97− 107. (103) Speranza, M.; Shiue, C.-Y.; Wolf, A. P.; Wilbur, D. S.; Angelini, G. Regiospecific Radiofluorination of Arylpentafluorosilicates as a General Route to 18F-Labelled Aryl Fluorides. J. Chem. Soc., Chem. Commun. 1984, 1448−1449. (104) Coenen, H. H.; Moerlein, S. M. Regiospecific Aromatic Fluorodemetallation of Group IVb Metalloarenes Using Elemental Fluorine or Acetyl Hypofluorite. J. Fluorine Chem. 1987, 36, 63−75. (105) Namavari, M.; Bishop, A.; Satyamurthy, N.; Bida, G.; Barrio, J. R. Regioselective Radiofluorodestannylation with [18F]F2 and [18F]CH3COOF: a High Yield Synthesis of 6-[18F]Fluoro-L-dopa. Appl. Radiat. Isot. 1992, 43, 989−996. (106) Dolle, F.; Demphel, S.; Hinnen, F.; Fournier, D.; Vaufrey, F.; Crouzel, C. 6-[18F]Fluoro-L-DOPA by Radiofluorodestannylation: A Short and Simple Synthesis of a New Labelling Precursor. J. Labelled Compd. Radiopharm. 1998, 41, 105−114. (107) Diksic, M.; Farrokhzad, S. New Synthesis of Fluorine-18Labeled 6-Fluoro-L-Dopa by Cleaving the Carbon-Silicon Bond with Fluorine. J. Nucl. Med. 1985, 26, 1314−1318. (108) de Vries, E. F.J.; Luurtsema, G.; Brussermann, M.; Elsinga, P. H.; Vaalburg, W. Fully automated synthesis module for the high yield one-pot preparation of 6-[18F]fluoro-L-DOPA. Appl. Radiat. Isot. 1999, 51, 389−394. (109) Hess, E.; Sichler, S.; Kluge, A.; Coenen, H. H. Synthesis of 2[18F]fluoro-L-tyrosine via regiospecific fluoro-de-stannylation. Appl. Radiat. Isot. 2002, 57, 185−191. (110) VanBrocklin, H. F.; Blagoev, M.; Hoepping, A.; O’Neil, J. P.; Klose, M.; Schubiger, P. A.; Ametamey, S. A new precursor for the preparation of 6-[18F]Fluoro-L-m-tyrosine ([18F]FMT): efficient synthesis and comparison of radiolabeling. Appl. Radiat. Isot. 2004, 61, 1289−1294. (111) Eskola, Olli.; Gronroos, T.; Bergman, J.; Haaparanta, M.; Marjamaki, P.; Lehikoinen, P.; Forsback, S.; Langer, O.; Hinnen, F.; Dolle, F.; Halldin, C.; Solin, O. A novel electrophilic synthesis and evaluation of medium specific radioactivity of cardiac sympathetic nerve integrity with PET. Nucl. Med. Biol. 2004, 31, 103−110. (112) Forsback, S.; Eskola, O.; Haaparanta, M.; Bergman, J.; Solin, O. Electrophilic synthesis of 6-[18F]fluoro-L-DOPA using post-target produced [18F]F2. Radiochim. Acta 2008, 96, 845−848. (113) Furuya, T.; Strom, A. E.; Ritter, T. Silver-Mediated Fluorination of Functionalized Aryl Stannaes. J. Am. Chem. Soc. 2009, 131, 1662−1663. (114) Furuya, T.; Ritter, T. Fluorination of Boronic Acids Mediated by Silver(I) Triflate. Org. Lett. 2009, 11, 2860−2863. (115) Fier, P. S.; Luo, J.; Hartwig, J. F. Copper-Mediated Fluorination of Arylboronate Esters. Identification of a Copper(III) Fluoride Complex. J. Am. Chem. Soc. 2013, 135, 2552−2559. (116) Ye, Y.; Sanford, M. S. Mild Copper-Mediated Fluorination of Aryl Stannanes and Aryl Trifluoroborates. J. Am. Chem. Soc. 2013, 135, 4648−4651.

(76) Kim, D. W.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H.; Chi, D. Y. Facile nucleophilic fluorination by synergistic effect between polymersupported ionic liquid catalyst and tert-alcohol reaction media system. Tetrahedron 2008, 64, 4209−4214. (77) Kim, D. W.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H. Tetrabutylammonium Tetra(tert-Butyl Alcohol)-Coordinated Fluoride as a Facile Fluoride Source. Angew. Chem., Int. Ed. 2008, 47, 8404− 8406. (78) Jiang, H.; DeGrado, T. Acyl [18F] fluorides as novel synthons for radiofluorination. J. Nucl. Med. 2014, 55, 161. (79) Nielsen, M. K.; Ugaz, C. R.; Li, W.; Doyle, A. G. PyFluor: A Low-Cost, Stable, and Selective Deoxyfluorination Reagent. J. Am. Chem. Soc. 2015, 137, 9571−9574. (80) Fukuhara, N.; Bigelow, L. A. The Action of Elementary Fluorine upon Organic Compounds. XI. The Vapor Phase Fluorination of Benzene. J. Am. Chem. Soc. 1941, 63, 2792−2795. (81) Cacace, F.; Wolf, A. P. Substrate Selectivity and Orientation in Aromatic Substitution by Molecular Fluorine. J. Am. Chem. Soc. 1978, 100, 3639−3641. (82) Firnau, G.; Chirakal, R.; Garnett, E. S. Aromatic Radiofluorination with [18F]Fluorine Gas: 6-[18F]Fluoro-L-Dopa. J. Nucl. Med. 1984, 25, 1228−1233. (83) Chirakal, R.; Firnau, G.; Garnett, E. S. High Yield Synthesis of 6[18F]Fluoro-L-Dopa. J. Nucl. Med. 1986, 27, 417−421. (84) Chirakal, R.; Vasdev, N.; Schrobilgen, G. J.; Nahmias, C. Radiochemical and NMR spectroscopic investigation of the solvent effect on the electrophilic elemental fluorination of L-DOPA: synthesis of [18F]5-fluoro-L-DOPA. J. Fluorine Chem. 1999, 99, 87−94. (85) Firnau, G.; Chirakal, R.; Sood, S.; Garnett, S. Aromatic fluorination with xenon difluoride: L-3,4-dihydroxy-6-fluoro-phenylalanine. Can. J. Chem. 1980, 58, 1449−1450. (86) Chirakal, R.; Firnau, G.; Couse, J.; Garnett, E. S. Radiofluorination with 18F-Labelled Acetyl Hypofluorite: [18F]L-6-Fluorodopa. Int. J. Appl. Radiat. Isot. 1984, 35, 651−653. (87) Adam, M. J.; Ruth, T. J.; Grierson, J. R.; Abeysekera, B.; Pate, B. D. Routine Synthesis fo L-[18F]6-Fluorodopa with Fluorine-18 Acetyl Hypofluorite. J. Nucl. Med. 1986, 27, 1462−1466. (88) Adam, M. J.; Grierson, J. R.; Ruth, T. J.; Jivn, S. Reaction of [18F]Acetyl Hypofluorite with Derivatives fo Dihydroxyphenylalanine: Synthesis of L-[18F]6-Fluorodopa. Appl. Radiat. Isot. 1986, 37, 877− 882. (89) Coenen, H. H.; Franken, K.; Kling, P.; Stocklin, G. Direct Electrophilic Radiofluorination of Phenylalanine, Tyrosine and Dopa. Appl. Radiat. Isot. 1988, 39, 1243−1250. (90) Ehrenkaufer, R. E.; MacGregor, R. R. F-18 Perchloryl Fluoride: Synthesis and Reactions. J. Labelled Compd. Radiopharm. 1982, 19, 1637. (91) Satyamurthy, N.; Bida, G. T.; Barrio, J. R.; Phelps, M. E. [F-18] N-Fluoro-N-Alkylsulfonamides: Novel Reagents for Radiofluorination. J. Nucl. Med. 1984, 25, P23. (92) Visser, G. W. M.; Halteren, B. W. v.; Herscheid, J. D. M.; Brinkman, G. A.; Hoeksta, A. Reaction of Acetyl Hypofluorite with Aromatic Mercury Compounds: a New Selective Fluorination Method. J. Chem. Soc., Chem. Commun. 1984, 655−656. (93) Visser, G. W. M.; Bakker, C. N. M.; Halteren, B. W. v.; Herscheid, J. D. M.; Brinkman, G. A.; Hoekstra, A. Fluorination and Fluorodemercuration of Aromatic Compounds with Acetyl Hypofluorite. J. Org. Chem. 1986, 51, 1886−1889. (94) Luxen, A.; Barrio, J. R. Fluorination of Substituted Veratroles via Regioselective Mercuration. Tetrahedron Lett. 1988, 29, 1501−1504. (95) Luxen, A.; Barrio, J. R.; Bida, G. T.; Satyamurthy, N. Regioselective Radiofluorodemercuration: a Simple, High Yield Synthesis of 6-[18F]Fluorodopa. J. Labelled Compd. Radiopharm. 1986, 23, 1066. (96) Adam, M. J.; Jivan, S. Synthesis and Purification of L-6[18F]Fluorodopa. Appl. Radiat. Isot. 1988, 39, 1203−1206. (97) Luxen, A.; Perlmutter, M.; Bida, G. T.; Van Moffaert, G.; Cook, J. S.; Satyamurthy, N.; Phelps, M. E.; Barrio, J. R. Remote, 757

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

arenediazonium sulfonates and 1-(aryldiazenyl)piperazines. Tetrahedron Lett. 2012, 53, 1717−1719. (138) Coenen, H. H.; Ermert, J. Direct nucleophilic 18F-fluorination of electron-rich arenes: Present limits of no-carrier-added reactions. Curr. Radiopharm. 2010, 3, 163−173. (139) Adams, D. J.; Clark, J. H. Nucleophilic routes to selectively fluorinated aromatics. Chem. Soc. Rev. 1999, 28, 225−231. (140) Irie, T.; Fukushi, K.; Inoue, O.; Yamasaki, T.; Ido, T.; Nozaki, T. Preparation of 18F-labeled 6- and 2-fluoro-9-benzylpurine as a Potential Brain-scanning Agent. Int. J. Appl. Radiat. Isot. 1982, 33, 633−636. (141) Lemaire, C.; Guillaume, M.; Christiaens, L.; Palmer, A. J.; Cantineau, R. A New Route for the Synthesis of [18F]Fluoroaromatic Substituted Amino Acids: No Carrier Added L-p-[ 18 F]Fluorophenylalanine. Appl. Radiat. Isot. 1987, 38, 1033−1038. (142) Shen, B.; Loffler, D.; Zeller, K.-P.; Ubele, M.; Reischl, G.; Machulla, H.-J. Decarbonylation of multi-substituted [ 18 F]benzaldehydes for modelling synthesis of 18F-labelled aromatic amino acids. Appl. Radiat. Isot. 2007, 65, 1227−1231. (143) Jang, S.-W.; Park, S.-W.; Lee, B. S.; Chi, D. Y.; Song, C. E.; Lee, S. Very Efficient Nucleophilic Aromatic Fluorination Reaction in Molten Salts: A Mechanistic Study. Bull. Korean Chem. Soc. 2012, 33, 881−884. (144) Seimbille, Y.; Phelps, M. E.; Czernin, J.; Silverman, D. H. S. Fluorine-18 labeling of 6,7-disubstituted anilinoquinazoline derivatives for positron emission tomography (PET) imaging of tyrosine kinase receptors: synthesis of 18F-Iressa and related molecular probes. J. Labelled Compd. Radiopharm. 2005, 48, 829−843. (145) Banks, W. R.; Satter, M. R.; Hwang, D.-H. A New Method for the NCA Production of [18F]Fluoromethane. Appl. Radiat. Isot. 1994, 45, 60−74. (146) Sun, H.; DiMagno, S. G. Competitive demethylation and substitution in N,N,N-trimethylanilinium fluorides. J. Fluorine Chem. 2007, 128, 806−812. (147) Lazarova, N.; Simeon, F. G.; Musachio, J. L.; Lu, S.; Pike, V. W. Integration of a microwave reactor with Synthia to provide a fully automated radiofluorination module. J. Labelled Compd. Radiopharm. 2007, 50, 463−465. (148) Hashizume, K.; Tamakawa, H.; Hashimoto, N.; Miyake, Y. Single-step sunthesis of [18F]haloperidol from the Chloro-precursor and its Application in PET Imaging of a Cat’s Brain. Appl. Radiat. Isot. 1997, 48, 1179−1185. (149) Pascali, C.; Luthra, S. K.; Pike, V. W.; Price, G. W.; Ahier, R. G.; Hume, S. P.; Mers, R.; Manjil, L.; Cremer, J. E. The Radiosynthesis of [18F]PK 14105 as an Alternative Radioligand for Peripheral Type Benzodiazepine Binding Sites. Appl. Radiat. Isot. 1990, 41, 477−482. (150) Richter, S.; Wuest, F. 18F-Labeled Peptides: The Futue Is Bright. Molecules 2014, 19, 20536−20556. (151) Schirrmacher, R.; Wangler, C.; Schirrmacher, R. Recent Developments and Trends in 18F-Radiochemistry: Syntheses and Applications. Mini-Rev. Org. Chem. 2007, 4, 317−329. (152) Vaidyanathan, G.; Zalutsky, M. R. Labeling Proteins with Fluorine-18 Using N-Succinimidyl 4-[18F]Fluorobenzoate. Nucl. Med. Biol. 1992, 19, 275−281. (153) Tang, G.; Zeng, W.; Yu, M.; Kabalka, G. Facile synthesis of Nsuccinimidyl 4-[18F]fluorobenzoate ([18F]SFB) for protein labeling. J. Labelled Compd. Radiopharm. 2008, 51, 68−71. (154) Thonon, D.; Goblet, D.; Goukens, E.; Kaisen, G.; Paris, J.; Aerts, J.; Lignon, S.; Franci, X.; Hustinx, R.; Luxen, A. Fully Automated Preparation and Conjugation of N-Succinimidyl 4[18F]Fluorobenzoate ([18F]SFB) with RGD Peptide Using a GE FASTlabTM Synthesizer. Mol. Imaging Biol. 2011, 13, 1088−1095. (155) Sutcliffe-Goulden, J. L.; O’Doherty, M. J.; Marsden, P. K.; Hart, I. R.; Marshall, J. F.; Bansal, S. S. Rapid solid phase synthesis and biodistribution of 18F-labelled linear peptides. Eur. J. Nucl. Med. Mol. Imaging 2002, 29, 754−759. (156) Kniess, T.; Kuchar, M.; Pietzsch, J. Automated radiosynthesis of the thiol-reactive labeling agent N-[6-(4-[18F]fluorobenylidene)-

(117) Stenhagen, I. S. R.; Kirjavainen, A. K.; Forsback, S. J.; Jorgensen, C. G.; Robins, E. G.; Luthra, S. K.; Solin, O.; Gouverneur, V. [18F]Fluorination of an arylboronic ester using [18F]selectfluor bis(triflate): application to 6-[18F]fluoro-L-DOPA. Chem. Commun. 2013, 49, 1386−1388. (118) Balz, G.; Schiemann, G. Uber aromatische Fluorverbindunged, I.: Ein neus Verfahren zu ihrer Darstellung. Ber. Dtsch. Chem. Ges. B 1927, 60, 1186−1190. (119) Nozaki, T.; Tanaka, Y. The Preparation of F18-labelled Aryl Fluorides. Int. J. Appl. Radiat. Isot. 1967, 18, 111−119. (120) Knochel, A.; Zwernemann, O. Aromatic n.c.a. Labelling with 18 − F by Modified Balz-Schiemann-Decomposition. Appl. Radiat. Isot. 1991, 42, 1077−1080. (121) Knochel, A.; Zwernemann, O. Development of a no-carrieradded method for 18 F-labelling of aromatic compounds by fluorodediazonation. J. Labelled Compd. Radiopharm. 1996, 38, 325− 336. (122) Palmer, A. J.; Clark, J. C.; Goulding, R. W. The Preparation of Fluorine-18 Labelled Radiopharmaceuticals. Int. J. Appl. Radiat. Isot. 1977, 28, 53−65. (123) Hoyte, R. M.; Lin, S. S.; Christman, D. R.; Atkins, H. L.; Hauser, W.; Wolf, A. P. Organic Radiopharmaceuticals Labeled with Short-Lived Nuclides. III. 18F-Labeled Phenylalanines. J. Nucl. Med. 1971, 12, 280−286. (124) Goulding, R. W.; Palmer, A. J. The Preparation of Fluorine-18 Labelled p-Fluorophenylalanine for Clinical Use. Int. J. Appl. Radiat. Isot. 1972, 23, 133−137. (125) Goulding, R. W.; Gunasekera, S. W. Fluorine-18 Labelled L-pFluoro-phenylalanine. Int. J. Appl. Radiat. Isot. 1975, 26, 561−564. (126) Atkins, H. L.; Christman, D. R.; Fowler, J. S.; Houser, W.; Hoyte, R. M.; Klopper, J. F.; Lin, S. S.; Wolf, A. P. Organic Radiopharmaceuticals Labeled with Isotopes of Short Half-Life. V. 18FLabeled 5- and 6-Fluorotryptophan. J. Nucl. Med. 1972, 13, 713−719. (127) Firnau, G.; Nahmias, C.; Garnett, S. Synthesis of 3,4Dihydroxy-5-fluoro-DL-phenylalanine and 3,4-Dihydroxy-5-[18F]Fluoro-DL-phenylalanine. J. Med. Chem. 1973, 16, 416−418. (128) Argentini, M.; Wiese, C.; Weinreich, R. Syntheses of 5-fluoroD/L-dopa and [18F]5-fluoro-L-dopa. J. Fluorine Chem. 1994, 68, 141− 144. (129) Tewson, T. J.; Welch, M. J. Preparation of Fluorine-18 Aryl Fluorides: Piperidyl Triazenes as a Source of Diazonium Salts. J. Chem. Soc., Chem. Commun. 1979, 1149−1150. (130) Rosenfeld, M. N.; Widdowson, D. A. A Mild and Efficient Method of Aromatic Fluorination. J. Chem. Soc., Chem. Commun. 1979, 914−916. (131) Ng, J. S.; Katzenellenbogen, J. A.; Kilbourn, M. R. Aromatic Fluorinations Suitable for Fluorine-18 Labeling of Estrogens. J. Org. Chem. 1981, 46, 2520−2528. (132) Satyamurthy, N.; Barrio, J. R.; Schmidt, D. G.; Kammerer, C.; Bida, G. T.; Phelps, M. E. Acid-Catalyzed Thermal Decomposition of 1-Aryl-3,3-dialkyltriazenes in the Presence of Nucleophiles. J. Org. Chem. 1990, 55, 4560−4564. (133) Pages, T.; Langlois, B. R. Fluorination of aromatic compounds from 1-aryl-3,3-dimethyltriazenes and fluoride anions in acidic medium 1. A model for 18F labelling. J. Fluorine Chem. 2001, 107, 321−327. (134) Tewson, T. J.; Raichle, M. E.; Welch, M. J. Preliminary studies with [18F]haloperidol: a radioligand for in vivo studies of the dopamine receptors. Brain Res. 1980, 192, 291−295. (135) Barrio, J. R.; Satyamurthy, N.; Ku, H.; Phelps, M. E. The Acid Decomposition of 1-Aryl-3,3-dialkyltriazenes. Mechanistic Changes as a Function of Aromatic Substitution, Nucleophile Strength, and Solvent. J. Chem. Soc., Chem. Commun. 1983, 443−444. (136) Pages, T.; Langlois, B. R.; Le Bars, D.; Landais, P. Fluorination of aromatic compounds from 1-aryl-3,3-dimethyltriazenes and fluoride anions in acidic medium 2. Synthesis of (S)-[18F]-3-fluoro-αmethylphenylalanine. J. Fluorine Chem. 2001, 107, 329−335. (137) Riss, P. J.; Kuschel, S.; Aigbirhio, F. I. No carrier-added nucleophilic aromatic radiofluorination using solid phase supported 758

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

aminooxyhexyl]maleimide ([18F]FBAM). Appl. Radiat. Isot. 2011, 69, 1226−1230. (157) Kiesewetter, D. O.; Jacobson, O.; Lang, L.; Chen, X. Automated radiochemical synthesis of [18F]FBEM: A thiol reactive synthon for radiofluorination of peptides and proteins. Appl. Radiat. Isot. 2011, 69, 410−414. (158) Li, L.; Hopkinson, M. N.; Yona, R. L.; Bejot, R.; Gee, A. D.; Gouverneur, V. Convergent 18F radiosynthesis: A new dimension for radiolabeling. Chem. Sci. 2011, 2, 123−131. (159) Lemaire, C.; Damhaut, P.; Plenevaux, A.; Cantineau, R.; Christiaens, L.; Guillaume, M. Synthesis of Fluorine-18 Substituted Aromatic Aldehydes and Benyl Bromides, New Intermediates for n.c.a. [18F]Fluorination. Appl. Radiat. Isot. 1992, 43, 485−494. (160) Lemaire, C.; Libert, L.; Plenevaux, A.; Aerts, J.; Franci, X.; Luxen, A. Fast and reliable method for the preparation of ortho- and para-[18F]fluorobenzyl halide derivtives: Key intermediates for the preparation of n.c.a. PET aromatic radiopharmaceuticals. J. Fluorine Chem. 2012, 138, 48−55. (161) Lemaire, C. F.; Aerts, J. J.; Voccia, S.; Libert, L. C.; Mercier, F.; Goblet, D.; Plenevaux, A. R.; Luxen, A. J. Fast Production of Highly Reactive No-Carrier-Added [18F]Fluoride for the Labeling of Radiopharmaceuticals. Angew. Chem., Int. Ed. 2010, 49, 3161−3164. (162) Aerts, J.; Voccia, S.; Lemaire, C.; Giacomelli, F.; Goblet, D.; Thonon, D.; Plenevaux, A.; Warnock, G.; Luxen, A. Fast production of highly concentrated reactive [18F] fluoride for aliphatic and aromatic nucleophilic radiolabelling. Tetrahedron Lett. 2010, 51, 64−66. (163) Wessman, S. H.; Henriksen, G.; Wester, H.-J. Cryptate mediated nucleophilic 18F-fluorination without azeotropic drying. Nuklearmedizin 2012, 50, 1−8. (164) Alexoff, D.; Schlyer, D. J.; Wolf, A. P. Recovery of [18F]fluoride from [18O]water in an electrochemical cell. Appl. Radiat. Isot. 1989, 40, 1−6. (165) Hamacher, K.; Hirschfelder, T.; Coenen, H. H. Electrochemical cell for separation of [18F]fluoride from irradtion O-18 water and subsequent no carrier added nucleophilic fluorination. Appl. Radiat. Isot. 2002, 56, 519−523. (166) Saiki, H.; Iwata, R.; Nakanishi, H.; Wong, R.; Ishikawa, Y.; Furumoto, S.; Yamahara, R.; Sakamoto, K.; Ozeki, E. Electrochemical concentration of no-carrier-added [18F]fluoride from [18O]water in a disposable microfluidic cell for radiosynthesis of 18F-labeled radiopharmaceuticals. Appl. Radiat. Isot. 2010, 68, 1703−1708. (167) Kugler, F.; Roehrens, D.; Stumpf, M.; Drerup, C.; Ermert, J.; Hamacher, K.; Coenen, H. H. Optimizing the transfer of [18F]fluoride from aqueous to organic solvents by electrodeposition using carbon electrodes. Appl. Radiat. Isot. 2014, 91, 1−7. (168) Wong, R.; Iwata, R.; Saiki, H.; Furumoto, S.; Ishikawa, Y.; Ozeki, E. Reactivity of electrochemically concentrated anhydrous [18F]fluoride for microfluidic radiosynthesis of 18F-labeled compounds. Appl. Radiat. Isot. 2012, 70, 193−199. (169) Sergeev, M. E.; Morgia, F.; Lazari, M.; Wang, C., Jr.; van Dam, R. M. Titania-Catalyzed Radiofluorination of Tosylated Precursors in Highly Aqueous Medium. J. Am. Chem. Soc. 2015, 137, 5686−5694. (170) Zhang, H.; Huang, R.; Pillarsetty, N. V. K.; Thorek, D. L. J.; Vaidyanathan, G.; Serganova; Blasberg, R. G.; Lewis, J. S. Synthesis and evaluation of 18F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter. Eur. J. Nucl. Med. Mol. Imaging 2014, 41, 322−332. (171) Ding, Y.-S.; Fowler, J. S.; Gately, S. J.; Dewey, S. L.; Wolf, A. P.; Schlyer, D. J. Synthesis of High Specific Activity 6-[18F]fluorodopamine for Positron Emission Tomography Studies of Sympathetic Nervous Tissue. J. Med. Chem. 1991, 34, 861−863. (172) Pretze, M.; Wangler, C.; Wangler, B. 6-[18F]Fluoro-L-DOPA: A Well-Established Neurotracer with Expanding Application Spectrum and Strongly Improved Radiosyntheses. BioMed Res. Int. 2014, 2014, 1−12. (173) Lemaire, C.; Guillaume, M.; Cantineau, R.; Christiaens, L. Nocarrier-added regioselective preparation of 6-[18F]Fluoro-L-DOPA. J. Nucl. Med. 1990, 31, 1247−1251.

(174) Reddy, G. N.; Haeberli, M.; Beer, H.-J.; Schubiger, A. P. An Improved Synthesis of No-carrier-added (NCA) 6-[18F]Fluoro-LDOPA and its Remote Routine Production for PET Investigations of Dopaminergic Systems. Appl. Radiat. Isot. 1993, 44, 645−649. (175) Kaneko, S.; Ishiwata, K.; Htano, K.; Omura, H.; Ito, K.; Senda, M. Enzymatic synthesis of no-carrier-added 6-[18F]fluoro-L-dopa with β-tyrosinase. Appl. Radiat. Isot. 1999, 50, 1025−1032. (176) Krasikova, R. N.; Zaitsev, V. V.; Ametamey, S. M.; Kuznetsova, O. F.; Federova, O. S.; Mosevich, I. K.; Belokon, Y. N.; Vyskocil, S.; Shatik, S. V.; Nader, M.; Schubiger, P. A. Catalytic enantioselective synthesis of 18F-fluorinated α-amino acids under phase-transfer conditions using (S)-NOBIN. Nucl. Med. Biol. 2004, 31, 597−603. (177) Lemaire, C.; Guillaume, M.; Cantineau, R.; Plenevaux, A.; Christiaens, L. An approach to the asymmetric synthesis of 6[18F]Fluoro-L-dopa via NCA nucleophilic fluorination. Appl. Radiat. Isot. 1991, 42, 629−635. (178) Lemaire, C.; Gillet, S.; Guillouet, S.; Plenevaux, A.; Aerts, J.; Luxen, A. Highly Enantioselective Synthesis of No-Carrier-Added 6[18F]Fluoro-L-dopa by Chiral Phase-Transfer Alkylation. Eur. J. Org. Chem. 2004, 2004, 2899−2904. (179) Shen, B.; Ehrlichmann, W.; Uebele, M.; Machulla, H.-J.; Reischl, G. Automated synthesis of n.c.a. [18F]FDOPA via nucleophilic aromatic aubstitution with [18F]fluoride. Appl. Radiat. Isot. 2009, 67, 1650. (180) Libert, L. C.; Franci, X.; Plenevaux, A. R.; Ooi, T.; Maruoka, K.; Luxen, A. J.; Lemaire, C. F. Production at the Curie Level of NoCarrier-Added 6-18F-Fluoro-L-DOPA. J. Nucl. Med. 2013, 54, 1154− 1161. (181) Lemaire, C.; Libert, L.; Franci, X.; Genon, J.-L.; Kuci, S.; Giacomelli, F.; Luxen, A. Automated production at the curie level of no-carrier-added 6-[18F]fluoro-L-dopa and 2-[18F]fluoro-L-tyrosine on a FASTlab synthesizer. J. Labelled Compd. Radiopharm. 2015, 58, 281− 290. (182) Wagner, F. M.; Ermert, J.; Coenen, H. H. Three-Step, “OnePot” Radiosynthesis of 6-Fluoro-3,4-Dihydroxy-L-Phenylalanine by Isotopic Exchange. J. Nucl. Med. 2009, 50, 1724−1729. (183) Kuik, W.-J.; Kema, I. P.; Brouwers, A. H.; Zijlma, R.; Neumann, K. D.; Dierckx, R. A.J.O.; DiMagno, S. G.; Elsinga, P. H. In Vivo Biodistribution of No-Carrier-Added 6-18F-Fluoro-3,4-Dihydroxy-LPhenylalanine (18F-DOPA), Produced by a New Nucleophilic Substitution Approach, Compared with Carrier-Added 18F-DOPA, Prepared by Conventional Electrophilic Substitution. J. Nucl. Med. 2015, 56, 106−112. (184) Zlatopolskiy, B. D.; Zischler, J.; Urusova, E. A.; Endepols, H.; Kordys, E.; Frauendorf, H.; Mottaghy, F. M.; Neumaier, B. A Practical One-Pot Synthesis of Positron Emission Tomography (PET) Tracers via Nickel-Mediated Radiofluorination. ChemistryOpen 2015, 4, 457− 462. (185) Meleán, J. C.; Humpert, S.; Ermert, J.; Coenen, H. H. Stereoselective radiosynthesis of L- and D-3-[18F]fluoro-α-methyltyrosine. J. Fluorine Chem. 2015, 178, 202−207. (186) Castillo, J. M.; Ermert, J.; Coenen, H. H. A three-step radiosynthesis of 6-[18F]fluoro-L-meta-tyrosine starting with [18F]fluoride. J. Labelled Compd. Radiopharm. 2015, 58, 133−140. (187) Weiss, P. S.; Ermert, J.; Melean, J. C.; Schafer, D.; Coenen, H. H. Radiosynthesis of 4-[18F]fluoro-L-tryptophan by isotopic exchange on carbonyl-activated precursors. Bioorg. Med. Chem. 2015, 23, 5856−5869. (188) Dollé, F. Fluorine-18-Labelled Fluoropyridines: Advances in Radiopharmaceutical Design. Curr. Pharm. Des. 2005, 11, 3221−3235. (189) Illuminati, G. Nucleophilic Heteroaromatic Substitution. Adv. Heterocycl. Chem. 1964, 3, 285−371. (190) Illuminati, G.; Stegel, F. The Formation of Anionic σ-Adducts from Heteroaromatic Compounds: Structures, Rates, and Equilibria. Adv. Heterocycl. Chem. 1983, 34, 305−444. (191) Schlosser, M.; Ruzziconi, R. Nucleophilic Substitutions of Nitroarenes and Pyridines: New Insight and New Applications. Synthesis 2010, 13, 2111−2123. 759

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

(209) Betts, H. M.; Robins, E. G. 2-Bromo-6-[18F]fluoropyridine: two-step fluorine-18 radiolabelling via transition metal-mediated chemistry. J. Labelled Compd. Radiopharm. 2014, 57, 215−218. (210) Sihver, W.; Nordberg, A.; Långstrom, B.; Mukhin, A. G.; Koren, A. O.; Kimes, A. S.; London, E. D. Development of ligands for in vivo imaging of cerebral nicotinic receptors. Behav. Brain Res. 2000, 113, 143−157. (211) Ding, Y.-S.; Fowler, J. New-generation radiotracers for nAChR and NET. Nucl. Med. Biol. 2005, 32, 707−718. (212) Horti, A. G.; Kuwabara, H.; Holt, D. P.; Dannals, R. F.; Wong, D. F. Recent PET radioligands with optimal brain kinetics for imaging nicotinic acetylcholine receptors. J. Labelled Compd. Radiopharm. 2013, 56, 159−166. (213) Knust, E. J.; Müller-Platz, C.; Schüller, M. Synthesis, Quality Control and Tissue Distribution of 2-[18F]-Nicocontinc Acid Diethylamide, A Potential Agent For regional Cerebral Function Studies. J. Radio. Anal. Chem. 1982, 74, 283−291. (214) Knust, E. J.; Machulla, H.-J.; Molls, M. 18F-Production in a water target with high yields for 18F-labelling of organic compounds: Synthesis of 6-(18F)-nicotonic acid diethylamide. J. Labelled Compd. Radiopharm. 1982, 19, 1643−1644. (215) Knust, E. J.; Machulla, H.-J.; Kafka, C. Influence of Labelling with Radiohalogens in 2-18F-, 6-18F−, and 6-123I-Nicotinic Acid Diethylamide on Biodistribution in Mice. J. Radioanal. Nucl. Chem. 1985, 92, 371−378. (216) Ballinger, J. R.; Bowen, B. M.; Firnau, G.; Garnett, E. S.; Teare, F. W. Radiofluorination with Reactor-produced Cesium [18F]Fluoride: No-Carrier-Added [18F]2-Fluoronicotine and [18F]6-Fluoronicotine. Int. J. Appl. Radiat. Isot. 1984, 35, 1125−1128. (217) Ding, Y.-S.; Gatley, S. J.; Fowler, J. S.; Volkow, N. D.; Aggarwal, D.; Logan, J.; Dewey, S.; Liang, F.; Carroll, F. I.; Kuhar, M. J. Mapping Nicotinic Acetylcholine Receptors With PET. Synapse 1996, 24, 403−407. (218) Horti, A.; Ravert, H. T.; London, E. D.; Dannals, R. F. J. Labelled Compd. Radiopharm. 1996, 38, 355−365. (219) Horti, A.; Scheffel, U.; Stathis, M.; Finley, P.; Ravert, H. T.; London, E. D.; Dannals, R. F. Fluorine-18-FPH for PET imaging of nicotinic acetylcholine receptors. J. Nucl. Med. 1997, 38, 1260−1265. (220) Villemagne, V. L.; Horti, A.; Scheffel, U.; Ravert, H. T.; Finley, P.; Clough, D. J.; London, E. D.; Wagner, H. N., Jr.; Dannals, R. F. Imaging Nicotinic Acetylcholine Receptors with Fluorine-18-FPH, an Epibatidine Analog. J. Nucl. Med. 1997, 38, 1737−1741. (221) Ding, Y.-S.; Liang, F.; Fowler, J. S.; Kuhar, M. J.; Carroll, F. I. J. Labelled Compd. Radiopharm. 1997, 39, 827−832. (222) Liang, F.; Navarro, H. A.; Abraham, P.; Kotian, P.; Ding, Y.-S.; Fowler, J.; Volkow, N.; Kuhar, M. J.; Carroll, F. I. Synthesis and Nicotinic Acetylcholine Receptor Binding Properties of exo-2-(2′Fluoro-5′-pyridinyl)-7-azabicyclo-[2.2.1]heptane: A New Positron Emission Tomography Ligand for Nicotinic Receptors. J. Med. Chem. 1997, 40, 2293−2295. (223) Dolci, L.; Dollé, F.; Valette, H.; Vaufrey, F.; Fuseau, C.; Bottlaender, M.; Crouzel, C. Synthesis of a fluorine-18 labeled derivative of Epibatidine for in vivo nicotinic acetylcholine receptor PET imaging. Bioorg. Med. Chem. 1999, 7, 467−479. (224) Patt, J. T.; Deuther-Conrad, W.; Wohlfarth, K.; Feuerbach, D.; Brust, P.; Steinbach, J. Norchloro-fluoro-homoepibatidine: 18F-Labelling and Evaluation of Affinity and Selectivity at Neuronal Nicotinic Aacetylcholine Receptors. J. Labelled Compd. Radiopharm. 2003, 46, S168. (225) Roger, G.; Hinnen, F.; Valette, H.; Saba, W.; Bottlaender, M.; Dollé, F. Radiosynthesis of 2-exo-(2′-[18F]Fluoro-3′-(4-fluorophenyl)pyridin-5′-yl)-7-azabicyclo[2.2.1]heptane ([18F]F2PhEP), a potent Epibatidine-based radioligand for nicotinic acetylcholine receptor PET imaging. J. Labelled Compd. Radiopharm. 2006, 49, 489−504. (226) Roger, G.; Saba, W.; Valette, H.; Hinnen, F.; Coulon, C.; Ottaviani, M.; Bottlaender, M.; Dollé, F. Synthesis and radiosynthesis of [18F]FPhEP, a novel α4β2-selective, Epibatidine-based antagonist for PET imaging of nicotinic acetylcholine receptors. Bioorg. Med. Chem. 2006, 14, 3848−3858.

(192) Terrier, F. Modern Nucleophilic Aromatic Substitution; WileyVCH: Weinheim, 2013. (193) Dolci, L.; Dollé, F.; Jubeau, S.; Vaufrey, F.; Crouzel, C. 2[18F]Fluoropyridines by No-Carrier-Added Nucleophilic Aromatic Substituition with [18F]FK-K222 − Comparative Study. J. Labelled Compd. Radiopharm. 1999, 42, 975−985. (194) Malik, N.; Solbach, C.; Voelter, W.; Machulla, H.-J. Nucleophilic aromatic substitution by [18F]fluoride at substituted 2nitropyridines. J. Radioanal. Nucl. Chem. 2010, 283, 757−764. (195) Angelini, G.; Margonelli, A.; Sparapani, C.; Ursini, O. 18FNucleophilic Heteroaromatic Substitution: Some Data on the Reactivity and Selectivity of the 18F-Fluorination Reaction. J. Labelled Compd. Radiopharm. 1994, 35, 562−564. (196) Malik, N.; Voelter, W.; Machulla, H.-J.; Solbach, C. Radiofluorination of 2-fluoropyridines by isotopic exchange with [18F]fluoride. J. Radioanal. Nucl. Chem. 2011, 287, 287−292. (197) Karramkam, M.; Hinnen, F.; Vaufrey, F.; Dollé, F. 2-, 3- and 4[18F]Fluoropyridine by no-carrier-added nucleophilic aromatic substitution with K[18F]F-K222 − a comparative study. J. Labelled Compd. Radiopharm. 2003, 46, 979−992. (198) Beer, H.-F.; Haeberli, M.; Ametamey, S.; Schubiger, P. A. Comparison of two synthetic methods to obtain [18F] N-(2aminoethyl)-5-fluoropyridine-2-carboxamide, a potential Mao-B imaging tracer for PET. J. Labelled Compd. Radiopharm. 1995, 36, 933−945. (199) Abrahim, A.; Angelberger, P.; Kletter, K.; Müller, M.; Joukhadar, C.; Erker, T.; Langer, O. Synthesis of fluorine-18-labelled 5- and 6-fluoro-2-pyridinamine. J. Labelled Compd. Radiopharm. 2006, 49, 345−356. (200) Kuhnast, B.; de Bruin, B.; Hinnen, F.; Tavitian, B.; Dollé, F. Design and ynthesis of a New [18F]Fluoropyridine-Based Haloacetamide Reagent for the Labeling of Oligonucleotides: 2-Bromo-N-[3-(2[18F]fluoropyridin-3-yloxy)propyl]acetamide. Bioconjugate Chem. 2004, 15, 617−627. (201) de Bruin, B.; Kuhnast, B.; Hinnen, F.; Yaouancq, L.; Amessou, M.; Johannes, L.; Samson, A.; Boisgard, R.; Tavitian, B.; Dollé, F. 1-[3(2-[18F]Fluoropyridin-3-yloxy)propyl]pyrrole-2,5-dione: Design, Sythesis, and Radiosynthesis of a New [18F]Fluoropyridine-Based Maleimide reagent for the Labeling of Peptides and Proteins. Bioconjugate Chem. 2005, 16, 406−420. (202) Kuhnast, B.; Hinnen, F.; Tavitian, B.; Dollé, F. [18F]FPyKYNE, a fluoropyridine-based alkyne reagent designed for the fluorine-18 labelling of macromolecules using click chemistry. J. Labelled Compd. Radiopharm. 2008, 51, 336−342. (203) Valdivia, A. C.; Estrada, M.; Hadizad, T.; Stewart, D. J.; Beanlands, R. S.; DaSilva, J. N. A fast, simple, and reproducible automated synthesis of [18F]FPyKYNE-c(RGDyK) for αvβ3 receptor positron emission tomography imaging. J. Labelled Compd. Radiopharm. 2012, 55, 57−60. (204) Inkster, J.; Lin, K.-S.; Ait-Mohand, S.; Gosselin, S.; Bénard, F.; Guérin, B.; Pourghiasian, M.; Ruth, T.; Schaffer, P.; Storr, T. 2Fluoropyridine prosthetic compounds for the 18F labeling of bombesin analogues. Bioorg. Med. Chem. Lett. 2013, 23, 3920−3926. (205) Inkster, J. A. H.; Guérin, B.; Ruth, T. J.; Adam, M. J. Radiosynthesis and bioconjugation of [18F]FP5yne, a prosthetic group for the 18F labeling of bioactive peptides. J. Labelled Compd. Radiopharm. 2008, 51, 444−452. (206) Inkster, J. A. H.; Adam, M. J.; Storr, T.; Ruth, T. J. Labeling of an Antisense Oligonucleotide with [18F]FPy5yne. Nucleosides, Nucleotides Nucleic Acids 2009, 28, 1131−1143. (207) Olberg, D. E.; Arukwe, J. M.; Grace, D.; Hjelstuen, O. K.; Solbakken, M.; Kindberg, G. M.; Cuthbertson, A. One Step Radiosynthesis of 6-[18F]Fluoronicotinic Acid 2,3,5,6-Tetra Ester ([18F]F-Py-TFP): A New Prosthetic Group for Efficient Labeling Biomolecules with Fluorine-18. J. Med. Chem. 2010, 53, 1732−1740. (208) Daumar, P.; Wagner-Baumann, C. A.; Pillarsetty, N. K.; Fabrizio, L.; Carlin, S. D.; Andreev, O. A.; Reshetnyak, Y. K.; Lewis, J. S. Efficient 18F-Labeling of Large 37-Amino-Acid pHLIP Peptide Analogues and Their Biological Evaluation. Bioconjugate Chem. 2012, 23, 1557−1566. 760

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

Nicotinic α4β2 Receptor Imaging with PET. Bioorg. Med. Chem. 2003, 11, 5333−5343. (239) Kung, H. F.; Choi, S. R.; Qu, W.; Zhang, W.; Skovronsky, D. 18 F Stilbenes and Styrylpyridines for PET Imaging of Aβ Plaques in Alzheimer’s Disease: A Miniperspective. J. Med. Chem. 2010, 53, 933− 941. (240) Hostetler, E. D.; Sanabria-Bohórquez, S.; Fan, H.; Zeng, Z.; Gammage, L.; Miller, P.; O’Malley, S.; Connolly, B.; Mulhearn, J.; Harrison, S. T.; Wolkenberg, S. E.; Barrow, J. C.; Williams, D. L., Jr.; Hargreaves, R. J.; Sur, C.; Cook, J. J. [18F]Fluoroazabenzoxazoles as potential amyloid plaque PET tracers: synthesis and in vivo evaluation in rhesus monkey. Nucl. Med. Biol. 2011, 38, 1193−1203. (241) Cselényi, Z.; Jönhagen, M. E.; Forsberg, A.; Halldin, C.; Julin, P.; Schou, M.; Johnström, P.; Varnäs, K.; Svensson, S.; Farde, L. Clinical validation of 18F-AZD4694, an Amyloid-β-Specific PET Radioligand. J. Nucl. Med. 2012, 53, 415−424. (242) Vasdev, N.; Cao, P.; van Oosten, E. M.; Wilson, A. A.; Houle, S.; Hao, G.; Sun, X.; Slavine, N.; Alhasan, M.; Antich, P. P.; Bonte, F. J.; Kulkarni, P. Synthesis and pet imaging studies of [18F]2fluoroquinolin-8-ol ([18F]CABS13) in transgenic mouse models of Alzheimer’s disease. MedChemComm 2012, 3, 1228−1230. (243) Liang, S. H.; Holland, J. P.; Stephenson, N. A.; Kassenbrock, A.; Rotstein, B. J.; Daignault, C. P.; Lewis, R.; Collier, L.; Hooker, J. M.; Vasdev, N. PET Neuroimaging Studies of [18F]CABS13 in a Double Transgenic Mouse Model of Alzheimer’s Disease and Nonhuman Primates. ACS Chem. Neurosci. 2015, 6, 535−541. (244) Lucatelli, C.; Honer, M.; Salazar, J.-F.; Ross, T. L.; Schubiger, P. A.; Ametamey, S. M. Synthesis, radiolabeling, in vitro and in vivo evaluation of [18F]-FPECMO as a positron emission tomography radioligand for imaging the metabotropic glutamate receptor subtype 5. Nucl. Med. Biol. 2009, 36, 613−622. (245) Karramkam, M.; Hinnen, F.; Berrehouma, M.; Hlavacek, C.; Vaufrey, F.; Halldin, C.; McCarron, J. A.; Pike, V. W.; Dollé, F. Synthesis of a [6-Pyridinyl-18F]-labelled Fluoro Derivative of WAY100635 as a Candidate Radioligand for Brain 5-HT1A Receptor Imaging with PET. Bioorg. Med. Chem. 2003, 11, 2769−2782. (246) Beer, H.-F.; Haeberli, M.; Ametamey, S.; Schubiger, P. A. Comparison of two synthetic methods to obtain [18F] N-(2aminoethyl)-5-fluoropyridine-2-carboxamide, a potential MAO-B imaging tracer for PET. J. Labelled Compd. Radiopharm. 1995, 36, 933−945. (247) Beer, H.-F.; Frey, L. D.; Haeberli, M.; Schubiger, P. A. [123I/18F] N-(2-aminoethyl)-5-halogeno-2-pyridinecarbox-amides, site specific tracers for MAO-B mapping with SPET and PET. Nucl. Med. Biol. 1995, 22, 999−1004. (248) Damont, A.; Boisgard, R.; Kuhnast, B.; Lemée, F.; Raggiri, G.; Scarf, A. M.; Da Pozzo, E.; Selleri, S.; Martini, C.; Tavitian, B.; Kassiou, M.; Dollé, F. Synthesis of 6-[18F]fluoro-PBR28, a novel radiotracer for imaging the TSPO 18 kDa with PET. Bioorg. Med. Chem. Lett. 2011, 21, 4819−4822. (249) Damont, A.; Lemée, F.; Raggiri, G.; Dollé, F. Novel 2,4,5Trisubstituted Pyridines as Key Intermediates for the Preparation of the TSPO Ligand 6-F-PBR28: Synthesis and Full 1H and 13C NMR Characterization. J. Hetercyclic. Chem. 2014, 51, 404−410. (250) Liu, J.; Zhu, L.; Plössl, K.; Lieberman, B. P.; Kung, H. F. Synthesis and evaluation of novel N-Fluoropyridyl derivatives of tropane as potential PET imaging agents for the dopamine transporter. Bioorg. Med. Chem. Lett. 2011, 21, 2962−2965. (251) Maisonial, A.; Kuhnast, B.; Papon, J.; Boisgard, R.; Bayle, M.; Vidal, A.; Auzeloux, P.; Rbah, L.; Bonnet-Duquennoy, M.; MiotNoirault, E.; Galmier, M.-J.; Borel, M.; Askienazy, S.; Dollé, F.; Tavitian, B.; Madelmont, J.-C.; Moins, N.; Chezal, J.-M. Single Photon Emisssion Computed Tomography/Positron Emission Tomography Imaging and Targeted Radionuclide Therapy of Melanoma: New Multimodal Fluorinated and Iodinated Radiotracers. J. Med. Chem. 2011, 54, 2745−2766. (252) Liu, H.; Liu, S.; Miao, Z.; Deng, Z.; Shen, B.; Hong, X.; Cheng, Z. Development of 18F-Labeled Picolinamide Probes for PET Imaging of Malignant Melanoma. J. Med. Chem. 2013, 56, 895−901.

(227) Gao, Y.; Kuwabara, H.; Spivak, C. E.; Xiao, Y.; Kellar, K.; Ravert, H. T.; Kumar, A.; Alexander, M.; Hilton, J.; Wong, D. F.; Dannals, R. F.; Horti, A. G. Discovery of (−)-7-Methyl-2-exo-[3′-(6[18F]fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane, a Radiolabeled Antagonist for Cerebral Nicotinic Acetylcholine Receptor (α4β2-nAChR) with Optimal Positron Emission Tomography Imaging Properties. J. Med. Chem. 2008, 51, 4751−4764. (228) Valette, H.; Dollé, F.; Saba, W.; Roger, G.; Hinnen, F.; Coulon, C.; Ottaviani, M.; Syrota, A.; Bottlaender, M. [18F]FPhEP and [18F]F2PhEP, two new Epibatidine-based radioligands: Evaluation for imaging nicotinic acetylcholine receptors in baboon brain. Synapse 2007, 61, 764−770. (229) Fischer, S.; Hiller, A.; Smits, R.; Hoepping, A.; Funke, U.; Wenzel, B.; Cumming, P.; Sabri, O.; Steinbach, J.; Brust, P. Radiosynthesis of racemic and enantiomerically pure (−)-[18F]flubatine-a promising PET radiotracer for neuroimaging of α4β2 nicotinic acetylcholine receptors. Appl. Radiat. Isot. 2013, 74, 128− 136. (230) Smits, R.; Fischer, S.; Hiller, A.; Deuther-Conrad, W.; Wenzel, B.; Patt, M.; Cumming, P.; Steinbach, J.; Sabri, O.; Brust, P.; Hoepping, A. Synthesis and biological evaluation of both enantiomers of [18F]flubatine, promising radiotracers with fast kinetics for the imaging of α4β2-nicotinic acetylcholine receptors. Bioorg. Med. Chem. 2014, 22, 804−812. (231) Horti, A. G.; Koren, A. O.; Ravert, H. T.; Musachio, J. L.; Mathews, W. B.; London, E. D.; Dannals, R. F. Synthesis of a Radiotracer for studying Nicotinic Acetylcholine Receptors: 2[18Ffluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]A-85380). J. Labelled Compd. Radiopharm. 1998, 41, 309−318. (232) Dollé, F.; Valette, H.; Bottlaender, M.; Hinnen, F.; Vaufrey, F.; Guenther, I.; Crouzel, C. Synthesis of 2-[18F]Fuoro-3-[2(S)-2azetidinylmethoxy]pyridine, a Highly Potent Radioligand for in Vivo Imaging Central Nicotinic Acetylcholine Receptors. J. Labelled Compd. Radiopharm. 1998, 41, 451−463. (233) Dollé, F.; Dolci, L.; Valette, H.; Hinnen, F.; Vaufrey, F.; Guenther, I.; Fuseau, C.; Coulon, C.; Bottlaender, M.; Crouzel, C. Synthesis and Nicotinic Acetylcholine Receptor in Vivo Binding Properties of 2-Fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine: A New Positron Emission Tomography Ligand for Nicotinic Receptors. J. Med. Chem. 1999, 42, 2251−2259. (234) Zhang, Y.; Pavlova, O. A.; Chefer, S. I.; Hall, A. W.; Kurian, V.; Brown, L. L.; Kimes, A. S.; Mukhin, A. G.; Horti, A. G. 5-Substituted Derivatives of 6-Halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-Halogeno-3-((2(S)-pyrrolidinyl)methoxy)pyridine with Low Picomolar Affinity for α4β2 Nicotinic Acetylcholine Receptor and Wide Range of Lipophilicity: Potential Probes for Imaging with Positron Emission Tomography. J. Med. Chem. 2004, 47, 2453−2465. (235) Zhang, Y.; Horti, A. G. Synthesis of 6-chloro-3-((2-(S)azetidinyl)methoxy)-5−2-[ 1 8 F]fluoropyridin-4-yl)pyridine ([18F]NIDA 522131), a novel potential radioligand for studying extrathalamic nicotinic acetylcholine receptors by PET. J. Labelled Compd. Radiopharm. 2004, 47, 947−952. (236) Zhang, Y.; Hall, A. W.; Horti, A. G. Efficient synthesis of 6chloro-3-((2(S)-azetidinyl)methyoxy)-5-((E)-2-(2-[18F]fluoropyridin4-yl)vinyl)pyridine ([18F]NIDA 522289), a very high affinity radioligand for nicotinic acetylcholine receptors. J. Labelled Compd. Radiopharm. 2004, 47, 385−392. (237) Pichika, R.; Easwaramoorthy, B.; Collins, D.; Christian, B. T.; Shi, B.; Narayanan, T. K.; Potkin, S. G.; Mukherjee, J. Nicotinic α4β2 receptor imaging agents Part II. Synthesis and biological evaluation of 2-[18F]fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine (18F-nifene) in rodents and imaging by PET in nonhuman primate. Nucl. Med. Biol. 2006, 33, 295−304. (238) Roger, G.; Lagnel, B.; Rouden, J.; Besret, L.; Valette, H.; Demphel, S.; Gopisetti, J. M.; Coulon, C.; Ottaviani, M.; Wrenn, L. A.; Lecthworth, S. R.; Bohme, G. A.; Benavides, J.; Lasne, M.-C.; Bottlaender, M.; Dollé, F. Synthesis of a [2-Pyridinyl-18F]-labelled Fluoro Derivative of (−)-Cystine as a Candidate Radioligand for Brain 761

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

(253) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles; WileyVCH: Weinheim, 2003. (254) Siméon, F. G.; Wendahl, M. T.; Pike, V. W. The [18F]2-fluoro1,3-thiazolyl moiety-an easily-accessible structural motif for prospective molecular imaging radiotracers. Tetrahedron Lett. 2010, 51, 6034− 6036. (255) Siméon, F. G.; Wendahl, M. T.; Pike, V. W. Syntheses of 2Amino and 2-Halothiazole derivatives as High-Affinity Metabotropic Glutamate Receptor Subtype 5 Ligands and Potential Radioligands for in Vivo Imaging. J. Med. Chem. 2011, 54, 901−908. (256) Irie, T.; Fukushi, K.; Ido, T. Synthesis of 18F-6-fluoropurine and 18F-6-fluoro-9-β-D-ribofuranosylpurine. Int. J. Appl. Radiat. Isot. 1982, 33, 445−448. (257) Cai, H.; Yin, D.; Zhang, L.; Wang, Y. The synthesis of a new probe for PET imaging reporter gene HSV1-tk: 2-amino-6-[18F] fluoro-9-(4-hydroxy-3-hydroxymethylbutyl) purine (6-[ 18 F]fluoropenciclovir). J. Labelled Compd. Radiopharm. 2006, 49, 653−661. (258) Irie, T.; Fukushi, K.; Inoue, O.; Yamasaki, T.; Ido, T.; Nozaki, T. Preparation of 18F-Labeled 6- and 2-fluoro-9-benzylpurine as a potential brain-scanning agent. Int. J. Appl. Radiat. Isot. 1982, 33, 633− 636. (259) Horti, A. G.; Ravert, H. T.; Mathews, W. B.; Abraham, E. H.; Wahl, R. L.; Dannals, R. F. Synthesis of 2-[18F]fluoroadenosine (2[18F]FAD) as potential radiotracer for studying malignancies by PET. J. Labelled Compd. Radiopharm. 2006, 49, 811−815. (260) Marchand, P.; Lorilleux, C.; Gilbert, G.; Gourand, F.; Sobrio, F.; Peyronnet, D.; Dhilly, M.; Barré, L. Efficient Radiosynthesis of 2[18F]Fluoroadenosine: A New Route to 2-[18F]Fluoropurine Nucleosides. ACS Med. Chem. Lett. 2010, 1, 240−243. (261) Merritt, El. A.; Olofsson, B. Diaryliodonium Salts: A Journey from Obscurity to Fame. Angew. Chem., Int. Ed. 2009, 48, 9052−9070. (262) Pike, V. W.; Aighirhio, F. I. Reactions of Cyclotron-produced [18F]Fluoride with Diaryliodonium Salts-a Novel Single-step Route to No-carrier-added [18F]Fluoroarenes. J. Chem. Soc., Chem. Commun. 1995, 2215−2216. (263) Shah, A.; Pike, V. W.; Widdowson, D. A. The synthesis of [18F]fluoroarenes from the reaction of cyclotron-produced [18F]fluoride ion with diaryliodonium salts. J. Chem. Soc., Perkin Trans. 1 1998, 2043−2046. (264) Ross, T. L.; Ermert, J.; Hocke, C.; Coenen, H. H. Nucleophilic 18 F-Fluorination of Hetroaromatic Iodonium Salts with No-CarrierAdded [18F]Fluoride. J. Am. Chem. Soc. 2007, 129, 8018−8025. (265) Carrol, M. A.; Jones, C.; Tang, S.-L. Fluoridation of 2thienyliodonium salts. J. Labelled Compd. Radiopharm. 2007, 50, 450− 451. (266) Carroll, M. A.; Martin-Santamaria, S.; Pike, V. W.; Rzepa, H. S.; Widdowson, D. A. An ab initio and MNDO-d SCF-MO computational study of stereoelectroni control in extrusion reactions of R2I-F iodine(III) intermediates. J. Chem. Soc., Perkin Trans. 2 1999, 2707−2714. (267) Martin-Santamaria, S.; Carroll, M. A.; Pike, V. W.; Rzepa, H. S.; Widdowson, D. A. An ab initio and MNDO-d SCF-MO computational study of the extrusion reactions of R2I-F iodine(III) via dimeric, trimeric and tetrameric transition states. J. Chem. Soc., Perkin Trans. 2 2000, 2158−2161. (268) Chun, J.-H.; Lu, S.; Lee, Y.-S.; Pike, V. W. Fast and High-Yield Microreactor Syntheses of ortho-Substittued [18F]Fluoroarenes from Reactions of [18F]Fluoride Ion with Diaryliodonium Salts. J. Org. Chem. 2010, 75, 3332−3338. (269) Seeman, J. I. Effect of Conformational Change on reactivity in Organic Chemistry. Evaluations, Applications, and Extensions of Curtin-Hammett/Winstein-Hoiness Kinetics. Chem. Rev. 1983, 83, 83−134. (270) Yamada, Y.; Kashima, K.; Okawara, M. Substituent Effect in the Nucleophilic Attack by the Bromide Ion on the p-TolylSubstituted Phenyliodonium Ions. Bull. Chem. Soc. Jpn. 1974, 47, 3179−3180. (271) Lancer, K. M.; Wiegard, G. H. The Ortho Effect in the Pyrolysis of Iodonium Halides. A Case for a Sterically Controlled

Nucleophilic Aromatic (SN) Substitution reaction. J. Org. Chem. 1976, 41, 3360−3364. (272) Yamada, Y.; Okawara, M. Steric Effect in the Nucleophilic Attack of Bromide Anion on Diaryl- and Aryl-2-thienyliodonium Ions. Bull. Chem. Soc. Jpn. 1972, 45, 1860−1863. (273) Grushin, V. V.; Demkina, I. I.; Tolstaya, T. P. Unified Mechanistic Analysis of Polar reactions of Diaryliodonium Salts. J. Chem. Soc., Perkin Trans. 2 1992, 505−511. (274) Chun, J.-H.; Lu, S.; Pike, V. W. Rapid and Efficient Radiosyntheses of meta-Substituted [18F]Fluoroarenes from [18F]Fluoride Ion and Diaryliodonium Tosylates within a Microreactor. Eur. J. Org. Chem. 2011, 2011, 4439−4447. (275) Irving, H.; Reid, R. W. The Photochemical Decomposition of Diphenyliodonium Iodide. J. Chem. Soc. 1960, 2078−2081. (276) Carrol, M. A.; Nairne, J.; Smith, J.; Widdowson, D. A. Radical scavengers: A practical solution to the reproducibility issue in the fluoridation of diaryliodonium salts. J. Fluorine Chem. 2007, 128, 127− 132. (277) Chun, J.-H.; Pike, V. W. Single-step syntheses of no-carrieradded functionalized [18F]fluoroarenes as labeling synthons from diaryliodonium salts. Org. Biomol. Chem. 2013, 11, 6300−6306. (278) Ermert, J.; Coenen, H. H. 18F-fluorination of complex molecules in activated carbocyclic aromatic position. Curr. Radiopharm. 2010, 3, 109−126. (279) Ermert, J.; Coenen, H. H. No-carrier-added [ 18 F]fluorobenzene derivatives as intermediates for built-up radiosyntheses. Curr. Radiopharm. 2010, 3, 127−160. (280) Glaser, M.; Arstad, E.; Luthra, S. K.; Robbins, E. G. Two-step radiosynthesis of [18F]N-succinimidyl-4-fluorobenzoate ([18F]SFB). J. Labelled Compd. Radiopharm. 2009, 52, 327−330. (281) Suzuki, H.; Yazawa, N.; Yoshida, Y.; Furusawa, O.; Kimura, Y. General and Highly Efficient Syntheses of m-Fluoro Arenes Using Potassium Fluoride-Exchange Method. Bull. Chem. Soc. Jpn. 1990, 63, 2010−2017. (282) Hwang, D.-R.; Dence, C. S.; McKinnon, Z. A.; Mathias, C. J.; Welch, M. J. Positron Labeled Muscarinic Acetylcholine Receptor Antagonist: 2- and 4-[18F]Fluorodexetimide. Syntheses and Biodistribution. Nucl. Med. Biol. 1991, 18, 247−252. (283) Lemaire, C.; Damhaut, P.; Plenevaux, A.; Cantineau, R.; Christiaens, L.; Guillaume, M. Synthesis of Fluorine-18 Substituted Aromatic Aldehydes and Benzyl Bromides, New Intermediates for n.c.a. [18F]Fluorination. Appl. Radiat. Isot. 1992, 43, 485−494. (284) Basuli, F.; Wu, H.; Griffiths, G. L. Syntheses of meta[18F]fluorobenzaldehyde and meta-[18F]fluorobenzylbromide from phenyl(3-Formylphenyl) iodonium salt precursors. J. Labelled Compd. Radiopharm. 2011, 54, 224−228. (285) Pretze, M.; Groβe-Gehling, P.; Mamat, C. Cross-Coupling Reactions as Valuable tool for the Preparation of PET Radiotracers. Molecules 2011, 16, 1129−1165. (286) Allain-Barbier, L.; Lasne, M. C.; Huard, C.; Barre, L. Palladium Mediated Synthesis of [18F]Fluorophenyl Alkenes or Arenes. J. Labelled Compd. Radiopharm. 1995, 37, 572. (287) Forngren, T.; Andersson, Y.; Lamm, B.; Långström, B. Synthesis of [4-18F]-1-Bromo-4-fluorobenzene and its Use in Palladium-Promoted Cross-Coupling Reactions with Organostannanes. Acta Chem. Scand. 1998, 52, 475−479. (288) Wust, F. R.; Kniess, T. No-carrier added synthesis of 18Flabelled nucleosides using Stille cross-coupling reactions with 4[18F]fluoroiodobenzene. J. Labelled Compd. Radiopharm. 2004, 47, 457−46. (289) Wust, F. R.; Hahne, A.; Metz, P. Synthesis of 18F-labelled cyclooxygenase-2 (COX-2) inhibitors via Stille reaction with 4[18F]fluoroiodobenzene as radiotracers for positron emission tomography (PET). Org. Biomol. Chem. 2005, 3, 503−507. (290) Marrière, E.; Rouden, J.; Tadino, V.; Lasne, M.-C. Synthesis of Analoques of (−)-Cystine for in Vivo Studies of Nicotinic Receptors Using Positron Emission Tomography. Org. Lett. 2000, 2, 1121−1124. (291) Allain-Barbier, L.; Lasne, M.-C.; Perrio-Huard, C.; Moreau, B.; Barre, L. Synthesis of 4-[18F]Fluorophenyl-alkenes and − arenes via 762

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

Palladium-Catalyzed Coupling of 4-[18F]Fluoroiodobenzene with Vinyl and Aryl Tin Reagents. Acta Chem. Scand. 1998, 52, 480−489. (292) Wust, F. R.; Kniess, T. Synthesis of 4-[18F]fluoroiodobenzene and its application in sonogashira cross-soupling reactions. J. Labelled Compd. Radiopharm. 2003, 46, 699−713. (293) Steiniger, B.; Wuest, F. R. Synthesis of 18F-labelled biphenyls via Suzuki cross-coupling with 4-[18F]fluoroiodobenzene. J. Labelled Compd. Radiopharm. 2006, 49, 817−827. (294) Wust, F. R.; Kniess, T. N-Arylation of indoles with 4[18F]fluoroiodobenzene: synthesis of 18F-labelled σ2 receptor ligands. J. Labelled Compd. Radiopharm. 2005, 48, 31−43. (295) Kugler, F.; Ermert, J.; Kaufholz, P.; Coenen, H. H. 4[18F]Fluorophenylpiperazines by Improved Hartwig-Buchwald NArylation of 4-[18F]fluoroiodobenzene, Formed via Hypervalent λ3Iodane Precursors: Application to Build-Up of the Dopamine D4 Ligand [18F]FAUC 316. Molecules 2015, 20, 470−486. (296) Gao, Z.; Gouverneur, V.; Davis, B. G. Enhanced Aquesous Suzuki-Miyaura Coupling Allows Site-Specific Polypeptide 18F-Labeling. J. Am. Chem. Soc. 2013, 135, 13612−13615. (297) Ermert, J.; Ludwig, T.; Gail, R.; Coenen, H. H. [18F]Fluorophenyl organometallics as intermediates of no-carrier-added 18 F-fluoroarylation reactions. J. Organomet. Chem. 2007, 692, 4084− 4092. (298) Ermert, J.; Hocke, C.; Ludwig, T.; Gail, R.; Coenen, H. H. Comparison of pathways to the versatile synthon of no-carrier-added 1-bromo-4-[18F]fluorobenzene. J. Labelled Compd. Radiopharm. 2004, 47, 429−441. (299) Chun, J.-H.; Pike, V. W. Single-Step Radiosynthesis of “18FLabeled Click Synthons” from Azide-Functionalized Diaryliodonium Salts. Eur. J. Org. Chem. 2012, 4541−4547. (300) Wadsworth, H. J.; Devenish, P. A. US2011/0196149 A1, 2011. (301) Chun, J.-H.; Telu, S.; Lu, S.; Pike, V. W. Radiofluorination of diaryliodonium tosylates under aqueous-organic and cryptand-free conditions. Org. Biomol. Chem. 2013, 11, 5094−5099. (302) Richarz, R.; Krapf, P.; Zarrad, F.; Urusova, E. A.; Neumaier, B.; Zlatopolskiy, B. D. Neither azeotropic drying, nor base nor other additives: a minimalist approach to 18F-labeling. Org. Biomol. Chem. 2014, 12, 8094−8099. (303) Carroll, M. A.; Nairne, J.; Woodcraft, J. L. Diaryliodonium salts: a solution to 3-[18F]fluoropyridine. J. Labelled Compd. Radiopharm. 2007, 50, 452−454. (304) Chun, J.-H.; Pike, V. W. Selective syntheses of no-carrier-added 2- and 3-[18F]fluorohalopyridines through the radiofluorination of halopyridinyl(4′-methoxyphenyl)iodonium tosylates. Chem. Commun. 2012, 48, 9921−9923. (305) Zhang, M.-R.; Kida, T.; Noguchi, J.; Furutsuka, K.; Maeda, J.; Suhara, T.; Suzuki, K. [11C]DAA1106: Radiosynthesis and in vivo binding to peripheral benzodiazepine receptors in mouse brain. Nucl. Med. Biol. 2003, 30, 513−519. (306) Zhang, M.-R.; Kumata, K.; Suzuki, K. A practical route for synthesizing a PET ligand containing [18F]fluorobenzene using reaction of diphenyliodonium salt with [18F]F¯. Tetrahedron Lett. 2007, 48, 8632−8635. (307) Telu, S.; Chun, J.-H.; Simèon, F. G.; Lu, S.; Pike, V. W. Synthesis of mGluR5 PET radioligands through the radiofluorination of diaryliodonium tosylates. Org. Biomol. Chem. 2011, 9, 6629−6638. (308) Simèon, F. G.; Brown, A. K.; Zoghbi, S. S.; Patterson, V. M.; Innis, R. B.; Pike, V. W. Synthesis and Simple 18F-Labeling of 3Fluoro-5-(2-(2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile as a High Affinity Radioligand for Imaging Monkey Brain Metabotropic Glutamte Subtype-5 Receptors with Positron Emission Tomography. J. Med. Chem. 2007, 50, 3256−3266. (309) Brown, A. K.; Kimura, Y.; Zoghbi, S. S.; Simeon, F. G.; Liow, J.-S.; Kreisl, W. C.; Taku, A.; Fujita, M.; Pike, V. W.; Innis, R. B. Metabotropic Glutamate Subtype 5 Receptors Are Quantified in the Human Brain with a Novel Radioligand for PET. J. Nucl. Med. 2008, 49, 2042−2048. (310) Kimur, Y.; Simeon, F. G.; Hatazawa, J.; Mozley, P. D.; Pike, V. W.; Innis, R. B.; Fujita, M. Biodistribution and radiation dosimetry of a

positron emission tomographic ligand, 18F-SP203, to image metabotropic glutamate subtype 5 receptors in humans. Eur. J. Nucl. Med. Mol. Imaging 2010, 37, 1943−1949. (311) Hamill, T. G.; Krause, S.; Ryan, C.; Bonnefous, C.; Govek, S.; Seiders, T. J.; Cosford, N. D. P.; Roppe, J.; Kamenecka, T.; Patel, S.; Gibson, R. E.; Sanabria, S.; Riffel, K.; Eng, W.; King, C.; Yang, X.; Green, M. D.; O’Malley, S. S.; Hargreaves, R.; Burns, H. D. Synthesis, characterization, and first successful monkey imaging studies of metabotropic glutamate receptor subtype 5 (mGluR5) PET radiotracers. Synapse 2005, 56, 205−216. (312) Moon, B. S.; Kil, H. S.; Park, J. H.; Kim, J. S.; Park, J.; Chi, D. Y.; Lee, B. C.; Kim, S. E. Facile aromatic radiofluorination of [18F]flumazenil from diaryliodonium salts with evalutiaon fo their stability and selectivity. Org. Biomol. Chem. 2011, 9, 8346−8355. (313) Mandap, K. S.; Ido, T.; Kiyono, Y.; Kobayashi, M.; Lohith, T. G.; Mori, T.; Kasamatsu, S.; Kudo, T.; Okazawa, H.; Fujibayashi, Y. Development of microwave-based nucleophilic [18F]fluorination system and its application to the production of [18F]flumazenil. Nucl. Med. Biol. 2009, 36, 403−409. (314) Massaweh, G.; Schirrmacher, E.; la Fougere, C.; Kovacevic, M.; Wangler, C.; Jolly, D.; Gravel, P.; Reader, A. J.; Thiel, A.; Schirrmacher, R. Improved work-up procedure for the production of [18F]flumazenil and first results of its use with a high-resolution research tomograph in human stroke. Nucl. Med. Biol. 2009, 36, 721− 727. (315) Satoh, A.; Nagatomi, Y.; Hirata, Y.; Ito, S.; Suzuki, G.; Kimura, T.; Maehara, S.; Hikichi, H.; Satow, A.; Hata, M.; Ohta, H.; Kawamoto, H. Discovery and in vitro and in vivo profiles of 4fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-Nmethylbenzamide as novel class of an orally active metabotropic glutamate receptor 1 (mGluR1) antagonist. Bioorg. Med. Chem. Lett. 2009, 19, 5464−5468. (316) Xu, R.; Zanotti-Fregonara, P.; Zoghbi, S. S.; Gladding, R. L.; Woock, A. E.; Innis, R. B.; Pike, V. W. Synthesis and Evaluation in Monkey of [18F]4-Fluoro-N-methyl(4-(6-(methylamino)pyrimidin-4yl)thiazol-2-yl)benzamide ([18F]FIMX): A Promising Radioligand for PET Imaging of Brain Metabotropic Glutamate Receptor 1 (mGluR1). J. Med. Chem. 2013, 56, 9146−9155. (317) Jang, K. S.; Jung, Y.-W.; Sherman, P. S.; Quesada, C. A.; Gu, G.; Raffel, D. M. Synthesis and bioevaluation of [18F]4-fluoro-mhydroxyphenethyl-guanidine ([18F]4F-MHPG): A novel radiotracer for quantitative PET studies of cardiac sympathetic innervation. Bioorg. Med. Chem. Lett. 2013, 23, 1612−1616. (318) Jang, K. S.; Jung, Y.-W.; Gu, G.; Koeppe, R. A.; Sherman, P. S.; Quesada, C. A.; Raffel, D. M. 4-[18F]Fluoro-m-hydroxyphenethylguanidine: A Radiopharmaceutical for Quantifying Cardiac Sympathetic Nerve Density wth Positron Emisson Tomography. J. Med. Chem. 2013, 56, 7312−7323. (319) Edwards, R.; Westwell, A. D.; Daniels, S.; Wirth, T. Convenient Synthesis of Diaryliodonium Salts for the Production of [18F]F-DOPA. Eur. J. Org. Chem. 2015, 2015, 625−630. (320) Ichiishi, N.; Canty, A. J.; Yates, B. F.; Sanford, M. S. CuCatalyzed Fluorination fo Diaryliodonium Salts with KF. Org. Lett. 2013, 15, 5134−5137. (321) (a) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. Cu(II)Catalyzed Direct and Site-Selective Arylation of Indoles Under Mild Conditions. J. Am. Chem. Soc. 2008, 130, 8172−8174. (b) Harvey, J. S.; Simonovich, S. P.; Jamison, C. R.; MacMillan, D. W. C. Enantioselective α-Arylation of Carbonyls via Cu(I)-Bisoxazoline Catalysis. J. Am. Chem. Soc. 2011, 133, 13782−13785. (322) Casitas, A.; Canta, M.; Solá, M.; Costas, M.; Ribas, X. Nucleophilic Aryl Fluorination and Aryl Halide Exchange Mediated by a CuI/CuIII Catalytic Cycle. J. Am. Chem. Soc. 2011, 133, 19386− 19392. (323) Yao, B.; Wang, Z.-L.; Zhang, H.; Wang, D.-X.; Zhao, L.; Wang, M.-X. Cu(ClO4)2-Mediated Arene C-H Bond Halogenations of Azacalixaromatics Using Alkali Metal Halides as Halogen Sources. J. Org. Chem. 2012, 77, 3336−3340. 763

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

(324) Ichiishi, N.; Brooks, A. F.; Topczewski, J. J.; Rodnick, M. E.; Sanford, M. S.; Scott, P. J. H. Copper-Catalyzed [18F]Fluorination of (Mesityl) (aryl)iodonium Salts. Org. Lett. 2014, 16, 3224−3227. (325) Zlatopolskiy, B. Z.; Zischler, J.; Krapf, P.; Zarrad, F.; Urusova, E. A.; Kordys, E.; Endepols, H.; Neumaier, B. Copper-Mediated Aromatic Radiofluorination Revisited: Efficient Production of PET Tracers on a Preparative Scale. Chem. - Eur. J. 2015, 21, 5972−5979. (326) Satyamurthy, N.; Barrio, J. R. WO2010/117435 A2, 2010. (327) Hill, D. E.; Holland, J. P. Computational studies on hypervalent iodonium(III) compounds as activated precursors for 18 F radiofluorination of electron-rich arenes. Comput. Theor. Chem. 2015, 1066, 34−46. (328) Cardinale, J.; Ermert, J.; Humpert, S.; Coenen, H. H. Iodonium ylides for one-step, no-carrier-added radiofluorination of electron rich arenes, exemplified with 4-(([18F]fluorophenoxy)-phenylmethyl)piperidine NET and SERT ligands. RSC Adv. 2014, 4, 17293−17299. (329) Graskemper, J. W.; Wang, B.; Qin, L.; Neumann, K. D.; DiMagno, S. G. Unprecedented Directing Group Ability of Cyclophanes in Arene Fluorinations with Diaryliodonium Salts. Org. Lett. 2011, 13, 3158−3161. (330) Rotstein, B. H.; Stephenson, N. A.; Vasdev, N.; Liang, S. H. Spirocyclic hypervalent iodine(III)-mediated radiofluorination of nonactivated and hindered aromatics. Nat. Commun. 2014, 5, 4365. (331) Wang, L.; Jacobson, O.; Avdic, D.; Rotstein, B. H.; Weiss, I. D.; Collier, L.; Chen, X.; Vasdev, N.; Liang, S. H. Ortho-Stabilized 18FAzido Click Agents and their Application in PET Imaging with SingleStranded DNA Aptamers. Angew. Chem., Int. Ed. 2015, 54, 12777− 12781. (332) Stephenson, N. A.; Holland, J. P.; Kassenbrock, A.; Yokell, D. L.; Livni, E.; Liang, S. H.; Vasdev, N. Iodonium Ylide-Mediated Radiofluorinatin of 18F-FPEB and Validation for Human Use. J. Nucl. Med. 2015, 56, 489−492. (333) Calderwood, S.; Collier, T. L.; Gouverneur, V.; Liang, S. H.; Vasdev, N. Synthesis of 18F-Arenes from Spirocyclic Iodonium(III) Ylides via Continuous-Flow Microfluidics. J. Fluorine Chem. 2015, 178, 249−253. (334) Meada, M.; Fukumura, T.; Kojima, M. The Dimethylsulfonium Moiety as a leaving Group in Aromatic Radiofluorination using Tetran-butylammonium [18F]Fluoride. Appl. Radiat. Isot. 1987, 38, 307− 310. (335) Mu, L.; Fischer, C. R.; Holland, J. P.; Becaud, J.; Schubiger, P. A.; Schibli, R.; Ametamey, S. M.; Graham, K.; Stellfeld, T.; Dinkelborg, L. M.; Lehmann, L. 18F-Radiolabeling of Aromatic Compounds Using Triarylsulfonium Salts. Eur. J. Org. Chem. 2012, 2012, 889−892. (336) Sander, K.; Gendron, T.; Yiannaki, E.; Cybulska, K.; Kalber, T. L.; Lythgoe, M. F.; Arstad, E. Sulfonium Salts as Leaving Groups for Aromatic Labelling of Drug-like Small Molecules with Fluorine-18. Sci. Rep. 2015, 5, 9941. (337) Chun, J.-H.; Morse, C. L.; Chin, F. T.; Pike, V. W. No-carrieradded [18F]fluoroarenes from the radiofluorination of diaryl sulfoxides. Chem. Commun. 2013, 49, 2151−2153. (338) Way, J. D.; Wuest, F. Automated radiosynthesis of no-carrieradded 4-[18F]fluoroiodobenzene: a versatile building block in 18F radiochemistry. J. Labelled Compd. Radiopharm. 2014, 57, 104−109. (339) Simeon, F. G.; Lu, S.; Pike, V. W. Diarylselenoxides as precursors to no-carrier-added [18F]fluoroarenes. J. Labelled Compd. Radiopharm. 2015, 58, S149. (340) Dadiboyena, S.; Simeon, F. G.; Lu, S.; Cai, L.; Pike, V. W. (Pyridinyl-phenyl)selenoxides and (pyridinyl-phenyl)selenones as precursors for preparing [18F]fluoropyridines from [18F]fluoride ion. J. Labelled Compd. Radiopharm. 2015, 58, S148. (341) Gao, Z.; Lim, Y. H.; Tredwell, M.; Li, L.; Verhoog, S.; Hopkinson, M.; Kaluza, W.; Collier, T. L.; Passchier, J.; Huiban, M.; Gouverneur, V. Metal-Free Oxidative Fluorination of Phenols with [18F]Fluoride. Angew. Chem., Int. Ed. 2012, 51, 6733−6737. (342) Kurti, L.; Herczegh, P.; Visy, J.; Simonyi, M.; Antus, S.; Pelter, A. New insights into the mechanism of phenolic oxidation with phenyliodonium(III) reagents. J. Chem. Soc., Perkin Trans. 1 1999, 4, 379−380.

(343) Kita, Y.; Takada, T.; Tohma, H. Hypervalent iodine reagents in organic synthesis: Nucleophilic substitution of p-substituted phenol ethers. Pure Appl. Chem. 1996, 68, 627−630. (344) Hanway, P. J.; Winter, A. H. Phenyloxenium Ions: More Like Phenylnitrenium Ions than Isoelectronic Phenylnitrenes. J. Am. Chem. Soc. 2011, 133, 5086−5093. (345) Bienvenu, A.; Barthelemy, A.; Boichut, S.; Marquet, B.; Billard, T.; Langlois, B. R. Synthesis of 4-Fluorophenols from 4-tertButylphenols and Fluoride Sources Under Oxidative Conditions. Collect. Czech. Chem. Commun. 2002, 67, 1467−1478. (346) Buckingham, F.; Calderwood, S.; Checa, B.; Keller, T.; Tredwell, M.; Collier, T. L.; Newington, I. M.; Bhalla, R.; Glaser, M.; Gouverneur, V. Oxidative Fluorination of N-Arylsulfonamides. J. Fluorine Chem. 2015, 180, 33−39. (347) Reischl, G.; Kienzle, G. J.; Machulla, H.-J. Electrochemical radiofluorination: Labeling of benzene with [18F]fluoride by nucleophilic substitution. J. Radioanal. Nucl. Chem. 2002, 254, 409− 411. (348) Eberson, L.; Blum, Z.; Helgée, B.; Nyberg, K. Radical ion reactivity-I: Application of the dewar-zimmerman rules to certain reactions of radical anions and cations. Tetrahedron 1978, 34, 731− 739. (349) Reishcl, G.; Kienzle, G. J.; Machulla, H.-J. Electrochemical radiofluorination. Part 2. Anodic monofluorination of substituted benzenes using [18F]fluoride. Appl. Radiat. Isot. 2003, 58, 679−683. (350) Kienzle, G. J.; Reischl, G.; Machulla, H.-J. Electrochemical radiofluorination. 3. Direct labeling of phenylalanine derivatives with [18F]fluoride after anodic oxidation. J. Labelled Compd. Radiopharm. 2005, 48, 259−273. (351) He, Q.; Wang, Y.; Alfeazi, I.; Sadeghi, S. Electrochemical nucleophilic synthesis of di-tert-butyl-(4-[18F]fluoro-1,2-phenylene)dicarbonate. Appl. Radiat. Isot. 2014, 92, 52−57. (352) Lyons, T. W.; Sanford, M. S. Palladium-Catalyzed LigandDirected C-H Functionalization Reactions. Chem. Rev. 2010, 110, 1147−1169. (353) Hull, K. L.; Anani, W. Q.; Sanford, M. S. Palladium-Catalyzed Fluorination fo Carbon-hydrogen Bonds. J. Am. Chem. Soc. 2006, 128, 7134−7135. (354) Wang, X.; Mei, T.-S.; Yu, J.-Q. Versatile Pd(OTf)2•2H2OCatalyzed ortho-Fluorination Using NMP as a Promoter. J. Am. Chem. Soc. 2009, 131, 7520−7521. (355) Lee, E.; Kamlet, A. S.; Powers, D. C.; Neumann, C. N.; Boursalian, G. B.; Furuya, T.; Choi, D. C.; Hooker, J. M.; Ritter, T. A Fluoride-Derived Electrophilic Late-Stage Fluorination Reagent for PET Imaging. Science 2011, 334, 639−642. (356) Furuya, T.; Ritter, T. Carbon-Fluorine Reductive Elimination from a High-Valent Palladium Fluoride. J. Am. Chem. Soc. 2008, 130, 10060−10061. (357) Furuya, T.; Benitez, D.; Tkatchouk, E.; Strom, A. E.; Tang, P.; Goddard, W. A., III; Ritter, T. Mechanism of C-F Reductive Elimination from Palladium(IV) Fluorides. J. Am. Chem. Soc. 2010, 132, 3793−3807. (358) Furuya, T.; Kaiser, H. M.; Ritter, T. Palladium-Mediated Fluorination of Arylboronic Acids. Angew. Chem., Int. Ed. 2008, 47, 5993−5996. (359) Brandt, J. R.; Lee, E.; Boursalian, G. B.; Ritter, T. Mechanism of electrophilic fluorination with Pd(IV): fluoride capture and subsequent oxidative fluoride transfer. Chem. Sci. 2014, 5, 169−179. (360) Kamlet, A. S.; Neumann, C. N.; Lee, E.; Carlin, S. M.; Moseley, C. K.; Stephenson, N.; Hooker, J. M.; Ritter, T. Application of Palladium-Mediated 18F-Fluorination to PET Radiotracer Development: Overcoming Hurdles to Translation. PLoS One 2013, 8, e59187. (361) Lee, E.; Hooker, J. M.; Ritter, T. Nickel-Mediated Oxidative Fluorination for PET with Aqueous [18F] Fluoride. J. Am. Chem. Soc. 2012, 134, 17456−17458. (362) Ren, H.; Wey, H.-Y.; Strebl, M.; Neelamegam, R.; Ritter, T.; Hooker, J. M. Synthesis and Imaging Validation of [18F]MDL100907 Enabled by Ni-Mediated Fluorination. ACS Chem. Neurosci. 2014, 5, 611−615. 764

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

(363) Grushin, V. V. Palladium Fluoride Complees: One More Step toward Metal-Mediated C-F Bond Formation. Chem. - Eur. J. 2002, 8, 1006−1014. (364) Marshall, W. J.; Grushin, V. V. Palladium(II) and Palladium(0) Complexes of BINAP(O) (2-(Diphenylphosphino)-2′-(diphenylphosphinyl)-1,1′-binaphthyl). Organometallics 2003, 22, 555−562. (365) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; GarciaFortanet, J.; Kinzel, T.; Buchwald, S. L. Formation of ArF from LPdAr(F): Catalytic Conversion of Aryl Triflates to Aryl Fluorides. Science 2009, 325, 1661−1664. (366) Noël, T.; Maimone, T. J.; Buchwald, S. L. Accelerating Palladium-Catalyzed C−F Bond Formation: Use of a Microflow Packed-Bed Reactor. Angew. Chem., Int. Ed. 2011, 50, 8900−8903. (367) Cardinale, J.; Ermert, J.; Kugler, F.; Helfer, A.; Brandt, M. R.; Coenen, H. H. Carrier-effect on palladium-catalyzed, nucleophilic 18Ffluorination of aryltriflates. J. Labelled Compd. Radiopharm. 2012, 55, 450−453. (368) Qiao, J. X.; Lam, P. Y. S. Copper-Promoted CarbonHeteroatom Bond Cross-Coupling with Boronic Acids and Derivatives. Synthesis 2011, 6, 829−856. (369) Fier, P. S.; Luo, J.; Hartwig, J. F. Copper-Mediated Fluorination of Arylboronate Esters. Identification of a Copper(III) Fluoride Complex. J. Am. Chem. Soc. 2013, 135, 2552−2559. (370) Ye, Y.; Sanford, M. S. Mild Copper-Mediated Fluorination of Aryl Stannanes and Aryl Trifluoroborates. J. Am. Chem. Soc. 2013, 135, 4648−4651. (371) Tredwell, M.; Preshlock, S. M.; Taylor, N. J.; Gruber, S.; Huiban, M.; Passchier, J.; Mercier, J.; Genicot, C.; Gouverneur, V. A General Copper-Mediated Nucleophilic 18F Fluorination of Arenes. Angew. Chem., Int. Ed. 2014, 53, 7751−7755. (372) Niwa, T.; Ochiai, H.; Watanabe, Y.; Hosoya, T. Ni/CuCatalyzed Defluoroborylation of Fluoroarenes for Diverse C-F Bond Functionalizations. J. Am. Chem. Soc. 2015, 137, 14313−14318. (373) Mossine, A. V.; Brooks, A. F.; Makaravage, K. J.; Miller, J. M.; Ichiishi, N.; Sanford, M. S.; Scott, P. J. H. Syntheis of [18F]Arenes via the Copper-Mediated [18F]Fluorination of Boronic Acids. Org. Lett. 2015, 17, 5780−5783. (374) Harsanyi, A.; Sandford, G. 2-Fluoromalonate Esters: Fluoroaliphatic Building Blocks for the Life Sciences. Org. Process Res. Dev. 2014, 18, 981−992. (375) Matthews, P. M.; Rabiner, E. A.; Passchier, J.; Gunn, R. N. Positron emission tomography molecular imaging for drug development. Br. J. Clin. Pharmacol. 2012, 73, 175−186. (376) Ido, T.; Irie, T.; Kasida, Y. Isotope Exchange with 18F on Superconjugate System. J. Labelled Compd. Radiopharm. 1979, 16, 153−154. (377) Angelini, G.; Speranza, M.; Wolf, A. P.; Shiue, C.-Y. Synthesis of N-(α,α,α-tri[18F]fluoro-m-toyl)piperazine. A Potent Serotonin Agonist. J. Labelled Compd. Radiopharm. 1990, 28, 1441−1448. (378) Kilbourn, M. R.; Pavia, M. R.; Gregor, V. E. Synthesis of Fluorine-18 Labeled GABA Uptake Inhibitors. Appl. Radiat. Isot. 1990, 41, 823−828. (379) Hammadi, A.; Crouzel, C. Synthesis of [18F]-(S)-Fluoxetine: A Selective Serotonine Uptake Inhibitor. J. Labelled Compd. Radiopharm. 1993, 33, 703−710. (380) Das, M. K.; Mukherjee, J. Radiosynthesis of [F-18]Fluoxetine as a Potential radiotracer for Serotonin Reuptake Sites. Appl. Radiat. Isot. 1993, 44, 835−842. (381) Mukherjee, J.; Das, M. K.; Yang, Z.-Y.; Lew, R. Evaluation of the Binding of the Radiolabeled Antidepressant Drug, 18F-Fluoxetine in the Rodent Brain: An In Vitro and In Vivo Study. Nucl. Med. Biol. 1998, 25, 605−610. (382) Prabhakaran, J.; Underwood, M. D.; Parsey, R. V.; Arango, V.; Majo, V. J.; Simpson, N. R.; Van Heertum, R.; Mann, J. J.; Kumar, J. S. D. Synthesis and in vivo evaluation of [18F]-4-[5-(4-methylphenyl)-3(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide as a PET imaging probe for COX-2 expression. Bioorg. Med. Chem. 2007, 15, 1802−1807.

(383) Grakauskas, V. Aqueous Fluorination of Carboxylic Acid Salts. J. Org. Chem. 1969, 34, 2446−2450. (384) Patrick, T. B.; Johri, K. K.; White, D. H. Fluorodecarboxylation with Xenon Difluoide. J. Org. Chem. 1983, 48, 4158−4159. (385) Patrick, T. B.; Johri, K. K.; White, D. H.; Bertrand, W. S.; Mokhtar, R.; Kilbourn, M. R.; Welch, M. J. Replacement of the carboxylic acid function with fluorine. Can. J. Chem. 1986, 64, 138− 141. (386) Patrick, T. B.; Khazaeli, S.; Nadji, S.; Hering-Smith, K.; Reif, D. Mechanistic Studies of Fuorodecarboxylation with Xenon Difluoride. J. Org. Chem. 1993, 58, 705−708. (387) Ramsden, C. A.; Shaw, M. M. Fluorodecarboxylation, rearrangement and cyclisation: the influence of structure and environment on the reaction of carboxylic acids with xenon difluoride. Tetrahedron Lett. 2009, 50, 3321−3324. (388) Rueda-Becerril, M.; Sazepin, C. C.; Leung, J. C. T.; Okbinoglu, T.; Kennepohl, P.; Paquin, J.-F.; Sammis, G. M. Fluorine Transfer to Alkyl Radicals. J. Am. Chem. Soc. 2012, 134, 4026−4029. (389) Leung, J. C. T.; Chatalova-Sazepin, C.; West, J. G.; RuedaBecerril, M.; Paquin, J.-F.; Sammis, G. M. Photo-fluorodecarboxylation of 2-Aryloxy and 2-Aryl Carboxylic Acids. Angew. Chem., Int. Ed. 2012, 51, 10804−10807. (390) Mizuta, S.; Stenhagen, I. S. R.; O’Duill, M.; Wolstenhulme, J.; Kirjavainen, A. K.; Forsback, S. J.; Tredwell, M.; Sandford, G.; Moore, P. R.; Huiban, M.; Luthra, S. K.; Passchier, J.; Solin, O.; Gouverneur, V. Catalytic Decarboxylation Fluorination for the Synthesis of Tri- and Difluoromethyl Arenes. Org. Lett. 2013, 15, 2648−2651. (391) Yin, F.; Wang, Z.; Li, Z.; Li, C. Silver-Catalyzed Decarboxylative Fluorination of Aliphatic Carboxylic Acids in Aqueous Solution. J. Am. Chem. Soc. 2012, 134, 10401−10404. (392) MacNeil, J. G., Jr.; Burton, D. J. Generation of trifluoromethylcopper from chlorodifluoroacetate. J. Fluorine Chem. 1991, 55, 225−227. (393) Duan, J.-X.; Su, D.-B.; Chen, Q.-Y. Trifluoromethylation of organic halides with methyl halodifluoroacetates − a process via difluorocarbene and trifluoromethide intermediates. J. Fluorine Chem. 1993, 61, 279−284. (394) Huiban, M.; Tredwell, M.; Mizuta, S.; Wan, Z.; Zhang, X.; Collier, T. L.; Gouverneur, V.; Passchier, J. A broadly applicable [18F]trifluoromethylation of aryl and heteroaryl iodides for PET imaging. Nat. Chem. 2013, 5, 941−944. (395) Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. A Broadly Applicable Copper Reagent for Trifluoromethylations and Perfluoroalkylations of Aryl Iodides and Bromides. Angew. Chem., Int. Ed. 2011, 50, 3793−3798. (396) Tomashenko, O. A.; Escudero-Adán, E. C.; Belmonte, M. M.; Grushin, V. V. Simple, Stable, and Easily Accessible Well-Defined CuCF3 Aromatic Trifluoromethylating Agents. Angew. Chem., Int. Ed. 2011, 50, 7655−7659. (397) Litvinas, N. D.; Fier, P. S.; Hartwig, J. F. A General Strategy for the Perfluoroalkylation of Arenes and Arylbromides by Using Arylboronate Esters and [(phen)CuRF]. Angew. Chem., Int. Ed. 2012, 51, 536−539. (398) Mormino, M. G.; Fier, P. S.; Hartwig, J. F. Copper-Mediated Perfluoroalkylation of Heteroaryl Bromides with (phen)CuRF. Org. Lett. 2014, 16, 1744−1747. (399) Lishchynskyi, A.; Mazloomi, Z.; Grushin, V. V. Trifluoromethylation and Pentafluoroethylation of Vinylic Halides with LowCost RfH-Derived CuRf (Rf = CF3, C2F5). Synlett 2014, 26, 45−50. (400) Ambler, B. R.; Peddi, S.; Altman, R. A. Ligand-Controlled Regioselective Copper-Catalyzed Trifluoromethylation To Generate (Trifluoromethyl)allenes. Org. Lett. 2015, 17, 2506−2509. (401) Panferova, L. I.; Miloserdov, F. M.; Lishchynskyi, A.; Belmonte, M. M.; Benet-Buchhol, J.; Grushin, V. V. Well-Defined CuC2F5 Complexes and Pentafluoroethylation of Acid Chlorides. Angew. Chem., Int. Ed. 2015, 54, 5218−5222. (402) van der Born, D.; Herscheid, J. D. M.; Orru, R. V. A.; Vugts, D. J. Efficient synthesis of [18F]trifluoromethane and its applicaton in the synthesis of PET tracers. Chem. Commun. 2013, 49, 4018−4020. 765

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766

Chemical Reviews

Review

(403) Rühl, T.; Rafique, W.; Lien, V. T.; Riss, P. J. Cu(I)-mediated F-trifluoromethylation of arenes: Rapid synthesis of 18F-labeled trifluoromethyl arenes. Chem. Commun. 2014, 50, 6056−6059. (404) van der Born, D.; Sewing, C.; Herscheid, J. D. M.; Windhorst, A. D.; Orru, R. V. A.; Vugts, D. J. A Universal Procedure for the [18F]Trifluoromethylation of Aryl Iodides and Aryl Boronic Acids with Highly Improved Specific Activity. Angew. Chem., Int. Ed. 2014, 53, 11046−11050. (405) Prakash, G. K. S.; Wang, F.; Zhang, Z.; Haiges, R.; Rahm, M.; Christe, K. O.; Mathew, T.; Olah, G. A. Long-Lived trifluoromethanide Anion: A Key Intermediate in Nucleophilic Trifluoromethylations. Angew. Chem., Int. Ed. 2014, 53, 11575−11578. (406) Zanardi, A.; Novikov, M. A.; Martin, E.; Benet-Buchholz, J.; Grushin, V. V. Direct Cupration of Fluoroform. J. Am. Chem. Soc. 2011, 133, 20901−20913. (407) Ivashkin, P.; Lemonnier, G.; Cousin, J.; Grégoire, V.; Labar, D.; Jubault, P.; Pannecoucke, X. [18F]CuCF3: A [18F]Trifluoromethylating Agent for Arylboronic Acids and Aryl Iodides. Chem. - Eur. J. 2014, 20, 9514−9518. (408) Landelle, G.; Panossian, A.; Leroux, F. R. Trifluoromethyl Ethers and − Thioethers as Tools for Medicinal Chemistry and Drug Discovery. Curr. Top. Med. Chem. 2014, 14, 941−951. (409) Boiko, V. N. Aromatic and heterocyclic perfluoroalkyl sulfides. Methods of preparation. Beilstein J. Org. Chem. 2010, 6, 880−921. (410) Leroux, F. R.; Manteau, B.; Vors, J.-P.; Pazenok, S. Trifluoromethyl ethers-synthesis and properties of an unusual substituent. Beilstein J. Org. Chem. 2008, 4, 13. (411) Khotavivattana, T.; Verhoog, S.; Tredwell, M.; Pfeifer, L.; Calderwood, S.; Wheelhouse, K.; Collier, T. L.; Gouverneur, V. 18FLabeling of Aryl-SCF3, -OCF3, and − OCHF2 with [18F]Fluoride. Angew. Chem., Int. Ed. 2015, 54, 9991−9995. (412) Huang, X.; Liu, W.; Ren, H.; Neelamegam, R.; Hooker, J. M.; Groves, J. T. Late Stage Benzylic C-H Fluorination with [18F]Fluoride for PET Imaging. J. Am. Chem. Soc. 2014, 136, 6842−6845. (413) Huang, X.; Liu, W.; Hooker, J. M.; Groves, J. T. Targeted Fluorination with the Fluoride Ion by Manganese-Catalyzed Decarboxylation. Angew. Chem., Int. Ed. 2015, 54, 5241−5245. (414) Graham, T. J. A.; Lambert, R. F.; Ploessl, K.; Kung, H. F.; Doyle, A. G. Enantioselective Radiosynthesis of Positron Emission Tomography (PET) Tracers Containing [18F]Fluorohydrins. J. Am. Chem. Soc. 2014, 136, 5291−5294. (415) Zheng, J.; Wang, L.; Lin, J.-H.; Xiao, J.-C.; Liang, S. H. Difluorocarbene-Derived Trifluoromethylthiolation and [ 18 F]Trifluoromethylthiolation of Aliphatic Electrophiles. Angew. Chem., Int. Ed. 2015, 54, 13236−13240. 18

766

DOI: 10.1021/acs.chemrev.5b00493 Chem. Rev. 2016, 116, 719−766