Article pubs.acs.org/accounts
[18F]-Organotrifluoroborates as Radioprosthetic Groups for PET Imaging: From Design Principles to Preclinical Applications David M. Perrin* Chemistry Department, 2036 Main Mall, University of British Columbia, Vancouver, BC V6T 1Z1, Canada S Supporting Information *
CONSPECTUS: Positron emission tomography (PET) is revolutionizing our ability to visualize in vivo targets for target validation and personalized medicine. Of several classes of imaging agents, peptides afford high affinity and high specificity to distinguish pathologically distinct cell types by the presence of specific molecular targets. Of various available PET isotopes, [18F]-fluoride ion is preferred because of its excellent nuclear properties and on-demand production in hospitals at Curie levels. However, the short half-life of 18F and its lack of reactivity in water continue to challenge peptide labeling. Hence, peptides are often conjugated to a metal chelator for late-stage, one-step labeling. Yet radiometals, while effective, are neither as desirable nor as available as [18F]fluoride ion. Despite considerable past success in identifying semifeasible radiosyntheses, significant challenges continue to confound tracer development. These interrelated challenges relate to (1) isotope/prosthetic choice; (2) bioconjugation for high affinity; (3) high radiochemical yields, (4) specific activities of >1 Ci/μmol to meet FDA microdose requirements; and (5) rapid clearance and in vivo stability. These enduring challenges have been extensively highlighted, while a single-step, operationally simple, and generally applicable means of labeling a peptide with [18F]-fluoride ion in good yield and high specific activity has eluded radiochemists and nuclear medicine practitioners for decades. Radiosynthetic ease is of primordial importance since multistep labeling reactions challenge clinical tracer production. In the past decade, as we sought to meet this challenge, appreciation of reactions with aqueous fluoride led us to consider organotrifluoroborate (RBF3−) synthesis as a means of rapid aqueous peptide labeling. We have applied principles of mechanistic chemistry, knowledge of chemical reactivity, and synthetic chemistry to design stable RBF3−s. Over the past 10 years, we have developed several new [18F]-RBF3− radioprosthetic groups, all of which guarantee radiosynthetic ease while in most cases providing high tumor:nontumor (T:NT) ratios and moderate-to-high tumor uptake. Although others have developed methods for labeling of peptides with [18F]-silylfluorides or [18F]-Al-NOTA chelates, this Account focuses on the synthesis of [18F]-organotrifluoroborates. In this Account, I detail mechanistic, kinetic, thermodynamic, synthetic, and radiosynthetic approaches that enabled the translation of fundamental principles regarding the chemistry of RBF3−s into a tantalizingly close realization of a clinical application of an [18F]-organotrifluoroborate−peptide conjugate for imaging of neuroendocrine tumors and the generalization of this method for labeling of several other peptides.
■
resolution;4 clean nuclear decay (∼97% β+ emission); facile production (18O(p,n)18F); and on-demand production in large quantities (>1 Ci for ∼$400) in >400 medical cyclotrons in North America. Increased cyclotron power now enables the production of >25 Ci, while many clinics are licensed to produce >10 Ci daily.
INTRODUCTION
Positron emission tomography (PET) imaging is playing an increasingly important role in preclinical target evaluation and noninvasive clinical cancer diagnosis.1−3 Compared to MRI or SPECT, PET combines very high sensitivity with dynamic spatiotemporal resolution to observe biodistribution and clearance. Of several useful PET radioisotopes, 18F is preferred for several reasons: a moderate half-life (109.8 min), which is long enough for synthesis but short enough to minimize patient radiation dose; low β+ emission energy for superior image © XXXX American Chemical Society
Received: August 31, 2015
A
DOI: 10.1021/acs.accounts.5b00398 Acc. Chem. Res. XXXX, XXX, XXX−XXX
Article
Accounts of Chemical Research
Figure 1. (A) [18F]-AMBF3−-octreotate (75 nmol), labeled in one step: 25 min, >3 Ci/μmol, RCY > 25% without HPLC purification. (B, C) PET images of blocked and unblocked mice, respectively, showing high-contrast tumor images with predominant bladder clearance.
conjugates are easily labeled in water.23 Indeed, the great ease of radiometalation overrides many potential disadvantages, including lower resolution, lower specific activity, increased radiotoxicity, higher costs, challenges to scalable production, and off-target transchelation in vivo. Notionally, if 18F labeling were as easy as radiometalation, access to and production of radiotracers would expand dramatically. A survey of the vast literature led us to articulate the following attributes for ideal 18 F PET tracer production:
While PET imaging is expanding into pharmacology, it is used clinically in neurology, cardiology, and mainly oncology. Early on, [18F]-deoxyglucose (FDG), [18F]-thymidine, and [18F]-misonidazole provided images based on heightened metabolic flux or hypoxia characteristic of many cancers. Yet because cancers are increasingly characterized by the presence of distinct extracellular targets, new target-specific imaging agents are needed to guide diagnosis and treatment. While new 18 F-labeling methods for small molecules serve diverse needs, our interest lies in larger molecules such as peptides, which predictably exhibit high affinity and specificity for many targets.5 Advances in proteomics and combinatorial screens6,7 have provided peptidic tracers that distinguish pathologically distinct molecular targets, which is impossible to achieve with FDG.8 Examples of peptide tracers include octreotate,9,10 bombesin,11 and RGD.12 The peculiar chemistry of fluorine has posed historic challenges to radiolabeling, particularly for polyfunctional, water-soluble macromolecules like peptides. Electrophilic fluorinating reagents (e.g., XeF2, NFSI, and F-TEDA) react readily with phenols and indoles and destructively with thiols, disulfides, and thioethers.13 Problematically, N−F reagents are generated at low specific activity (e.g., 25%); 7. high radiochemical purity (>98%); 8. high specific activity (>3 Ci/μmol); 9. in vivo stability; 10. generally applicable; 11. easy bioconjugation to provide stockable precursors for labeling of microgram quantities. In 2004, when we sought to meet these conditions, contemporary publications summarized the state of biomolecule labeling as follows: “All fluorine-18-labeled prosthetic groups described so far have been prepared using the relatively restricted labeling strategies offered by homoaromatic and aliphatic substitution reactions.”17 “No new 18F-labelled fluorinating reagents have appeared over the past ten years and efforts have been mainly concentrated on the development of small 18F-labelled precursors or on the improvement of radiolabeling methods.”24 In seeking new methods, we eschewed C−F bond formation in favor of B−F bond formation, hypothesizing that an organotrifluoroborate, which can be readily prepared in water, would afford late-stage, one-step labeling. A decade later, our work on [18F]-organotrifluoroborates would provide a means of 18F labeling that satisfies the aforementioned conditions, typified by 1. 2. 3. 4. 5.
B
DOI: 10.1021/acs.accounts.5b00398 Acc. Chem. Res. XXXX, XXX, XXX−XXX
Article
Accounts of Chemical Research
Figure 2. Mechanism of acid-catalyzed ArBF3− formation. The relative stabilities of intermediates 2a, 3, 4, 4a, and 5 are unknown, and relative arrow lengths reflect a supposition that electron-deficient boranes are less stable than borates.
Figure 3. Mechanism of ArBF3− solvolysis.
Figure 4. (left) Representative 19F NMR spectra showing ArBF3− solvolysis to fluoride ion without any intermediates. (right) Rate fit of the solvolysis data. Adapted from ref 30. Copyright 2008 American Chemical Society.
the radiosynthesis of [18F]-AMBF3−-octreotate, to provide high-contrast tumor images and bladder clearance (Figure 1).25 The development of such [18F]-organotrifluoroborate bioconjugates for single-step labeling is the subject of this Account.
ArB(OH)2 + 2HF + KF ⇄ ArBF3−K+ + 2H 2O
(1)
Pinacolate esters and borimidines are also fluoridated, either directly or following solvolysis to give the boronic acid, as shown mechanistically in Figure 2. The stoichiometry of eq 1 demands that the ArB(OH)2 concentration be lower than the fluoride ion concentration. A priori, this contradicted standard radiosynthetic logic, where large amounts of precursor(s) must be used to increase the reaction rate with limiting fluoride ion. Moreover, a prevailing (yet erroneous) view held that the total fluoride ion in a sample of NCA [18F]-fluoride ion would be far too low to afford sufficient quantities of [18F]-ArBF3− via stepwise addition of three fluoride ions. Prevailing opinion notwithstanding, the fluoride ion concentration need only be high enough to ensure that the [18F]-ArBF3− forms to a sufficient extent (RCY > 25%) at reasonable specific activity. Indeed, ArBF3−s form rapidly in reasonable yield at ∼10 mM fluoride, a concentration that is achievable with NCA [18F]-fluoride ion,27 while microreactors deliver submolar concentrations.28 Whereas the mechanism (Figure 2) implies steady-state formation of intermediate boranes (3 and 5) or -ates (2 and 4), no mono- or
■
AQUEOUS FLUORIDATION AND IN VIVO KINETIC STABILITY Initially, we anticipated three advantages of organotrifluoroborates: (1) as polar, hydrophilic salts anions, they would enhance in vivo clearance to provide higher-contrast images compared with lipophilic organofluorides, which retard clearance; (2) the strong B−F bond, being bio-orthogonal, would be metabolically stable; and (3) they are nontoxic.26 In addition, since peptides are deprotected in concentrated HF or in 80% trifluoroacetic acid (TFA) (pH < 0) and HPLC-purified in 0.5% TFA (pH 1.3), acid-catalyzed (pH 2−3) organotrifluoroborate synthesis would pose no problems. Two concerns befall all radiotracers: (1) radiolabeling must be kinetically rapid and sufficiently favorable thermodynamically to ensure reasonable yields, and (2) the tracer must be stable in vivo. To address these issues, we studied the synthesis of aryltrifluoroborates (ArBF3−), wherein three fluoride ions condense with an arylboronic acid (eq 1): C
DOI: 10.1021/acs.accounts.5b00398 Acc. Chem. Res. XXXX, XXX, XXX−XXX
Article
Accounts of Chemical Research
Figure 5. Resonance forms of cumyl cation and the analogous difluoroborane. Adapted from ref 30. Copyright 2008 American Chemical Society.
Figure 6. Synthesis of tetraphenylpinacolate ester 7 and borimidine 8, which can be converted to NHS esters and then to the kinetically stable ArBF3−.
Figure 7. Structure of ArB(dan)−bis(RGD) 9 and one-step radiofluoridation to give [18F]-ArBF3−-bis(RGD) (10). Adapted with permission from ref 35. Copyright 2013 Elsevier.
highly favored (even at 25 mM ArBF3− or 100 mM F).27,30 At high dilution (in vivo), the equilibrium ArBF3− concentration approaches zero. Hence, ArBF3− solvolysis is solely under kinetic control (as is the case for all chemical bonds in all radiotracers). Nevertheless, according to the principle of microscopic reversibility, solvolysis must proceed through intermediates 5−2 in Figure 3, which are identical to 2−5 in Figure 2.30 Because NMR spectroscopy is sensitive to 19F, we used 19F NMR spectroscopy to measure the kinetic stability of a series of ArBF3−s at pH 7. Surprisingly, certain ArBF3−s solvolyze rapidly. For example, p-aminosulfonylphenyl-BF3− solvolyzes with a half-life of 22 min (Figure 4), while p-anisyl-BF3− solvolyzes upon mixing.30 Solvolysis follows a pseudo-first-order rate law governed by loss of one fluoride ion, where kobs = k1 (Figure 3). Notably,
difluoroborane/ate has ever been isolated at pH 7, suggesting that only the trifluoroborate is stable. Vis-à-vis in vivo stability, we reasoned that all bond scissions, including B−F bond scission, must be thermodynamically favorable at high dilution (e.g., in vivo tracer levels) simply because of a negligible back reaction, thereby rendering the reaction irreversible. Moreover, at pH > 4, liberated HF is deprotonated, causing the reaction to be even more irreversible. This is appreciated by considering Keq for ArBF3− solvolysis (eq 2): Keq =
[ArB(OH)2 ][F−]3 ≈ 0.006 M−3 at pH 7 [ArBF3−]
(2)
Although the free energy (ΔG°′) is estimated to be uphill by 3 kcal/mol,29 because Keq is third-order in fluoride, solvolysis is D
DOI: 10.1021/acs.accounts.5b00398 Acc. Chem. Res. XXXX, XXX, XXX−XXX
Article
Accounts of Chemical Research
Figure 8. (left) PET-CT image of [18F]-10 injected into tumor-bearing mice: unblocked mouse (left) and blocked mouse control (right). T denotes tumor and B bladder. (right) Biodistribution data. Adapted with permission from ref 35. Copyright 2013 Elsevier.
intermediates 2−5 could not be detected by 19F NMR spectroscopy, consistent with their predicted instability at pH 7. This has important ramifications for radiosynthesis: only the [18F]-ArBF3− can be isolated.
combined with 36 mCi of NCA [18F]-fluoride ion and 30 nmol of [19F]-fluoride ion. Solvent was removed in vacuo, whereupon the reaction mixture was basified. [18F]-10 was separated from both [18F]-fluoride ion and 9 by HPLC in ∼10% RCY. This one-step method is considerably more efficient and much quicker than that reported in 2012 by Chin et al.,20 who described state-of-the-art labeling of dimeric RGD. In their case, the required steps included (1) azeotropic drying of [18F]KF (1 Ci), (2) nucleophilic substitution in dry MeCN, (3) ester saponification, (4) a second azeotropic drying, (5) esterification, (6) HPLC purification, (7) coupling to bis(RGD) peptide (2 mg), and (8) a final HPLC purification, requiring a total of 170 min to provide radiotracer at 3 ± 2 Ci/ μmol in 16% RCY (see the Supporting Information). For in vivo testing, [18F]-10 was injected into two U87Mxenografted mice. The unblocked mouse showed specific tumor uptake, while the blocked mouse, which had been injected with a large excess of unlabeled bis(RGD), showed diminished uptake (Figure 8). Little bone uptake was observed, confirming the in vivo stability of [18F]-10, which cleared predominantly to the bladder. The tumor:muscle and tumor:blood ratios of 9 and 6, respectively, were comparable to those in other reports, yet the tumor uptake was low, 0.5% injected dose per gram of tissue (ID/g), likely because of rapid clearance of the anionic ArBF3−. Although the effective specific activity was low (0.3 Ci/ μmol), this was due to coelution of ArB(OH)2 with [18F]-13 and not to the addition of carrier [19F]-fluoride ion, even though carrier addition was seen as a major shortcoming. Hence, the importance of specific activity and the unique potential for achieving exceptionally high specific activity warrant discussion.
■
DESIGNING A KINETICALLY STABLE ARBF3− In order to design kinetically stable ArBF3−s, we sought structure−activity relationships that govern the solvolysis rate. From the mechanism (Figure 3), we drew an analogy between an sp2-hybridized boron and an sp2-hybridized carbocation (Figure 5). Hammett analysis of cumyl chloride solvolysis showed that electron-donating groups (EDGs) at the para position greatly accelerate solvolysis while electron-withdrawing groups (EWGs) retard solvolysis.31 We therefore performed a Hammett analysis to quantify the effects of EDGs and EWGs in terms of published σ and σ+ values; log(ksolv) is negatively correlated with the sum of the σ values: ρ ≈ −1 (R ≈ 0.9).32 In addition, ortho substituents sterically clash with the fluorine atoms of difluoroborane 5, disfavoring its production and thereby retarding solvolysis of the trifluoroborate.29 Finally, we found that electron-deficient N-heterocycles significantly retard solvolysis.33,34 With this understanding, we designed a new EWGsubstituted ArBF3− (Figure 6), in which the three fluorine atoms on the ring predictably increased the solvolytic half-life to ∼1000 min while the m-carboxylate enabled bioconjugation via an amide bond, which further enhanced the stability (σm= 0.28 for −CONH2 vs −0.1 for −COO−). Initially, we prepared tetraphenylpinacolate ester 7 for enhanced chromatographic separation and stability toward deborylation and then borimidine 8, which is base-stable for bioconjugation yet acid-labile for ArBF3− synthesis (Figure 6).
■
■
ON THE IMPORTANCE OF SPECIFIC ACTIVITY Specific activity, defined in units of Ci/μmol of tracer, represents a measure of tracer quality36 for two reasons: (1) high specific activity ensures low injected mass, which reduces the risk of toxicity, which must be documented for regulatory approval (vide infra),3,37,38 and (2) at low specific activity, unlabeled molecules compete for the target and reduce the image contrast, particularly for low-abundance targets. A related term, “effective specific activity”, defined as Ci/(μmol of all target binding components), applies to chemically impure
IN VIVO STABILITY AND IMAGES Acids 7 and 8 can be readily coupled to a free amine and then converted to a stable [18F]-ArBF3−; a biotin conjugate showed in vivo stability, as evidenced by lack of bone uptake in the PET image (free [18F]-fluoride ion accumulates in Ca2+-rich bone).27 However, the real test came with the one-step radiosynthesis of [18F]-ArBF3−−bis(RGD) (10) from bis(RGD)borimidine 9 (Figure 7) along with its application to in vivo imaging (Figure 8).35 To obtain 10, miniscule quantities of 9 (20 μg) were E
DOI: 10.1021/acs.accounts.5b00398 Acc. Chem. Res. XXXX, XXX, XXX−XXX
Article
Accounts of Chemical Research
from this measurement: (1) a significant quantity of [19F]fluoride ion is present in NCA [18F]-fluoride ion, and it arises during bombardment, or from Teflon radiolysis,43 or from anion exchange trapping, but not from the reagents used in radiosynthesis; (2) NCA [18F]-fluoride ion at 6.5 Ci/μmol would normally provide tracers at ≤3 Ci/μmol following a standard 3 h radiosynthesis, which suggests that our measured value is on par with specific activities of NCA [18F]-fluoride ion obtained worldwide. We added carrier [19F]-fluoride ion (4 nmol) to 19 mCi of NCA [18F]-fluoride ion, which had decayed to a value of 5 Ci/ μmol, which further reduced the specific activity to 2.7 Ci/ μmol, at which point it was reacted with borimidine 11 to give [18F]-12, which was click-conjugated to rhodamine to give radiochemically pure [18F]-13 in 11 days! To understand this relationship, we plotted pkB−F values for 12 organotrifluoroborates versus the pKa values of the corresponding carboxylic acids. The correlation is strikingly good (Figure 12).47
Whereas the solvolytic stabilities of 18−25 portend their use as radioprosthetic groups, 23, which we named “AMBF3−” on account of the ammoniomethyl-BF3−, was readily appended by “click” reaction to octreotate to give AMBF3−-TATE. H
DOI: 10.1021/acs.accounts.5b00398 Acc. Chem. Res. XXXX, XXX, XXX−XXX
Accounts of Chemical Research
■
Article
■
PRECLINICAL STUDIES WITH [18F]-AMBF3−-TATE AND LABELING OF OTHER PEPTIDES IEX labeling with only 80 μg (75 nmol) of AMBF3−-TATE and ∼1 Ci of NCA [18F]-fluoride ion provided RCYs of 15−30% at 3 Ci/μmol and PET images with T:NT ratios far superior to those acquired with 68Ga-DOTA-TATE, the current gold standard for imaging of neuroendocrine tumors (Figure 1).25 To demonstrate generality, 23 was conjugated to other peptides, including fluorescent bis(RGD), which enabled dual-mode fluorescence imaging of the tumor. Each was labeled routinely at 2−4 Ci/μmol within 25 min (∼200 mCi) and gave high-contrast PET images (Figure 13).48−51 When the fluorescent bis(RGD) was injected at 3 Ci/μmol, tumor uptake values of 5% ID/g provided excellent PET images, yet the chemical mass within the tumor was far below fluorescent detection limits, which suggested that much lower specific activities will be needed for use with fluorescent imaging. However, at lower specific activity, tumor uptake in the PET image is likely to be eroded, as we showed.
FUTURE APPLICATIONS In the near future, AMBF3−-TATE will enter a first-in-human trial. Amine-bearing drugs can be converted to zwitterionic [18F]-RBF3−s that may penetrate the blood−brain barrier for neurological imaging. Combinatorial peptide arrays containing an RBF3− can be screened against targets where the RBF3− contributes to, or at least does not interfere with, binding; once a lead is found, facile labeling speeds the in vivo validation process. Furthermore, this method should apply to any molecule that has been tagged with a 99mTc chelate; such would include antibodies, nanoparticles, aptamers, peptides, and glycosides, with applications in multimodal imaging. Finally, 10B-enriched compositions that afford both [18F]BF3− imaging and boron neutron-capture therapy now merit consideration as theranostics.
■
CONCLUSIONS In under a decade, we have advanced the notion of [18F]-RBF3− labeling to a tantalizing preclinical lead, AMBF3−-TATE, and have applied this method to several other peptides, all of which have been labeled in a clinical setting in RCYs of ≥25% in ≤25 min at high specific activities. The ease of bioconjugation, the mild conditions for labeling, and the rapidity by which radiochemically pure tracers are delivered in a single, aqueous, user-friendly step make this method competitive with radiometal chelation.
■
TOXICOLOGY TESTING FOR CLINICAL APPLICATIONS In order to clinically translate these tracers, toxicity testing will be necessary. While RBF3−s are considered nontoxic,26 one cannot be certain that bioconjugated RBF3−s will be nontoxic. In this regard, high specific activity is important because it ensures injection of very low mass doses. For example, at 3 Ci/ μmol, injection of 10 mCi corresponds to 3 nmol or ∼6 μg of tracer (at a molecular weight of 2000 g/mol); in a 60 kg patient, this represents 0.1 μg/kg (50 pmol/kg). For eIND filing, toxicity must be assessed in rodents at 100-fold higher doses than those normally used for imaging, e.g., 5 nmol/kg.52 At such levels, even the chemical weapon VX gas is not toxic (LD50 = 26 nmol/kg). Yet while the chances of toxicity are remote at such high specific activities, a thorough evaluation will be required for each bioconjugated RBF3− prior to human translation.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.accounts.5b00398. Synthetic scheme providing an indication of the steps that are required to produce a peptidic tracer by standard means in 170 min (based on ref 20) (PDF)
■
■
AUTHOR INFORMATION
Corresponding Author
APPLICATIONS TO SMALL MOLECULES Organotrifluoroborates can be grafted onto small molecules. Recently, Li and Gabbai ̈ used IEX with a stable [18F]-Nheterocyclic-carbene-BF3− that can be subsequently appended to various peptides.53 Toward these ends, we have labeled sulfonamide-based inhibitors of carbonic anhydrase for imaging of hypoxia.54 An outstanding validation of this approach was recently published by Liu et al.:55 [18F]-α-aminoalkyl-BF3−s are taken up by amino acid transporters that are overexpressed in certain cancers. With such promise, low-molecular-weight [18F]-RBF3−s may start to rival [18F]-FDG and [18F]-MISO. Other applications toward hypoxia sensors and cardiology agents are being pursued.
*E-mail:
[email protected]. Notes
The author declares the following competing financial interest(s): UBC has sought patent protection on various [18F]-organotrifluoroborates. Eventual royalties are shared between the assignee and the inventors, one of whom is the author of this Account. Biography David M. Perrin graduated from UC Berkeley, obtained a Ph.D. from UCLA with David Sigman, and did postdoctoral work in France with Claude Helene. He has published on chemically modified DNAzymes, heterocycles for recognizing DNA, indole-cross-linked peptides and natural products, ribozymology, and PET imaging agents.
■
SIMILAR APPROACHES BY OTHERS: 18F-SIFA AND [18F]-Al-NOTA Paralleling our work, Schirrmacher and McBride conceived 18Flabeled organosilyl fluoride bioconjugates44,56 and [18F]-AlNOTA-peptide chelates,57−59 respectively, that afford one-step 18 F-labeling with great ease and generally excellent images. I would be remiss if I did not acknowledge these competing methods, as they have overturned paradigms regarding how peptides can be easily labeled and inspired much of our work.
■
ACKNOWLEDGMENTS I am indebted to the Canadian Cancer Society, which funded high-risk proposals with no requirement for preliminary data but rather a novel concept predicated on scientific logic. I am eternally grateful to three graduate students, Richard Ting, Ying Li, and Zhibo Liu, who worked tirelessly with me to create this knowledge. I also thank my students and co-workers: Justin Lo, I
DOI: 10.1021/acs.accounts.5b00398 Acc. Chem. Res. XXXX, XXX, XXX−XXX
Article
Accounts of Chemical Research
(16) Chun, J. H.; Telu, S.; Lu, S. Y.; Pike, V. W. Radiofluorination of diaryliodonium tosylates under aqueous-organic and cryptand-free conditions. Org. Biomol. Chem. 2013, 11, 5094−5099. (17) Kuhnast, B.; de Bruin, A.; Hinnen, F.; Tavitian, B.; Dolle, F. Design and synthesis of a new F-18 fluoropyridine-based haloacetamide reagent for the labeling of oligonucleotides: 2-bromo-N- 3-(2- F18 fluoropyridin-3-yloxy)propyl acetamide. Bioconjugate Chem. 2004, 15, 617−627. (18) Glaser, M.; Arstad, E. ″Click labeling″ with 2- F-18 fluoroethylazide for positron emission tomography. Bioconjugate Chem. 2007, 18, 989−993. (19) 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. (20) Chin, F. T.; Shen, B.; Liu, S. L.; Berganos, R. A.; Chang, E.; Mittra, E.; Chen, X. Y.; Gambhir, S. S. First Experience with ClinicalGrade F-18 FPP(RGD)(2): An Automated Multi-step Radiosynthesis for Clinical PET Studies. Mol. Imag. Biol. 2012, 14, 88−95. (21) Olberg, D. E.; Cuthbertson, A.; Solbakken, M.; Arukwe, J. M.; Qu, H.; Kristian, A.; Bruheim, S.; Hjelstuen, O. K. Radiosynthesis and Biodistribution of a Prosthetic Group (F-18-FENMA) Conjugated to Cyclic RGD Peptides. Bioconjugate Chem. 2010, 21, 2297−2304. (22) Jeon, J.; Shen, B.; Xiong, L.; Miao, Z.; Lee, K. H.; Rao, J.; Chin, F. T. Efficient Method for Site-Specific 18F-Labeling of Biomolecules Using the Rapid Condensation Reaction between 2-Cyanobenzothiazole and Cysteine. Bioconjugate Chem. 2012, 23, 1902−1908. (23) Fani, M.; Del Pozzo, L.; Abiraj, K.; Mansi, R.; Tamma, M. L.; Cescato, R.; Waser, B.; Weber, W. A.; Reubi, J. C.; Maecke, H. R. PET of Somatostatin Receptor-Positive Tumors Using Cu-64- and Ga-68Somatostatin Antagonists: The Chelate Makes the Difference. J. Nucl. Med. 2011, 52, 1110−1118. (24) Lasne, M. C.; Perrio, C.; Rouden, J.; Barre, L.; Roeda, D.; Dolle, F.; Crouzel, C. Chemistry of beta(+)-emitting compounds based on fluorine-18. Top. Curr. Chem. 2002, 222, 201−258. (25) Liu, Z.; Pourghiasian, M.; Benard, F.; Pan, J.; Lin, K.-S.; Perrin, D. M. Preclinical Evaluation of a High-Affinity 18F-Trifluoroborate Octreotate Derivative for Somatostatin Receptor Imaging. J. Nucl. Med. 2014, 55, 1499−1505. (26) Molander, G. A.; Ellis, N. Organotrifluoroborates: Protected boronic acids that expand the versatility of the Suzuki coupling reaction. Acc. Chem. Res. 2007, 40, 275−286. (27) Ting, R.; Harwig, C. W.; auf dem Keller, U.; McCormick, S.; Austin, P.; Overall, C. M.; Adam, M. J.; Ruth, T. J.; Perrin, D. M. Towards [18F]-Labeled Aryltrifluoroborate Radiotracers - In Vivo PET Imaging of Stable Aryltrifluoroborate Clearance in Mice. J. Am. Chem. Soc. 2008, 130, 12045−12055. (28) Lazari, M.; Collins, J.; Shen, B.; Farhoud, M.; Yeh, D.; Maraglia, B.; Chin, F. T.; Nathanson, D. A.; Moore, M.; van Dam, R. M. Fully automated production of diverse 18F-labeled PET tracers on the ELIXYS multireactor radiosynthesizer without hardware modification. J. Nucl. Med. Technol. 2014, 42, 203−210. (29) Liu, Z. B.; Li, Y.; Ting, R.; Perrin, D. M. Designing kinetically stable aryltrifluoroborates as F-18-capture agents for PET imaging. J. Phys. Org. Chem. 2015, 28, 210−214. (30) Ting, R.; Harwig, C.; Lo, J.; Li, Y.; Adam, M. J.; Ruth, T. J.; Perrin, D. M. Substituent Effects on Aryltrifluoroborate Solvolysis in Water: Implications for Suzuki-Miyaura Coupling and the Design of Stable 18F-Labeled Aryltrifluoroborates for Use in PET Imaging. J. Org. Chem. 2008, 73, 4662−4670. (31) Okamoto, Y.; Inukai, T.; Brown, H. C. Directive Effects of Aromatic Substitution, Rates of Solvolysis of Phenyldimethylcarbinyl Chlorides Containing Meta Directing Substituents. J. Am. Chem. Soc. 1958, 80, 4969−4972. (32) Hansch, C.; Leo, A.; Unger, S. H.; Kim, K. H.; Nikaitani, D.; Lien, E. J. Aromatic Substituent Constants for Structure-Activity Correlations. J. Med. Chem. 1973, 16, 1207−1216.
Daniel Chao, Jerome Lozada, M. Alex Radtke, Jihyoon Oh, Curtis Harwig, Maral Pourghiasian, Joseph Lau, Jinhe Pan, Zhengxing Zhang, and Jennifer Greene, and my collaborators: Michael Adam, Thomas Ruth, Paul Schaffer, Chris Overall, Xiaoyuan Chen, Emmanuel Gras, Donald Yapp, Kuo-Shyan Lin, and Francois Benard.
■
REFERENCES
(1) Tsien, R. Y. Imagining imaging’s future. Nat. Rev. Mol. Cell Biol. 2003, 4, SS16−SS21. (2) Aina, O. H.; Liu, R. W.; Sutcliffe, J. L.; Marik, J.; Pan, C. X.; Lam, K. S. From combinatorial chemistry to cancer-targeting peptides. Mol. Pharmaceutics 2007, 4, 631−651. (3) Cai, L. S.; Lu, S. Y.; Pike, V. W. Chemistry with F-18 fluoride ion. Eur. J. Org. Chem. 2008, 2008, 2853−2873. (4) Kemerink, G. J.; Visser, M. G. W.; Franssen, R.; Beijer, E.; Zamburlini, M.; Halders, S.; Brans, B.; Mottaghy, F. M.; Teule, G. J. J. Effect of the positron range of F-18, Ga-68 and I-124 on PET/CT in lung-equivalent materials. Eur. J. Nucl. Med. Mol. Imaging 2011, 38, 940−948. (5) Smith, G.; Carroll, L.; Aboagye, E. O. New Frontiers in the Design and Synthesis of Imaging Probes for PET Oncology: Current Challenges and Future Directions. Mol. Imag. Biol. 2012, 14, 653−666. (6) Xiao, W. W.; Wang, Y.; Lau, E. Y.; Luo, J. T.; Yao, N. H.; Shi, C. Y.; Meza, L.; Tseng, H.; Maeda, Y.; Kumaresan, P.; Liu, R. W.; Lightstone, F. C.; Takada, Y.; Lam, K. S. The Use of One-Bead OneCompound Combinatorial Library Technology to Discover HighAffinity alpha v beta 3 Integrin and Cancer Targeting ArginineGlycine-Aspartic Acid Ligands with a Built-in Handle. Mol. Cancer Ther. 2010, 9, 2714−2723. (7) Lee, S.; Xie, J.; Chen, X. Y. Peptide-Based Probes for Targeted Molecular Imaging. Biochemistry 2010, 49, 1364−1376. (8) Avril, N.; Menzel, M.; Dose, J.; Schelling, M.; Weber, W.; Janicke, F.; Nathrath, W.; Schwaiger, M. Glucose metabolism of breast cancer assessed by F-18-FDG PET: Histologic and immunohistochemical tissue analysis. J. Nucl. Med. 2001, 42, 9−16. (9) Kwekkeboom, D. J.; Kam, B. L.; van Essen, M.; Teunissen, J. J. M.; van Eijck, C. H. J.; Valkema, R.; de Jong, M.; de Herder, W. W.; Krenning, E. P. Somatostatin receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors. Endocr.-Relat. Cancer 2010, 17, R53−R73. (10) Wester, H.; Schottelius, M.; Scheidhauer, K.; Meisetschlager, G.; Herz, M.; Rau, F.; Reubi, J.; Schwaiger, M. PET imaging of somatostatin receptors: design, synthesis and preclinical evaluation of a novel F-18-labelled, carbohydrated analogue of octreotide. Eur. J. Nucl. Med. Mol. Imaging 2003, 30, 117−122. (11) Yu, Z. L.; Ananias, H. J. K.; Carlucci, G.; Hoving, H. D.; Helfrich, W.; Dierckx, R.; Wang, F.; de Jong, I. J.; Elsinga, P. H. An Update of Radiolabeled Bombesin Analogs for Gastrin-Releasing Peptide Receptor Targeting. Curr. Pharm. Des. 2013, 19, 3329−3341. (12) Wan, W.; Guo, N.; Pan, D.; Yu, C.; Weng, Y.; Luo, S.; Ding, H.; Xu, Y.; Wang, L.; Lang, L.; Xie, Q.; Yang, M.; Chen, X. First Experience of F-18-Alfatide in Lung Cancer Patients Using a New Lyophilized Kit for Rapid Radiofluorination. J. Nucl. Med. 2013, 54, 691−698. (13) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.; Wong, C. H. Selectfluor: Mechanistic insight and applications. Angew. Chem., Int. Ed. 2005, 44, 192−212. (14) Teare, H.; Robins, E. G.; Kirjavainen, A.; Forsback, S.; Sandford, G.; Solin, O.; Luthra, S. K.; Gouverneur, V. Radiosynthesis and Evaluation of F-18 Selectfluor bis(triflate). Angew. Chem., Int. Ed. 2010, 49, 6821−6824. (15) Stewart, M. N.; Hockley, B. G.; Scott, P. J. H. Green approaches to late-stage fluorination: radiosyntheses of F-18-labelled radiopharmaceuticals in ethanol and water. Chem. Commun. 2015, 51, 14805− 14808. J
DOI: 10.1021/acs.accounts.5b00398 Acc. Chem. Res. XXXX, XXX, XXX−XXX
Article
Accounts of Chemical Research (33) Li, Y.; Asadi, A.; Perrin, D. M. Hydrolytic stability of nitrogenous-heteroaryltrifluoroborates under aqueous conditions at near neutral pH. J. Fluorine Chem. 2009, 130, 377−382. (34) Liu, Z.; Hundal-Jabal, N.; Wong, M.; Yapp, D.; Lin, K. S.; Benard, F.; Perrin, D. M. A new F-18-heteroaryltrifluoroborate radioprosthetic with greatly enhanced stability that is labelled by F-18-F-19isotope exchange in good yield at high specific activity. MedChemComm 2014, 5, 171−179. (35) Li, Y.; Liu, Z. B.; Lozada, J.; Wong, M. Q.; Lin, K. S.; Yapp, D.; Perrin, D. M. Single step F-18-labeling of dimeric cycloRGD for functional PET imaging of tumors in mice. Nucl. Med. Biol. 2013, 40, 959−966. (36) 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. 2012, 39, 601−608. (37) Maestrup, E. G.; Fischer, S.; Wiese, C.; Schepmann, D.; Hiller, A.; Deuther-Conrad, W.; Steinbach, J.; Wunsch, B.; Brust, P. Evaluation of Spirocyclic 3-(3-Fluoropropyl)-2-benzofurans as sigma(1) Receptor Ligands for Neuroimaging with Positron Emission Tomography. J. Med. Chem. 2009, 52, 6062−6072. (38) Eckelman, W. C.; Bonardi, M.; Volkert, W. A. True radiotracers: are we approaching theoretical specific activity with Tc-99m and I123? Nucl. Med. Biol. 2008, 35, 523−527. (39) Bergman, J.; Eskola, O.; Lehikoinen, P.; Solin, O. Automated synthesis and purification of F-18 bromofluoromethane at high specific radioactivity. Appl. Radiat. Isot. 2001, 54, 927−933. (40) Liu, Z. B.; Li, Y.; Lozada, J.; Schaffer, P.; Adam, M. J.; Ruth, T. J.; Perrin, D. M. Stoichiometric Leverage: Rapid 18F-Aryltrifluoroborate Radiosynthesis at High Specific Activity for Click Conjugation. Angew. Chem., Int. Ed. 2013, 52, 2303−2307. (41) Ting, R.; Adam, M. J.; Ruth, T. J.; Perrin, D. M. Arylfluoroborates and alkylfluorosilicates as potential PET imaging agents: high-yielding aqueous biomolecular 18F-labeling. J. Am. Chem. Soc. 2005, 127, 13094−13095. (42) Kim, S. Y.; Hong, J. I. Chromogenic and fluorescent chemodosimeter for detection of fluoride in aqueous solution. Org. Lett. 2007, 9, 3109−3112. (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) Schirrmacher, R.; Bradtmoller, G.; Schirrmacher, E.; Thews, O.; Tillmanns, J.; Siessmeier, T.; Buchholz, H. G.; Bartenstein, P.; Waengler, B.; Niemeyer, C. M.; Jurkschat, K. F-18-labeling of peptides by means of an organosilicon-based fluoride acceptor. Angew. Chem., Int. Ed. 2006, 45, 6047−6050. (45) Li, Z. B.; Chansaenpak, K.; Liu, S. L.; Wade, C. R.; Conti, P. S.; Gabbai, F. P. Harvesting F-18-fluoride ions in water via direct F-18-F19 isotopic exchange: radiofluorination of zwitterionic aryltrifluoroborates and in vivo stability studies. MedChemComm 2012, 3, 1305− 1308. (46) Liu, Z.; Li, Y.; Lozada, J.; Pan, J.; Lin, K.-S.; Schaffer, P.; Perrin, D. M. Rapid, One-Step, High Yielding 18F-Labeling of an Aryltrifluoroborate Bioconjugate by Isotope Exchange at Very High Specific Activity. J. Labelled Compd. Radiopharm. 2012, 55, 491−496. (47) Liu, Z. B.; Chao, D.; Li, Y.; Ting, R.; Oh, J.; Perrin, D. M. From Minutes to Years: Predicting Organotrifluoroborate Solvolysis Rates. Chem. - Eur. J. 2015, 21, 3924−3928. (48) Liu, Z. B.; Pourghiasian, M.; Radtke, M. A.; Lau, J.; Pan, J. H.; Dias, G. M.; Yapp, D.; Lin, K. S.; Benard, F.; Perrin, D. M. An Organotrifluoroborate for Broadly Applicable One-Step F-18-Labeling. Angew. Chem., Int. Ed. 2014, 53, 11876−11880. (49) Pourghiasian, M.; Liu, Z. B.; Pan, J. H.; Zhang, Z. X.; Colpo, N.; Lin, K. S.; Perrin, D. M.; Benard, F. F-18-AmBF3-MJ9: A novel radiofluorinated bombesin derivative for prostate cancer imaging. Bioorg. Med. Chem. 2015, 23, 1500−1506. (50) Liu, Z. B.; Amouroux, G.; Zhang, Z. X.; Pan, J. H.; Hundal-Jabal, N.; Colpo, N.; Lau, J.; Perrin, D. M.; Benard, F.; Lin, K. S. F-18Trifluoroborate Derivatives of Des-Arg(10) Kallidin for Imaging
Bradykinin B1 Receptor Expression with Positron Emission Tomography. Mol. Pharmaceutics 2015, 12, 974−982. (51) Liu, Z.; Radtke, M. A.; Wong, M. Q.; Lin, K.-S.; Yapp, D. T.; Perrin, D. M. Dual Mode Fluorescent 18F-PET Tracers: Efficient Modular Synthesis of Rhodamine-[cRGD]2-[18F]-Organotrifluoroborate, Rapid, and High Yielding One-Step 18F-Labeling at High Specific Activity, and Correlated in Vivo PET Imaging and ex Vivo Fluorescence. Bioconjugate Chem. 2014, 25, 1951−1962. (52) Mosessian, S.; Duarte-Vogel, S. M.; Stout, D. B.; Roos, K. P.; Lawson, G. W.; Jordan, M. C.; Ogden, A.; Matter, C.; Sadeghi, S.; Mills, G. Q.; Schelbert, H. R.; Radu, C. G.; Czernin, J.; Couto, M.; Phelps, M. E. INDs for PET Molecular Imaging Probes-Approach by an Academic Institution. Mol. Imag. Biol. 2014, 16, 441−448. (53) Chansaenpak, K.; Wang, M. Z.; Wu, Z. H.; Zaman, R.; Li, Z. B.; Gabbai, F. P. F-18 -NHC-BF3 adducts as water stable radio-prosthetic groups for PET imaging. Chem. Commun. 2015, 51, 12439−12442. (54) Lau, J.; Liu, Z. B.; Lin, K. S.; Pan, J. H.; Zhang, Z. X.; Vullo, D.; Supuran, C. T.; Perrin, D. M.; Benard, F. Trimeric Radiofluorinated Sulfonamide Derivatives to Achieve In Vivo Selectivity for Carbonic Anhydrase IX-Targeted PET Imaging. J. Nucl. Med. 2015, 56, 1434− 1440. (55) Liu, Z.; Chen, H.; Chen, K.; Shao, Y.; Kiesewetter, D. O.; Niu, G.; Chen, X. Boramino acid as a marker for amino acid transporters. Sci. Adv. 2015, 1, e1500694. (56) Niedermoser, S.; Chin, J.; Wangler, C.; Kostikov, A.; BernardGauthier, V.; Vogler, N.; Soucy, J. P.; McEwan, A. J.; Schirrmacher, R.; Wangler, B. In Vivo Evaluation of F-18-SiFAlin-Modified TATE: A Potential Challenge for Ga-68-DOTATATE, the Clinical Gold Standard for Somatostatin Receptor Imaging with PET. J. Nucl. Med. 2015, 56, 1100−1105. (57) McBride, W. J.; Sharkey, R. M.; Karacay, H.; D’Souza, C. A.; Rossi, E. A.; Laverman, P.; Chang, C. H.; Boerman, O. C.; Goldenberg, D. M. A Novel Method of F-18 Radiolabeling for PET. J. Nucl. Med. 2009, 50, 991−998. (58) Laverman, P.; D’Souza, C. A.; Eek, A.; McBride, W. J.; Sharkey, R. M.; Oyen, W. J. G.; Goldenberg, D. M.; Boerman, O. C. Optimized labeling of NOTA-conjugated octreotide with F-18. Tumor Biol. 2012, 33, 427−434. (59) McBride, W. J.; Sharkey, R. M.; Goldenberg, D. M. Radiofluorination using aluminum-fluoride (Al18F). EJNMMI Res. 2013, 3, 36.
K
DOI: 10.1021/acs.accounts.5b00398 Acc. Chem. Res. XXXX, XXX, XXX−XXX
