From Unorthodox to Established: The Current ... - ACS Publications

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From Unorthodox to Established: The Current Status of 18 F‑Trifluoroborate- and 18F‑SiFA-Based Radiopharmaceuticals in PET Nuclear Imaging Vadim Bernard-Gauthier,† Justin J. Bailey,† Zhibo Liu,‡ Björn Wan̈ gler,§ Carmen Wan̈ gler,∥ Klaus Jurkschat,⊥ David M. Perrin,*,# and Ralf Schirrmacher*,† †

Division of Oncological Imaging, Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton, Alberta T6G 1Z2, Canada ‡ Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, United States § Molecular Imaging and Radiochemistry and Biomedical Chemistry and ∥Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany ⊥ Department of Chemistry and Chemical Biology, Technical University of Dortmund, 44227 Dortmund, Germany # Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada

ABSTRACT: Unorthodox 18F-labeling strategies not employing the formation of a carbon-18F bond are seldom found in radiochemistry. Historically, the formation of a boron- or silicon-18F bond has been introduced very early on into the repertoire of labeling chemistries, but is without translation into any clinical radiotracer besides inorganic B[18F]F4− for brain tumor diagnosis. For many decades these labeling methodologies were forgotten and have just recently been revived by a handful of researchers thinking outside the box. When breaking with established paradigms such as the inability to obtain labeled compounds of high specific activity via isotopic exchange or performing radiofluorination in aqueous media, the research community often reacts skeptically. In 2005 and 2006, two novel labeling methodologies were introduced into radiochemistry for positron emission tomography (PET) tracer development: RBF3− labeling reported by Perrin et al. and the SiFA methodology by Schirrmacher, Jurkschat, and Waengler et al. which is based on isotopic exchange (IE). Both labeling methodologies have been complemented by other noncanonical strategies to introduce 18F into biomolecules of diagnostic importance, thus profoundly enriching the landscape of 18F radiolabeling. B- and Si-based labeling strategies finally revealed that IE is a viable alternative to established and traditional radiochemistry with the advantage of simplifying both the labeling effort as well as the necessary purification of the radiotracer. Hence IE will be the focus of this contribution over other noncanonical labeling methods. Peptides for tumor imaging especially lend themselves favorably toward one-step labeling via IE, but small molecules have been described as well, taking advantage of these new approaches, and have been used successfully for brain imaging. This Review gives an account of both radiochemistries centered on boron and silicon, describing the very beginnings of their basic research, the path that led to optimization of their chemistries, and the first encouraging preclinical results paving the way to their clinical use. This side by side approach will give the reader the opportunity to follow the development of a new basic discovery into a clinically applicable radiotracer including all the hurdles that have had to be overcome.

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INTRODUCTION The introduction of new chemistry into an established and broadly accepted contingent of methodologies is often accompanied by skepticism, doubt, and even disbelief, © XXXX American Chemical Society

Special Issue: Molecular Imaging Probe Chemistry Received: October 14, 2015 Revised: November 10, 2015

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DOI: 10.1021/acs.bioconjchem.5b00560 Bioconjugate Chem. XXXX, XXX, XXX−XXX

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Bioconjugate Chemistry

Figure 1. Overview of RBF3− and SiFA radiolabeling. Representative displacement reactions of silanol/silane precursors to form 18F-SiFA (A) and arylboronate precursors (C) to form R[18F]BF3− (B). Archetypal SiFA (D) and RBF3− and RBF3 (E) scaffolds used for isotopic exchange reactions with 18F−.

Unfortunately the necessary reaction conditions such as a high precursor concentration (the 19F-labeled compound) and high reaction temperatures resulted in the formation of radioactive and chemical byproducts which had to be separated from the tracer by high performance liquid chromatography (HPLC). Furthermore, only compounds of low specific activity (SA = amount of radioactivity of radiotracer divided by the total mass of compound including radioactive and nonradioactive compound) could be obtained as a result of the high precursor amount required. It was common textbook knowledge for many years that isotopic exchange leads to a useful radiotracer of low to medium specific activity in only a few cases. The nonradioactive “contaminant” is considered detrimental to the PET image quality because any nonradioactive molecule that binds to its biological target will not contribute to a detectable signal for the PET camera. Historically, this is the main reason that isotopic exchange has not found many useful applications in the synthesis of PET radiopharmaceuticals and has essentially been discarded from the list of suitable labeling reactions for PET tracer development. Interestingly, IE with 18 − F has rarely been considered for other elements besides carbon with only a few reports in the literature describing noncarbon-based 18F-fluorination. Two prominent examples for that general observation are boron and silicon. The usage of both elements dates back to the early 1960s, but neither B−18F nor Si−18F chemistries have found entry into any routine clinical application or even invigorated any further research efforts until about a decade ago. The early syntheses of Si[18F]F compounds mainly applied to metal [18F]fluorides, such as Li[18F]F or Cs[18F]F, in combination with various fluorosilanes, and were therefore based on simple isotopic exchange.13,14 In the case of B−18F only one particular compound, namely, [18F]tetrafluoroborate, has been synthesized from metal [18F]fluorides and boron trifluoride.15,16 The concept of IE for B−18F labeling was developed nearly half a century later concomitantly with the IE for 18F-fluorosilanes. Boron-18F chemistry together with the synthesis of a [18F]tetrafluoroborate was rediscovered in 2005 by Perrin and coworkers.17 Just a few months later, Schirrmacher, Jurkschat, and Waengler reported on the IE labeling of a fluorosilane derivatized Tyr3-octreate (TATE), a peptide used in its radiolabeled form to diagnose tumors of neuroendocrine

especially when the new method challenges a well acknowledged paradigm in the field. It is also interesting to see that often the publication of one and the same innovative idea happens isochronally, even though the basic science that led to the new discovery had been known for decades. This situation has occurred many times in chemistry, physics, and other natural sciences where novel findings were published at the same time by different groups independently. In radiochemistry, a great plethora of radiolabeling methods has been published for numerous different radioisotopes to yield radiotracers for in vivo molecular imaging.1−3 One important imaging modality is positron emission tomography (PET) which depends on efficient ways to introduce the radioisotope into compounds used as radiotracers to visualize receptors in the brain or surface receptors on cancer cells, for example.4−6 PET is the most modern imaging system available and is used for clinical diagnostic imaging worldwide. Among many other radionuclides that decay by positron emission, the utilization of radiohalogens7 such as radioiodine,8 -bromine,9 and -fluorine10,11 for PET imaging relies on covalent bond formation between the radioisotope and the nonradioactive carbon. Only iodine and bromine can be successfully oxidized to form a reactive positively charged species that reacts preferentially with systems of high electron density like an aromatic ring or a double bond. Fluorine in stark contrast does not lend itself to oxidation and can only react via simple nucleophilic substitution with electron deficient aromatic rings and aliphatic systems comprising a suitable leaving group. The reactivity of radioactive fluoride (fluorine-18; t1/2 = 109.8 min; 97% β+; Emax (β+) = 0.64 MeV) is comparatively low: it requires special activation in nonaqueous solvents, in addition to elevated temperatures for the formation of a carbon-18F bond. In most cases these reaction conditions lead to the formation of radioactive byproducts that have to be laboriously separated from the radiotracer. In order to reduce the chemical participants in such a labeling reaction and to simplify the purification of the labeled compound, isotopic exchange (IE) was considered as a viable alternative labeling approach early on.12 Omitting the labeling precursor from the labeling equation was anticipated to decrease the efforts necessary for purification, since only unreacted 18F− and labeled/unlabeled 18 F-compound should be part of the crude reaction mixture. B


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μmol 18F-SiFA have been reported, owing to high radiochemical yields (RCYs > 80%) and minute amounts of precursor required (99% radiochemical purity, and 111 GBq/ μmol SA. Evaluated in AR42J tumor-bearing mice as well, 18FAmBF3-TATE displayed 10.11 ± 1.67%ID/g and tumor-toblood and tumor-to-muscle ratios of 25 and 89, respectively, without any significant defluorination in vivo (60 min p.i.). In a separate study, Liu et al.43 also reported on the synthesis and preliminary imaging assessment of the radiolabeled sstr2 antagonist 18F-AmBF3-LM3 (18F-15, Figure 2E,L) which displayed high tumor accumulation and fast blood clearance in tumor-bearing mice. Gastrin-Releasing Peptide Receptor (GRPr) Imaging. Fluorine-18-radiolabeled bombesin (BBN)-type peptides are relevant for the imaging of the GRP receptor overexpressed in a number of human cancers, especially prostate cancer. These have been the focus of intensive preclinical work56−58 and more recent clinical applications59 for PET imaging. In a very recent study, Pourghiasian and colleagues40 demonstrated the potential of the direct one step, HPLC-free, 18F−19F isotopic exchange using the AmBF3-modified antagonist bombesin

synthon in conjunction with various auxiliaries composed of carbohydrates, PEGs, and aspartic acid residues. The lead radiotracer emanating from this study, 18F-SiFAlin-Glc-Asp2PEG1-TATE (18F-12), compared advantageously with 68GaDOTATATE in a preclinical setting (Figure 2D,F,G). In particular, 18F-12 displayed 18.51 ± 4.89%ID/g in tumor (AR42J tumor-bearing mice) at 60 min post injection, above that observed for 68Ga-DOTATATE (14.10 ± 4.84%ID/g). The radiotracer also showed >55 and >210 tumor-to-blood and tumor-to-muscle ratios, respectively, and negligible bone uptake (90 min p.i.). Importantly, derivatives lacking the permanent charge carried by the SiFAlin group displayed significantly reduced tumor-to-blood and tumor-to-muscle ratios. Overall, the improvement of those different generations of 18F-SiFATATE could be linked in part to the reduction of their lipophilicities as reflected by their measured LogD (from 2.2 for 18 F-10 to −1.21 for 18F-12). In a very recent study, additional evidence of the synergetic effect of the auxiliary components in 18 F-SiFAlin-Glc-Asp2-PEG1-TATE (18F-12) was provided upon evaluation of a novel series of 18F-SiFAlin-radiopeptides lacking the carbohydrate fragment (for example, 18F-13, Figure 2D).38 Despite excellent tumor accumulation (Figure 2H,I), the reduced tumor-to-background ratio observed was attributed to a decreased rate of blood clearance coupled with greater kidney uptake which furthermore confirmed 18F-12 as the primary lead with the most suitable balance between specific binding, tumor uptake, and excretion identified to date. Ultimately, benefiting from the optimization of the isotopic exchange in the context of SiFAs,36,37,55 all 18F-SiFAlin-bearing peptides could be obtained in high RCYs (50−80%) at room E


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Figure 4. 18F-labeled RGD radiotracers. (A) RGD peptide scaffold. (B) Chemical structure of aryl- and heteroaryl-BF3− peripheral moieties used for PET imaging.30,44,64 (C) Chemical structure of trimeric RGD tracer used for PET imaging U87MG glioblastoma tumor-bearing mouse (D).43 (E,F) PET images of 18F-20 in U87 MG tumor-bearing mice. (G) Fluciclatide, a bicyclic-RGD analog scaffold. (H) 18F-SiFA-derivatized fluciclatide used for PET imaging, with representative images of 18F-SiFA-LysMe3-γ-carboxy-D-Glu-RGD (18F-24) in U87 MG tumor-bearing mice (J) with or (I) without blocking.63 White arrows denote tumor location in each image. ((D) This research was originally published in Angew. Chem., Int. Ed., ref 43, Copyright 2014 WILEY; (E,F) Reprinted from ref 64, Copyright 2013, with permission from Elsevier; (I,J) Reprinted with permission from ref 63, Copyright 2014 American Chemical Society).

derivative MJ9 (18F-16, Figure 3A−C). This study furthermore illustrated the prospective application of this novel tracer using PC-3 prostate tumor bearing-mice. 18F-AmBF3-MJ9 was altogether stable, showed good tumor uptake (2.20 ± 0.13% ID/g, 2 h p.i.), low background uptake (tumor-to-muscle ratios of ∼77) and favorable renal clearance enabling excellent tumor visualization. Despite a lower PC-3 tumor uptake than other promising 18F-labeled probes, e.g., Al18F-NOTA-P2-RM2660 and Al18F-NODAGA-RM1,57 18F-AmBF3-MJ9 demonstrated a comparable tumor-to-background profile. This work was preceded by a study describing the synthesis and evaluation of 18F-17, an octapeptide BBN antagonist analogue, obtained via the coupling of an alkyne-modified 18F-ArBF3 with an azidebearing BBN precursor (18F-17, Figure 3D).31 This work was reported prior to the identification of the favorable 18F-AmBF3 radiosynthon in use with the trifluoroborate IE method and exploited the KHF2 carrier-added method for the synthesis of the clickable 18F-AmBF3 fragment. The limited tumor uptake (1.27 ± 0.35%ID/g versus 0.88 ± 0.26%ID/g under blocking conditions, 1 h p.i.) and tumor-to-background ratios in the PC3 prostate adenocarcinoma tumor-bearing mice model observed in this study were ascribed to a combination of factors including the serum stability and defluorination as well as the nature of the selected peptide probe itself (Figure 3E,F). Most of the limitations raised in this initial study were addressed with the characterization of 18F-AmBF3-MJ9 (vide supra). The Ametamay group has also explored the potential of 18FSiFA in GRPr preclinical imaging.61,62 In a study making use of the displacement labeling technique using a hydride leaving group (18F-18, Figure 3G), a bombesin analogue containing an auxiliary composed of two L-cysteic acids (Ala(SO3H))

displayed an improved in vivo profile in the PC-3 model compared to previous arginine-containing 18F-SiFA derivatives from a previous generation (Figure 3H,I).61 Despite detectable tumor uptake (1.8 ± 0.7%ID/g versus 1.24 ± 0.09%ID/g under blocking conditions, 117 min p.i.), 18F-18 displayed extensive hepatobiliary clearance, an unfavorable tumor-to-blood ratio, and was obtained in low RCY following an HPLC purificationbased procedure (1.8% decay corrected, compared to 20−25% for 18F-16 and 18F-17). The Wängler group similarly attempted imaging GRPr-expressing PC-3 tumors using a series of PEGylated bombesin derivatives with embedded lipophilicityreducing structural components such as carbohydrates, lactose derived amino acids, and carboxylic acid- and sulfonic acidbearing residues.63 The ensuing radiotracers failed to successfully image the tumors and were characteristically accumulated in the liver upon injection, in spite of favorable in vivo stabilities, affinities, and lipophilicity reflected by LogD values ranging between 2.29 and −1.22. It is worth pointing out that those SiFA studies preceded the identification of the 18FSiFAlin-Glc-Asp2-PEG1 synthon/auxiliary successfully applied in the context of TATE-based imaging agents. In this context, both the bombesin and RGD analogue platforms (vide inf ra) constitute viable targets to validate whether or not the recently identified 18F-SiFAlin-Glc-Asp2-PEG1 construct can be readily applied to other structurally diverse peptide scaffolds, leading to improved in vivo profiles and pharmacokinetics. It should be expected that further studies will address this important question which is likely to impact the applicability of the 18FSiFA technique. Robust indications already suggest a good translational potential for the isotopic 18F-BF3 exchange technique, using the 18F-AmBF3 radiosynthon, among different F


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Bioconjugate Chemistry 18

peptide classes based on investigations illustrated by the bombesin- and RGD-type peptide discussed herein. Integrins Imaging. Radiolabeled RGD (Arg-Gly-Asp) containing peptides have been the subject of numerous imaging studies to determine integrins density, mostly αVβ3/αVβ5, due to the upregulation of those glycoproteins in vascular endothelial cells during angiogenesis in human tumors.52 In a series of reports, the analogous 18F-labeled RGD arytrifluoroborate radiotracers 18F-19−21 have been detailed (Figure 4A,B). The initial study by Liu et al. described the radiosyntheses of RDG-trAz-18F-ArBF3 (18F-19) and RDGSuPi-18F-ArBF3 (18F-20) via isotopic exchange leading to remarkably high SA tracers (e.g., ∼520 GBq/μmol, ∼50% isolated RCYs).64 The initial in vivo evaluation of these two radiotracers was thereafter reported as part of a study which utilized the carried-added method.30 Following this approach, 18 F-19 and 18F-20 were obtained in a fraction of the RCYs and SAs initially reported (∼2−6 GBq/μmol, 4−6.8% isolated RCYs) and evaluated in a murine U87 MG glioblastoma model. A relatively low tumor accumulation of 1.17−1.51%ID/g (1 h p.i.) was observed. Unexpectedly this uptake did not improve upon re-evaluation of a high SA version of RDG-SuPi-18F-ArBF3 (18F-20) suggesting that additional factors, other than SA, explain the tumor uptake of these RGD derivatives (Figure 4E,F). As part of a following report, a novel 18F-heteroaryltrifluoroborate with a 10-fold increased in vivo stability was described and conjugated with the previously used cyclic RGD pentapeptide.44 The corresponding radiotracer, RDG-18FPyrBF3 (18F-21), was only assessed for stability in healthy nude mice (Figure 4B). Following the identification of the robust zwitterionic radioprosthesis 18F-AmBF3, two novel RGD-based multimeric radiotracers were added to the ensemble of already described 18F-BF3 RGD imaging tracer candidates (Figure 4C,D; Figure 5A).43,65 Interestingly, while the tumor uptake in the U87 MG tumor-bearing mouse model for the trivalent radiotracer 18F-22 was in line with the previous

F-BF3 RGD tracers already described (e.g., 1.8%ID/g, 1 h p.i.), the dual mode fluorescent 18F-PET tracer 18F-25 was significantly more promising with a tumor uptake of 5.5%ID/g (Figure 5B). Additionally, whereas experiments with 18F-25 at ∼130 GBq/μmol generated high tumor uptake, the lower specific activity 18F-25 (0.37 GBq/μmol) readily allowed fluorescence detection while maintaining tumor uptake of about 2.9%ID/g (Figure 5C). The synthesis and in vivo evaluation of 18F-SiFA RGD peptides was also reported. Lindner et al. described a series of PEGylated SiFA RGD peptides bearing various auxiliaries (Figure 4G,H).63 As expected, in vivo PET imaging comparison in U87 MG xenograft determined that the derivative bearing a LysMe3-g-carboxy-D-Glu auxiliary (18F-24) resulted into a superior tumor uptake (I,J) and pharmacokinetics compared to the parent SiFA-RGD (18F-23). The RDG probe 18F-24 performed similarly to the trifluoroborate 18F-25 and displayed promising biodistribution with 5.30 ± 1.05%ID/g tumor uptake with primarily renal clearance. Notably, the radioligand 18F-24 was obtained in 43% isolated RCY in a total synthesis time of less than 20 min. Despite those promising results, the question remained whether or not the SiFAlin-type auxiliary described in previous sections could be beneficial in the context of RGDtype peptides and lead to additional improvements in terms of tumor uptake especially as seen in the context of TATE peptides. Other Radiolabeled Peptides. A recent study by Perrin’s group further illustrates the scope of isotopically exchangeable 18 F-trifluoroborate, especially 18F-AmBF3, in the context of peptide labeling for PET. 66 This study describes the comparison of two modified radiolabeled bradykinin B1 receptor (B1R) antagonists, 18F-AmBF3−B9858 (18F-26) and 18 F-AmBF3−B9958 (18F-27), in B1R− and B1R+ double xenograft tumor-bearing mice (Figure 6). Both 18F-26 and 18 F-27 were shown to bind selectively to B1R+ tumors and displayed favorable clearance profile and good tumor uptakes with 3.94 ± 1.24%ID/g and 4.20 ± 0.98%ID/g, with B1R+ tumor-to-B1R− tumor ratios of 12.2 ± 3.02 and 23.4 ± 7.77, respectively (1 h p.i.). A report presenting a potential strategy to deliver neuroreceptor ligands across the highly restrictive blood-brain barrier (BBB) has also recently illustrated an additional application of the 18F-SiFA technique.67 Although limited to in vitro results, this study suggests a conceptual framework in which small molecule ligands which bind receptors within the central nervous system (CNS) are bound to endogenous peptide transported through transcytosis. One of the peptide−small molecule constructs delineated in this study was a transferrin receptor binding peptide (TfR) fused with the dopamine D2 receptor antagonist fallypride and bearing a linker decorated with a 18F-SiFA prosthetic (18F-28, Figure 7). The ensuing fused peptide was efficiently radiolabeled, displayed single digit nanomolar affinity for the human D2 receptor and was not subjected to P-gp efflux. Further in vivo evaluation will be required in order to validate this strategy.

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SMALL MOLECULE-BASED IMAGING PROBES Labeling small molecule ligands with the intrinsically lipophilic SiFA moiety can significantly alter the physicochemical properties and in vivo biodistribution of the parent ligand. Such changes can be detrimental to target binding affinity and in vivo clearance rates.68 A recent account by Bohn and co-

Figure 5. Dual mode fluorescent 18F-PET radiotracer. (A) Chemical structure of Cy7 fluorescent AmBF3 18F-radiotracer (18F-25) and accompanying 3D PET/CT images of (B) U87 M tumor-bearing mice and (C) ex vivo fluorescence images of liver, kidney, and tumor.65 (Reprinted with permission from ref 65, Copyright 2014 American Chemical Society.) G


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Figure 6. 18F-AmBF3-functionalized derivatives of the bradykinin B1 receptor agonist peptide [des-Arg10]kallidin.66 (A) Chemical structure of 18FAmBF3−B9858 (18F-26) and the corresponding PET images in mice bearing both (B) HEK293 BIR+ (yellow arrows) and (E) BIR− (red arrows) tumors. (D) Chemical structure of 18F-AmBF3−B9958 (18F-27) and the corresponding PET images in mice bearing both (C) HEK293 BIR+ (yellow arrows) and (F) BIR− (red arrows) tumors. Blocking experiments were performed with coinjection of 100 μg cold standard. (Reprinted with permission from ref 66, Copyright 2015 American Chemical Society.)

Figure 7. Chemical structure of 18F-SiFA-containing TfR targeting peptide HAIYPRH (TfR-Ps) TfR-Ps-SiFA-PEG3 (18F-28).67

workers describes the SiFA-derivatized nitroimidazole 18F-34 (Figure 8A) for imaging tumor hypoxia. Initial in vivo biodistribution studies in a rat revealed thorough distribution throughout the body, with accumulation in the liver, intestines, bladder, and bones after 90 min (Figure 8H,I).69 Unfortunately, no hypoxic tumor-bearing animal model was evaluated with this tracer. In contrast and as mentioned above, 18F-BF3-labeled small molecules can typically benefit from the high water solubility, high polarity/low lipophilicity, and rapid clearance imparted by the ionic radioprosthetic. Perrin and co-workers recently labeled marimastat with 18F-ArBF3 (Figure 8A, 18F29), a ligand for matrix metalloproteinases (MMP), to demonstrate the applicability of this radioprosthetic for small molecule labeling.45,70 PET images of mice bearing MMP+ tumors revealed low tumor-specificity (Figure 8B). A potential strategy to reduce the lipophilic and steric impact of the SiFA fragment is to increase the ratio of ligands relative to SiFA through multivalent tracer design. This strategy was employed by Hazari and co-workers with their design and evaluation of a potent bivalent 5-HT1A-selective radiotracer 18F35 (Figure 8A) for imaging dimeric serotonin receptors (Figure 8J,K).71 The bivalent SiFA-derivatized radiotracer 18F-35 displayed enhanced affinity for 5-HT1A with preferential uptake in 5-HT1A receptor-rich regions in the brain (hippocampus (HIP), cingulate cortex (CG), and caudate putamen (CPU) and moderate accumulation in the nucleus raphe dorsalis (Figure 8J,K)). Thus, multivalency may, in applicable cases, be

a viable approach to avert complications due to the unfavorable physicochemical properties of SiFA. The multivalent ligand strategy was also utilized by Bénard and co-workers with 18F-AmBF3-labeled carbonic anhydrase (CA) inhibitors 4-(2-aminoethyl)benzenesulfonamide (AEBS), and 4-aminobenzenesulfonamide (ABS) (Figure 8A, inhibitors 18 F-30-33) to simultaneously increase avidity and image contrast.72 In the authors’ previous work with an 18Ffluoroaniline-labeled sulfonamide (18F−U-104), high blood uptake was observed presumably due to binding to intracellular CA in erythrocytes.73 By increasing the molecular weight of the inhibitor through trimerization (Figure 8A, 18F-32, 18F-33) and using the zwitterionic AmBF3 radioprosthetic to reduce membrane permeability, blood uptake dropped from ∼13.92%ID/g for 18F−U-104 to an average of 0.54%ID/g and 0.14%ID/g for the monomeric and trimeric sulfonamides, respectively. The trimeric sulfonamides 18F-32 and 18F-33 provided enhanced visualization of CA-expressing HT-29 tumor xenographs (Figure 8E,G) with 3-fold greater tumor:blood ratios than the monomeric sulfonamides 8F-30 and 18F31.

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OTHER RADIOLABELED PROBES FOR PET IMAGING The SiFA approach was used in imaging studies involving affibody, protein, and nanomaterial systems. Work from GE H


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Figure 8. (A) Chemical structures of 18F-labeled small molecules used for PET imaging.45,69−72 PET/CT image of 18F-29 (B) in 67NR tumorbearing mice.45,70 PET/CT images of (C) 18F-30, (D) 18F-31, (E) 18F-32, (F,G) 18F-33 in HT-29 tumor-bearing mice (tumors indicated by white arrows).72 (H,I) 18F-34-PET images of rat, where A = liver, B = digestive tract, C = bladder, D = bones.69 18F-35-PET images of rat brain, (J) sagittal and (K) horizontal planes.71 ((B) This research was originally published in Cancer Res., ref 70, Copyright 2010 American Association for Cancer Research; (C−G) This research was originally published in J. Nucl. Med., ref 72, Copyright by the Society of Nuclear Medicine and Molecular Imaging, Inc., (H,I) Reprinted from ref 69, Copyright 2013 with permission from Elsevier, (J,K) This research was originally published in ChemMedChem, ref 71, Copyright 2014 WILEY).

Figure 9. Radiolabeled proteins with 18F-SiFA. (A) Chemical representation of 18F-SiFA conjugate of ZHER2:2891 affibody and rat serum albumin. (B) PET biodistribution of RSA conjugates labeled with (B,D) 18F-SFB or (C,E) 18F-SiFB. (B,C) and (D,E) represent two differing coronal planes. (This research was originally published in Bioconj. Chem., ref 74, Copyright 2012 American Chemical Society).

Healthcare41 described the first 18F-SiFA-affibody construct for diagnostic PET imaging. This study detailed the comparative preclinical assessment of three 18F-labeled human epidermal growth factor (HER2) ligands including 18F-SiFA-ZHER2:2891 (18F-36, Figure 9). Interestingly, the isotopic exchange proceeded efficiently in aqueous solvent (38 ± 2% RCY), conditions which have proven challenging in most other SiFA applications. Despite the fact that 18F-36 was shown to have limited tumor uptake and was partially defluorinated as revealed by bone uptake, which may be related to this specific construct, this study provided a proof-of-concept of the compatibility of the 18F-SiFA one step labeling chemistry with small proteins such as affibody molecules. In another study by Kostikov et al.,74 the utilization of a small active ester 18F-SiFA prosthetic group, N-succinimidyl 3-(ditert-butyl[18F]fluorosilyl)benzoate (18F-SiFB), was shown to be significantly more efficient than the more common carbon-

based N-succinimidyl-4-[18F]fluorobenzoate (18F-SFB) for protein coupling experiments. When conjugated to rat serum albumin (RSA) for blood pool visualization, the ensuing siliconbased radiotracer displayed, in healthy rats, results comparable to the 18F-SFB carbon-based counterpart (18F-SFB-RSA), but only required of a fraction of the technical effort needed to obtain 18F-SFB-RSA. The Schirrmacher group has expanded the 18F-SiFA technology to nanomaterial labeling.49,75 In one particular study,49 water-soluble 3 nm maleimide-terminated PEGylated gold nanoparticles (AuNP) were efficiently coupled with another known 18F-SiFA prosthetic group, 18F-SiFA-SH,37,76 and used in preliminary PET imaging studies in healthy rats. Surprisingly, one such nanoparticle construct, which was obtained in high RCYs (60−80%) following size exclusion chromatography (18F-38, Figure 10), displayed detectable brain uptake. Although preliminary, this study supports further I


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Figure 10. Partially hydrolyzed 18F-labeled PEGylated gold nanoparticle 18F-38 (A) used in rat PET imaging: brain scans in (B) coronal, (C) sagittal, and (D) transverse planes; body scans in (E) coronal, (F) sagittal, and (G) transverse planes. (Reprinted with permission from ref 49, Copyright 2014 American Chemical Society).

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detailed investigation of such bioconjugation platforms, especially considering the simplicity of the 18F-SiFA labeling used. A SiFA-tetrazine prosthetic has since been used to derivatize an sp2-hybridized graphite surface via an inverse electron demand Diels−Alder reaction, demonstrating a mild chemical approach to modify a chemically inert carbon surface.77

The authors declare no competing financial interest.

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CONCLUDING REMARKS This Review has described the current status of both the 18FSiFA and 18F-BF3 technologies in terms of preclinical PET imaging. It is fair to observe that within less than one decade, these two approaches have evolved tremendously, moving from unorthodox and undefined radiochemical research to valuable, efficient, and in many instances superior alternatives to the classical 18F-carbon chemistry. Inasmuch as the definite benefit of 18F-SiFA and 18F-BF3 remain to be clarified further in a number of applications (e.g., small molecules, nanomaterial, protein, or affibody), the potential of both techniques for their primary field of study, e.g., peptide radiolabeling, has been definitely established with the characterization of the 18FSiFAlin and 18F-AmBF3 radiosynthons. Considering peptides specifically, it is clear that the IE labeling of 18F-SiFA and 18FBF3 not only expands the radiochemical method repertoire, but also significantly simplifies and expedites the entire radiolabeling process to an extent that enables a real kit process for the synthesis of 18F-radiopharmaceuticals. Although unique with regard to specific synthetic details, this Review also provides a detailed insight into the shared pathway taken by both methods in their optimization processes. An important and imminent next stage will be directed toward the clinical translation and validation of the most advanced 18F-SiFAlinand 18F-AmBF3-containing peptide PET imaging tracers. While our manuscript was being processed, a review on 18FGroup 13 fluoride derivatives as radiotracers for positron emission tomography78 and a study on boramino acid as a marker for amino acid transporters79 were published.

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REFERENCES

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Bioconjugate Chemistry osilanesand fluorides, or fluoride methoxides, of tungsten(VI), molybdenum(VI), tellurium(VI), and iodine(V). J. Chem. Soc., Dalton Trans., 1557−1560. (15) Askenasy, H. M., Laor, Y., Anbar, M., Lewitus, Z., Kosary, I. Z., and Guttmann, S. (1962) Localizaton of intracranial space occupying lesions by fluoroborate ions labelled with fluorine 18. Am. J. Roentgenol Radium Ther. Nucl. Med. 88, 350. (16) Entzian, W., Aronow, S., Soloway, A. H., and Sweet, W. H. (1964) A preliminary evaluation of F18-labeled tetrafluoroborate as a scanning agent for intracranial tumors. J. Nucl. Med. 5, 542−550. (17) Ting, R., Adam, M. J., Ruth, T. J., and Perrin, D. M. (2005) Arylfluoroborates and alkylfluorosilicates as potential PET imaging agents: High-yielding aqueous biomolecular 18F-labeling. J. Am. Chem. Soc. 127, 13094−13095. (18) Schirrmacher, R., Bradtmöller, G., Schirrmacher, E., Thews, O., Tillmanns, J., Siessmeier, T., Buchholz, H. G., Bartenstein, P., Wängler, B., Niemeyer, C. M., and Jurkschat, K. (2006) 18F-labeling of peptides by means of an organosilicon-based fluoride acceptor. Angew. Chem., Int. Ed. 45, 6047−6050. (19) Mu, L., Höhne, A., Schubiger, P. A., Ametamey, S. M., Graham, K., Cyr, J. E., Dinkelborg, L., Stellfeld, T., Srinivasan, A., Voigtmann, U., and Klar, U. (2008) Silicon-based building blocks for one-step 18Fradiolabeling of peptides for pet imaging. Angew. Chem., Int. Ed. 47, 4922−4925. (20) Li, Z., Chansaenpak, K., Liu, S., Wade, C. R., Conti, P. S., and Gabbai, F. P. (2012) Harvesting 18F-fluoride ions in water via direct 18F-19F isotopic exchange: Radiofluorination of zwitterionic aryltrifluoroborates and in vivo stability studies. MedChemComm 3, 1305− 1308. (21) D’Souza, C. A., McBride, W. J., Sharkey, R. M., Todaro, L. J., and Goldenberg, D. M. (2011) High-yielding aqueous 18F-labeling of peptides via Al18F chelation. Bioconjugate Chem. 22, 1793−1803. (22) McBride, W. J., Sharkey, R. M., and Goldenberg, D. M. (2013) Radiofluorination using aluminum-fluoride (Al18F). EJNMMI Res. 3, 36−36. (23) Bernard-Gauthier, V., Wängler, C., Schirrmacher, E., Kostikov, A., Jurkschat, K., Waengler, B., and Schirrmacher, R. (2014) 18Flabeled silicon-based fluoride acceptors: Potential opportunities for novel positron emitting radiopharmaceuticals. BioMed Res. Int. 2014, 1. (24) Wängler, C., Kostikov, A., Zhu, J., Chin, J., Wängler, B., and Schirrmacher, R. (2012) Silicon-[18F]fluorine radiochemistry: Basics, applications and challenges. Appl. Sci. 2, 277. (25) Zeng, J.-L., Wang, J., and Ma, J.-A. (2015) New strategies for rapid 18F-radiolabeling of biomolecules for radionuclide-based in vivo imaging. Bioconjugate Chem. 26, 1000−1003. (26) Burke, B. P., Clemente, G. S., and Archibald, S. J. (2015) Boron−18F containing positron emission tomography radiotracers: Advances and opportunities. Contrast Media Mol. Imaging 10, 96−110. (27) Mu, L., August Schubiger, P., and M. Ametamey, S. (2010) [18F]fluorosilicon- and [18F]fluoroboron-based biomolecules for PET imaging. Curr. Radiopharm. 3, 224−242. (28) Ting, R., Harwig, C. W., Lo, J., Li, Y., Adam, M. J., Ruth, T. J., and Perrin, D. M. (2008) 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. 73, 4662−4670. (29) Ting, R., Lo, J., Adam, M. J., Ruth, T. J., and Perrin, D. M. (2008) Capturing aqueous [18F]-fluoride with an arylboronic ester for pet: Synthesis and aqueous stability of a fluorescent [18F]-labeled aryltrifluoroborate. J. Fluorine Chem. 129, 349−358. (30) Li, Y., Guo, J., Tang, S., Lang, L., Chen, X., and Perrin, D. M. (2013) One-step and one-pot-two-step radiosynthesis of cyclo-RGD18F-aryltrifluoroborate conjugates for functional imaging. Am. J. Nucl. Med. Mol. Imaging 3, 44−56. (31) Li, Y., Liu, Z., Harwig, C. W., Pourghiasian, M., Lau, J., Lin, K.S., Schaffer, P., Benard, F., and Perrin, D. M. (2013) 18F-click labeling of a bombesin antagonist with an alkyne-18F-ArBF3−: In vivo pet imaging of tumors expressing the GRP-receptor. Am. J. Nucl. Med. Mol. Imaging 3, 57−70.

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NOTE ADDED AFTER ASAP PUBLICATION This paper was published to the Web on November 25, 2015, with an error in Figure 3. This was corrected in the version published to the Web on December 17, 2015.

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