A practical route for synthesizing a PET ligand containing [18F]fluorobenzene using reaction of diphenyliodonium salt with [18F]F-

The aim of this study was to develop a practical route for preparing a fluorine-18 ([18F]) labelled ligand ([18F]1) containing [18F]fluorobenzene ring by employing the reaction of diphenyliodonium salt with [18F]F−. Diphenyliodonium tosylate (2) was synthesized from tributylphenylstannyl compound (6) with [hydroxy(tosyloxy)iodo]benzene (7). Using this method, [18F]DAA1106 ([18F]3a), a positron emission tomography ligand for imaging peripheral-type benzodiazepine receptor, was prepared

PRACTICAL SYNTHESIS OF [18F]FLUOROBENZENE STARTING FROM PHENYLTRIBUTYLSTANNE

17th International Symposium on Radiopharmaceutical Science

Development of scandium-catalyzed N-[18F]fluoroalkylation of aryl and heteroaryl amines with [18F]epifluorohydrin.

Objectives: [18F]Fluoroalkylation is a useful method for introduction of fluorine-18 into molecules containing NH, OH, and SH-groups. Using various [18F]fluoroalkylating agents, we are routinely producing clinically-useful 18F-radiotracers, such as [18F]FMeNER-d2, [18F]FEDAA1106, [18F]FEDAC, [18F]FE-SPARQ and [18F]FEtPE2I. Recently, we have reported a convenient [18F]fluoroalkylation route for introducing 3-[18F]fluoro-2-hydroxypropyl ([18F]FHP) group into a targeted molecule via ring-opening reaction of [18F]epifluorohydrin ([18F]2) with phenol analogs by using an automated synthesis system [1]. However, despite the usefulness of epifluorohydrin in organic chemistry, the reaction of [18F]2 with low nucleophilic reagents, such as aromatic amine has rarely been reported. To extend application of this technique, in this study, we developed a simple method for introducing [18F]FHP group into aryl or heteroaryl amines in the presence of Sc(OTf)3. Methods: Unlabeled 3a-n were prepared by reactions of aryl or heteroaryl amines with epifluorohydrin in the presence of Sc(OTf)3 at moderate chemical yields (40-84%). [18F]2 was synthesized by the reaction of glycidyl tosylate 1 (10 mg) and [18F]KF/K2.2.2 in 1,2-dichlorobenzene at 130 oC for 2 min and immediately transferred by distillation into a reaction vial including aromatic amine in CCl4. The reaction conditions for the N-[18F]fluoroalkylation of p-anisidine as a model compound with [18F]2 were optimized with regard to solvents, temperatures and times. Under the optimized conditions, [18F]3a-n were synthesized by the reaction of various aryl or heteroaryl amines and [18F]2. Radiochemical conversions (RCCs) were determined by radio-HPLC for these reaction mixtures. Figure 1. Synthesis of [18F]3a–nResults: Firstly, a suitable solvent for N-[18F]fluoroalkylation of p-anisidine with [18F]2 in the presence of Sc(OTf)3 (10 mol%) was examined. In coordinating solvents such as THF and DMF, the reaction did not effectively proceed. On the other hand, the reaction efficiency was significantly increased by the use of nonpolar solvent such as CCl4. Under several temperatures and times investigated, the reaction performed in CCl4 at 50 oC for 20 min was found to give the best [18F]fluoroalkylating result. According to the optimized conditions, [18F]3a was synthesized by reaction of p-anisidine and [18F]2 using an automated synthesis system. By purification for the reaction mixture with semi-preparative HPLC and formulation, [18F]3a was obtained with a synthesis time of 85 ± 3 min and 27% radiochemical yield (isolated-yield based on the cyclotron-produced [18F]F-). To demonstrate suitability of this method, [18F]3b-n were synthesized from various aryl or heteroaryl amines containing halogen, alkyl, acetyl or hydroxyl groups. Radio-HPLC analyses for the reaction mixtures indicated that [18F]3b-l and [18F]3m-n were yielded in 25–69% and 6–16% RCCs, respectively. Using 2,2,2-trifluoroethanol (TFE) as a co-solvent, N-[18F]fluoroalkylation of aryl amines proceeded more effectively to give the corresponding product [18F]3b-l in 30–98% RCCs.Conclusion: Scandium-catalyzed N-[18F]fluoroalkylation with [18F]2 allowed facile introduction of [18F]FHP group into aryl or heteroaryl amines under mild conditions. Next, we will focus on improving efficiency for the N-[18F]fluoroalkylation of heteroaryl amines.References: [1] M. Fujinaga, T. Ohkubo, T. Yamasaki, et al. ChemMedChem. 2018, 13, 1723–1731.ISRS201

One-Pot Radiosynthesis of [13N]Carbamate and [13N]Urea Using No-carrier Added [13N]NH3

Seventh International Conference on Nuclear and Radiochemistr

Development and preliminary evaluations of novel PET tracers for imaging TARP γ-8 receptors

Purpose/Background:AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor is an important protein in humans that is implicated in the increased risk of central nervous system (CNS) diseases including epilepsy and schizophrenia. Transmembrane AMPA receptor regulatory proteins subtype γ-8 (TARP γ-8) exhibits regiospecific expression in the brain, which could serve as a potential therapeutic target for CNS disorders with high selectivity. TARP γ-8 dependent AMPA receptors enrich primarily in the hippocampus. Through our previous in vitro studies, 6-(2-cyclobutyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]thiazol-2(3H)-one (compound 8, IC50 value of 0.02) and (2-cyclobutyl-3-(1H-indazol-5-yl)-5-methyl-3H-imidazo[4,5-b]pyridine (compound 15, IC50 value of 1.26) from their categories were screened out as two potent and selective TARP γ-8 antagonist. Herein we report the radiosynthesis of their 11C-isotopologue ([11C]8 and [11C]15) and the preliminary evaluation to test the feasibility of imaging TARP γ-8 dependent receptors in vivo by positron emission tomography (PET).Methods:Radiosynthesis of two potential PET tracers [11C]8 and [11C]15, and synthesis of the corresponding precursors 22 and 27 were carried out as shown in Figure 1A. The reactions between [11C]CH3I and precursor 22 or 27 were carried out by heating a mixture of the precursor (0.8 mg), [11C]CH3I, Pd2(dba)3 (0.2 mg), P(o-tol)3 (6.0 mg), CuBr (1.0 mg) and K2CO3 (1.0 mg) in DMF (0.45 mL) at 130 oC for 5 min. As a result, [11C]8 and [11C]15 were obtained in an average radiochemical yield (RCY) of 9% and 22%, respectively (relative to [11C]CO2, decay corrected) with both high radiochemical purity (>99%) and excellent molar activity (>150 GBq/μmol at the end of synthesis (EOS)) with total synthesis time 27 minutes. Both radiotracers [11C]8 and [11C]15 exhibited excellent in vitro stability up to 90 min after formulation. The novel radiosynthesis, combined with high radiochemical purity and molar activities of [11C]8 and [11C]15 prompted us to perform the subsequent PET evaluation studies.Results:The radioligand [11C]8 and [11C]15 were synthesized in 9% and 22% decay-corrected radiochemical yield (RCY) respectively, based on the starting [11C]CO2 at the end-of-synthesis with >99% radiochemical purity (n = 5). Both of their molar activities were greater than 150 GBq/µmol (4.1 Ci/µmol). No sign of radiolysis was observed up to 90 min after re-formulation for both of [11C]8 and [11C]15. In PET studies, the radioligand [11C]8 failed to penetrate the BBB with no significant heterogeneous distribution in the hippocampus, frontal cortex, and cerebellum was observed in the baseline PET study. [11C]15 exhibited improved BBB penetration with great heterogeneous regional distribution pattern (high uptake in hippocampus while low uptake in cerebellum). The dramatic reduction of bound signals of [11C]15 in blocking studies were observed as well. These collective results indicated excellent in vivo binding specificity of [11C]15 rather than [11C]8 toward TARP γ-8, indicating [11C]15 would be a potential PET tracer for the clinical translation.Conclusion:We have evaluated the radiochemical method to prepare 11C-labeled labeled TARP ɣ-8 antagonists (compound 8 and 15) based on Stille coupling-based labeling methodology. Ultimately, the desired compounds [11C]8 and [11C]15 were labeled by [11C]CH3I in high radiochemical yield (9% and 22% respectively), high molar activity (>150 GBq/μmol) and high radiochemical purity (>99%). Besides, the PET studies of [11C]15 showed higher in vivo binding specificity toward TARP γ-8 in hippocampus than [11C]8, indicating its potential in clinical translation.SNMMI202