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Radiosynthesis of 6-(2-cyclobutyl-5-(methyl-11C)-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]thiazol-2(3H)-one and (2-cyclobutyl-3-(1H-indazol-5-yl)-5-[11C]methyl-3H-imidazo[4,5-b]pyridine for imaging γ-8 dependent transmembrane AMPA receptor regulatory protein
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Objectives: Transmembrane AMPA receptor regulatory proteins subtype γ8 (TARP γ8) exhibits regiospecific expression in the brain, which could serve as a potential therapeutic target for central nervous system disorders with high selectivity. Based on two potent and selective TARP γ-8 antagonists, 6-(2-cyclobutyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]thiazol-2(3H)-one (compound 8) and (2-cyclobutyl-3-(1H-indazol-5-yl)-5-methyl-3H-imidazo[4,5-b]pyridine (compound 15), we perform the radiosynthesis of its 11C-isotopologue and conduct preliminary evaluation to test the feasibility of imaging TARP γ-8 dependent receptors in vitro and in vivo.
Methods: The synthesis of precursor 22 was shown in Scheme 1A. Initially, the preparation of the compound 19 was achieved in 81% through the SN2 coupling reaction between 6-aminobenzo[d] thiazol-2(3H)-one 2 and 2,6-dibromo-3-nitropyridine in the presence of NEt3. As follows, the mild condition of Fe/NH4Cl instead of Pd/C-H2 system was used in the reduction of nitro group to amine in the terms of sensitive bromo-substitution group of 19, which offered 6-((3-Amino-6-bromopyridin-2-yl)amino)benzo[d]thiazol-2(3H)-one 20 with high chemoselectivity in the yield of 76%. The compound 20 then underwent condensation with cyclobutanecarbaldehyde, followed by oxidation, to afford benzothiazolone 21. The subsequent Pd catalyzed Stannylation generated 22 as a precursor in the yield of 36%. Similarly, the other precursor 27 was obtained from commercially available starting material of 1H-indazol-5-amine 10 in 6 steps (Scheme 1B). The radiosynthesis of [11C]8 and [11C]15 from the corresponding precursors were carried out. As a result, [11C]8 and [11C]15 were obtained in an average radiochemical yield (RCY) of 9% and 22%, respectively, with high radiochemical purity (>99%) and excellent molar activity (>150 GBq/μmol). The autoradiography (ARG) studies for [11C]8 were conducted to evaluate target binding in vitro. Figure 1 indicated heterogeneous regional distribution pattern from high to low in the order of hippocampus, cerebral cortex, striatum, thalamus and cerebellum in [11C]8 ARG studies. The distribution profile was consistent with the mRNA expression pattern of TARP γ-8 with the highest signal level in the region of the hippocampus and the lowest level in the cerebellum. For ligand [11C]8, blocking studies by compound 8 (1 µM) led to markedly decrease of the bound radioactivity in the TARP γ8 rich hippocampus.
Results: The radioligand [11C]8 and [11C]15 were synthesized in 9% and 22% 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 ARG studies, the radioligand [11C]8 exhibited great heterogeneous regional distribution pattern (high uptake in hippocampus while low uptake in cerebellum).
Conclusion: We have evaluated the radiochemical method to prepare 11C-labeled labeled TARP ɣ-8 antagonists 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%).
Radiosynthesis of 6-(2-cyclobutyl-5-(methyl-11C)-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]thiazol-2(3H)-one and (2-cyclobutyl-3-(1H-indazol-5-yl)-5-[11C]methyl-3H-imidazo[4,5-b]pyridine for imaging γ-8 dependent transmembrane AMPA receptor regulatory protein
