Synthesis and evaluation of N-(5-fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoromethoxy-d2-5-methoxybenzyl)acetamide: a deuterium-substituted radioligand for peripheral benzodiazepine receptor Original Research Article

N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoromethoxy-d2-5-methoxybenzyl)acetamide ([18F]2) is a potent ligand (IC50: 1.71 nM) for peripheral benzodiazepine receptor (PBR). However, in vivo evaluation on rodents and primates showed that this ligand was unstable and rapidly metabolized to [18F]F− by defluorination of the [18F]fluoromethyl moiety. In this study, we designed a deuterium-substituted analogue, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoromethoxy-d2-5-methoxybenzyl)acetamide ([18F]5) as a radioligand for PBR to reduce the in vivo metabolic rate of the non-deuterated [18F]2. The design principle was based on the hypothesis that the deuterium substitution may reduce the rate of defluorination initiated by cleavage of the C–H bond without altering the binding affinity for PBR. The non-radioactive 5 was prepared by reacting diiodomethane-d2 (CD2I2, 6) with a phenol precursor 7, followed by treatment with tetrabutylammonium fluoride. The ligand [18F]5 was synthesized by the alkylation of 7 with [18F]fluoromethyl iodide-d2 ([18F]FCD2I, [18F]9). Compound 5 displayed a similar in vitro affinity to PBR (IC50: 1.90 nM) with 2. In vivo evaluation demonstrated that [18F]5 was metabolized by defluorination to [18F]F− as a main radioactive component, but its metabolic rate was slower than that of [18F]2 in the brain of mice. The deuterium substitution decreased the radioactivity level of [18F]5 in the bone of mouse, augmented by the percentage of specific binding to PBR in the rat brain determined by ex vivo autoradiography. However, the PET image of [18F]5 for monkey brain showed high radioactivity in the brain and skull, suggesting a possible species difference between rodents and primates.