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

N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[F-18]fluoromethoxy-d(2)-5-methoxybenzyl)acetamide ([F-18]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 [F-18]F- by defluorination of the [F-18]fluoromethyl moiety. In this study, we designed a deuterium-substituted analogue, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[F-18]fluoromethoxy-d2-5-methoxybenzyI)acetamide ([F-18]5) as a radioligand for PBR to reduce the in vivo metabolic rate of the non-deuterated [F-18]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-d(2) (CD2I2, 6) with a phenol precursor 7, followed by treatment with tetrabutylammonium fluoride. The ligand [F-18]5 was synthesized by the alkylation of 7 with [F-18]fluoromethyl iodide-d(2) ([F-18]FCD2I, [F-18]9). Compound 5 displayed a similar in vitro affinity to PBR (IC50: 1.90nM) with 2. In vivo evaluation demonstrated that [F-18]5 was metabolized by defluorination to [F-18]F- as a main radioactive component, but its metabolic rate was slower than that of [F-18]2 in the brain of mice. The deuterium substitution decreased the radioactivity level of[F-18]5 in the bone of mouse, augmented by 1 the percentage of specific binding to PBR in the rat brain determined by ex vivo autoradiography. However, the PET image of [F-18]5 for monkey brain showed high radioactivity in the brain and skull, suggesting a possible species difference between rodents and primates. (C) 2004 Elsevier Ltd. All rights reserved.