title: Synthesis and evaluation of N-(5-fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoromethoxy-d(2)-5-methoxybenzyl)acetamide: a deuterium-substituted radioligand for peripheral benzodiazepine receptor.
abstract: N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoromethoxy-d(2)-5-methoxybenzyl)acetamide ([(18)F]2) is a potent ligand (IC(50): 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 [(18)F]F(-) by defluorination of the [(18)F]fluoromethyl moiety. In this study, we designed a deuterium-substituted analogue, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoromethoxy-d(2)-5-methoxybenzyl)acetamide ([(18)F]5) as a radioligand for PBR to reduce the in vivo metabolic rate of the non-deuterated [(18)F]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) (CD(2)I(2), 6) with a phenol precursor 7, followed by treatment with tetrabutylammonium fluoride. The ligand [(18)F]5 was synthesized by the alkylation of 7 with [(18)F]fluoromethyl iodide-d(2) ([(18)F]FCD(2)I, [(18)F]9). Compound 5 displayed a similar in vitro affinity to PBR (IC(50): 1.90 nM) with 2. In vivo evaluation demonstrated that [(18)F]5 was metabolized by defluorination to [(18)F]F(-) as a main radioactive component, but its metabolic rate was slower than that of [(18)F]2 in the brain of mice. The deuterium substitution decreased the radioactivity level of [(18)F]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 [(18)F]5 for monkey brain showed high radioactivity in the brain and skull, suggesting a possible species difference between rodents and primates.
authors.affiliation: Department of Medical Imaging, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan. zhang@nirs.go.jp
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Takehito
authors.initials: T
authors.lastname: Ito
authors.forename: Takashi
authors.initials: T
authors.lastname: Okauchi
authors.forename: Masanao
authors.initials: M
authors.lastname: Ogawa
authors.forename: Junko
authors.initials: J
authors.lastname: Noguchi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D003903:Deuterium; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D014018:Tissue Distribution
chemical_list: D000081:Acetamides; D001593:Benzyl Compounds; C502257:N-(5-fluoro-2-phenoxyphenyl)-N-(2-fluoromethoxy-d(2)-5-methoxybenzyl)acetamide; D011963:Receptors, GABA-A; D003903:Deuterium