title: Development of a new radioligand, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoroethyl-5-methoxybenzyl)acetamide, for pet imaging of peripheral benzodiazepine receptor in primate brain.
abstract: To develop a positron emission tomography (PET) ligand for imaging the 'peripheral benzodiazepine receptor' (PBR) in brain and elucidating the relationship between PBR and brain diseases, four analogues (4-7) of N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide (2) were synthesized and evaluated as ligands for PBR. Of these compounds, fluoromethyl (4) and fluoroethyl (5) analogues had similar or higher affinities for PBR than the parent compound 2 (K(i) = 0.16 nM for PBR in rat brain sections). Iodomethyl analogue 6 displayed a moderate affinity, whereas tosyloxyethyl analogue 7 had weak affinity. Radiolabeling was performed for the fluoroalkyl analogues 4 and 5 using fluorine-18 ((18)F, beta(+); 96.7%, T(1/2) = 109.8 min). Ligands [(18)F]4 and [(18)F]5 were respectively synthesized by the alkylation of desmethyl precursor 3 with [(18)F]fluoromethyl iodide ([(18)F]8) and 2-[(18)F]fluoroethyl bromide ([(18)F]9). The distribution patterns of [(18)F]4 and [(18)F]5 in mice were consistent with the known distribution of PBR. However, compared with [(18)F]5, [(18)F]4 displayed a high uptake in the bone of mice. The PET image of [(18)F]4 for monkey brain also showed significant radioactivity in the bone, suggesting that this ligand was unstable for in vivo defluorination and was not a useful PET ligand. Ligand [(18)F]5 displayed a high uptake in monkey brain especially in the occipital cortex, a region with richer PBR than the other regions in the brain. The radioactivity level of [(18)F]5 in monkey brain was 1.5 times higher than that of [(11)C]2, and 6 times higher than that of (R)-(1-(2-chlorophenyl)-N-[(11)C]methyl,N-(1-methylpropyl)isoquinoline ([(11)C]1). Moreover, the in vivo binding of [(18)F]5 was significantly inhibited by PBR-selective 2 or 1, indicating that the binding of [(18)F]5 in the monkey brain was mainly due to PBR. Metabolite analysis revealed that [(18)F]4 was rapidly metabolized by defluorination to [(18)F]F(-) in the plasma and brain of mice, whereas [(18)F]5 was metabolized by debenzylation to a polar product [(18)F]13 only in the plasma. No radioactive metabolite of [(18)F]5 was detected in the mouse brain. The biological data indicate that [(18)F]5 is a useful PET ligand for PBR and is currently used for imaging PBR in human brain.
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: Masanao
authors.initials: M
authors.lastname: Ogawa
authors.forename: Junko
authors.initials: J
authors.lastname: Noguchi
authors.forename: Takehito
authors.initials: T
authors.lastname: Ito
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Takashi
authors.initials: T
authors.lastname: Okauchi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Obayashi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D005462:Fluorine Radioisotopes; D066298:In Vitro Techniques; D007553:Isotope Labeling; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D000081:Acetamides; D005462:Fluorine Radioisotopes; D008024:Ligands; C475621:N-(5-fluoro-2-phenoxyphenyl)-N-(2-fluoroethyl-5-methoxybenzyl)acetamide; D011963:Receptors, GABA-A