title: N-(3,4-Dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[(11)C]methylphenyl)thiazol-2-yl]-1-carboxamide: A promising positron emission tomography ligand for fatty acid amide hydrolase.
abstract: To visualize fatty acid amide hydrolase (FAAH) in brain in vivo, we developed a novel positron emission tomography (PET) ligand N-(3,4-dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[(11)C]methylphenyl)thiazol-2-yl]-1-carboxamide ([(11)C]DFMC, [(11)C]1). DFMC (1) was shown to have high binding affinity (IC50: 6.1nM) for FAAH. [(11)C]1 was synthesized by C-(11)C coupling reaction of arylboronic ester 2 with [(11)C]methyl iodide in the presence of Pd catalyst. At the end of synthesis, [(11)C]1 was obtained with a radiochemical yield of 20±10% (based on [(11)C]CO2, decay-corrected, n=5) and specific activity of 48-166GBq/μmol. After the injection of [(11)C]1 in mice, high uptake of radioactivity (>2% ID/g) was distributed in the lung, liver, kidney, and brain, organs with high FAAH expression. PET images of rat brains for [(11)C]1 revealed high uptakes in the cerebellar nucleus (SUV=2.4) and frontal cortex (SUV=2.0), two known brain regions with high FAAH expression. Pretreatment with the FAAH-selective inhibitor URB597 reduced the brain uptake. Higher than 90% of the total radioactivity in the rat brain was irreversible at 30min after the radioligand injection. The present results indicate that [(11)C]1 is a promising PET ligand for imaging of FAAH in living brain.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shimoda
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujinaga
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Hatori
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Joji
authors.initials: J
authors.lastname: Yui
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Yiding
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan; SHI Accelerator Service Co. Ltd, 1-17-6 Osaki, Shinagawa-ku, Tokyo 141-0032, Japan.
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nengaki
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan; SHI Accelerator Service Co. Ltd, 1-17-6 Osaki, Shinagawa-ku, Tokyo 141-0032, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kurihara
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kumata
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ishii
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan. Electronic address: zhang@nirs.go.jp.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology; D002250:Carbon Radioisotopes; D006801:Humans; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000032:analysis* / Q000737:chemistry; D051381:Rats; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014018:Tissue Distribution; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001549:Benzamides; D002219:Carbamates; D002250:Carbon Radioisotopes; D008024:Ligands; D010879:Piperazines; D019275:Radiopharmaceuticals; D013844:Thiazoles; D000099252:Fatty Acid Amide Hydrolases; C000611508:N-(3,4-dimethylisoxazol-5-yl)piperazine-4-(4-(2-fluoro-4-((11)C)methylphenyl)thiazol-2-yl)1-carboxamide; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
keywords: Fatty acid amide hydrolase; Irreversible specific binding; PET; [(11)C]methyl iodide