title: [(11)C-carbonyl]CEP-32496: radiosynthesis, biodistribution and PET study of brain uptake in P-gp/BCRP knockout mice.
abstract: CEP-32496 is a novel, orally active serine/threonine-protein kinase B-raf (BRAF) (V600E) kinase inhibitor that is being investigated in clinical trials for the treatment of some cancers in patients. In this study, we developed [(11)C-carbonyl]CEP-32496 as a novel positron emission tomography (PET) probe to study its biodistribution in the whole bodies of mice. [(11)C]CEP-32496 was synthesized by the reaction of 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine hydrochloride (1·HCl) with [(11)C]phosgene, followed by treatment with 3-(6,7-dimethoxyquinozolin-4-yloxy)aniline (2). Small-animal PET studies with [(11)C]CEP-32496 indicated that radioactivity levels (AUC0-90 min, SUV×min) accumulated in the brains of P-gp/BCRP knockout mice at a 8-fold higher rate than in the brains of wild-type mice.
authors.affiliation: Molecular Probe Program, 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 Probe Program, 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 Probe Program, 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 Probe Program, 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 Probe Program, 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 Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan; SHI Accelerator Service Co. Ltd, 5-9-11 Kitashinagawa, Shinagawa-ku, Tokyo 141-8686, Japan.
authors.forename: Masanao
authors.initials: M
authors.lastname: Ogawa
authors.affiliation: Molecular Probe Program, 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 Probe Program, 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 Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.affiliation: Molecular Probe Program, 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: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002247:Carbon Isotopes; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D010671:Phenylurea Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D011799:Quinazolines / Q000737:chemistry / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D002247:Carbon Isotopes; D010671:Phenylurea Compounds; D011799:Quinazolines; D019275:Radiopharmaceuticals; C575620:agerafenib
keywords: BCRP; BRAF; P-gp; PET; [(11)C]CEP-32496; [(11)C]phosgene