title: Development of Novel PET Probes for Central 2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic Acid Receptors.
abstract: We document the development of PET probes for central AMPA receptors and their application to in vivo animal imaging. An initial screening of perampanel derivatives was performed to identify probe candidates. Despite the high autoradiographic contrast yielded by several radioligands, rat PET scans did not support their in vivo suitability. Further focused derivatization and a second screening by ex vivo LC-MS measurements led to the selection of 2-[1-(3-methylaminophenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl]benzonitrile, 21a, and its analogues as candidates. [(11)C]21a was shown by autoradiography to specifically bind to the neocortex and hippocampus, consistent with AMPA receptor localization. PET imaging with [(11)C]21a demonstrated moderate uptake of radioactivity in rat and monkey brains, with the retention of radiosignals being consistent with that from the autoradiogram data, and the uptake was blocked by pretreatment with unlabeled 21a in a dose-dependent manner. The current approach has facilitated the discovery of a PET probe potentially suitable for translational research and development focused on AMPA receptors.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd. , 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.|Molecular Imaging Center, National Institute of Radiological Sciences , 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan.
authors.forename: Norihito
authors.initials: N
authors.lastname: Oi
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences , 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Tokunaga
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd. , 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.|Molecular Imaging Center, National Institute of Radiological Sciences , 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan.
authors.forename: Michiyuki
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences , 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nagai
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd. , 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.|Molecular Imaging Center, National Institute of Radiological Sciences , 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Nakatani
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd. , 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences , 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences , 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Minamimoto
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences , 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences , 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences , 4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
mesh_terms: D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000000981:diagnostic imaging* / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000737:chemistry* / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D009570:Nitriles / Q000737:chemistry* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000032:analysis* / Q000378:metabolism
chemical_list: D002250:Carbon Radioisotopes; D009570:Nitriles; D018091:Receptors, AMPA; C014356:benzonitrile