Journal Article Development of Novel PET Probes for Central 2-Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) Receptors

Oi, Norihito  ,  Tokunaga, Masaki  ,  Suzuki, Michiyuki  ,  Nagai, Yuji  ,  Nakatani, Yosuke  ,  Yamamoto, Noboru  ,  Maeda, Jun  ,  Minamimoto, Takafumi  ,  Ming-Rong, Zhang  ,  Suhara, Tetsuya  ,  Higuchi, Makoto

58 ( 21 )  , pp.8444 - 8462 , 2015-10 , ACS Publications
We document the development of PET probes for central AMPA receptors and their application to in vivo imaging of animals. 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 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 analogs as candidates. [11C]21a was shown by autoradiography to specifically bind to the neocortex and hippocampus, consistent with AMPA receptor localization. PET imaging with [11C]21a demonstrated moderate uptake of radioactivity in rat and monkey brains, with the retention of radiosignals being consistent with autoradiograms, 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.

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