@article{oai:repo.qst.go.jp:00048777,
 author = {Takahata, Keisuke and Kimura, Yasuyuki and Seki, Chie and Tokunaga, Masaki and Ichise, Masanori and Kawamura, Kazunori and Ono, Maiko and Kitamura, Soichiro and Kubota, Manabu and Moriguchi, Sho and Ishii, Tatsuya and Takado, Yuhei and Niwa, Fumitoshi and Endo, Hironobu and Nagashima, Tomohisa and Ikoma, Yoko and Zhang, Ming-Rong and Suhara, Tetsuya and Higuchi, Makoto and 高畑 圭輔 and 木村 泰之 and 関 千江 and 徳永 正希 and 市瀬 正則 and 河村 和紀 and 小野 麻衣子 and 北村 聡一郎 and 久保田 学 and 森口 翔 and 石井 辰弥 and 高堂 裕平 and 丹羽 文俊 and 遠藤 浩信 and 永嶌 朋久 and 生駒 洋子 and 張 明栄 and 須原 哲也 and 樋口 真人},
 issue = {63},
 journal = {EJNMMI Research},
 month = {Aug},
 note = {Background: α-Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor is a primary mediator of fast
glutamatergic excitatory signaling in the brain and has been implicated in diverse neuropsychiatric diseases. We
recently developed a novel positron emission tomography (PET) ligand, 2-(1-(3-([11C]methylamino)phenyl)-2-oxo-5-
(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl) benzonitrile ([11C]HMS011). This compound is a radiolabelled derivative of
perampanel, an antiepileptic drug acting on AMPA receptors, and was demonstrated to have promising in vivo
properties in the rat and monkey brains. In the current study, we performed a human PET study using [11C]HMS011
to evaluate its safety and kinetics.
Four healthy male subjects underwent a 120-min PET scan after injection of [11C]HMS011. Arterial blood sampling
and metabolite analysis were performed to obtain parent input functions for three of the subjects using highperformance
liquid chromatography. Regional distribution volumes (VTs) were calculated based on kinetic models
with and without considering radiometabolite in the brain. The binding was also quantified using a reference tissue
model with white matter as reference.
Results: Brain uptake of [11C]HMS011 was observed quickly after the injection, followed by a rapid clearance. Three
hydrophilic and one lipophilic radiometabolites appeared in the plasma, with notable individual variability. The kinetics
in the brain with apparent radioactivity retention suggested that the lipophilic radiometabolite could enter the brain. A
dual-input graphical model, an analytical model designed in consideration of a radiometabolite entering the brain, well
described the kinetics of [11C]HMS011. A reference tissue model showed small radioligand binding potential (BP*ND)
values in the cortical regions (BP*ND = 0–0.15). These data suggested specific binding component of [11C]HMS011 in
the brain.
Conclusions: Kinetic analyses support some specific binding of [11C]HMS011 in the human cortex. However, this ligand
may not be suitable for practical AMPA receptor PET imaging due to the small dynamic range and metabolite in the brain.
Keywords: PET, Perampanel, AMPA, [11C]HMS011, Interspecies differences},
 title = {A human PET study of [¹¹C]HMS011, a potential radioligand for AMPA receptors},
 volume = {7},
 year = {2017}
}