@misc{oai:repo.qst.go.jp:00072882,
 author = {Nagai, Yuji and Miyakawa, Naohisa and Ji, Bin and Hori, Yukiko and Huang, Xi-Ping and Slocum, Sam and Yan, Xiong and Ono, Maiko and Shimojo, Masafumi and English, Justin and Liu, Jing and Inoue, Ken-Ichi and Kumata, Katsushi and Hirabayashi, Toshiyuki and Seki, Chie and Fujimoto, Atsushi and Mimura, Koki and Oyama, Kei and Zhang, Ming-Rong and Suhara, Tetsuya and Takada, Masahiko and Higuchi, Makoto and Jin, Jian and Roth, Bryan and Minamimoto, Takafumi and 永井 裕司 and 宮川 尚久 and 季 斌 and 堀 由紀子 and 小野 麻衣子 and 下條 雅文 and 熊田 勝志 and 平林 敏行 and 関 千江 and 藤本 淳 and 三村 喬生 and 小山 佳 and 張 明栄 and 須原 哲也 and 樋口 真人 and 南本 敬史},
 month = {Jul},
 note = {The chemogenetic technology, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), offers a means to reversibly and remotely control the activity of a target cell population expressing a "designer receptor" by systemic delivery of an exogenous agonist (Armbruster et al. 2007). The major agonist for muscarinic receptor-based DREADDs, clozapine-N-oxide (CNO), has been commonly used for neuroscience research with rodents and monkeys. However, because CNO does not enter the brain easily, the mechanism of its action at DREADDs is complicated (Gomez et al. 2017). Our previous positron emission tomography (PET) study has shown that radio-labelled compound X - a derivative of clozapine analogue - selectively binds to both excitatory (hM3Dq) and inhibitory (hM4Di) DREADDs in monkeys (Nagai et al. SfN meeting 2017). This study aimed to pharmacologically validate X as a selective DREADD agonist that works effectively in monkeys. In vitro TANGO assay demonstrated that X is a potent agonist for both hM3Dq and hM4Di (EC50 ~1 nM and ~0.1 nM, respectively), being 10-fold more potent than CNO (EC50 ~20 nM and ~3 nM, respectively). X does not have significant agonist potency for any of over 300 endogenous G-protein coupled receptors at a dose < 10 μM. PET occupancy study with [11C]X indicated that intravenous injection (i.v.) of X at a dose of 1 and 100 μg/kg yields < 5% and ~80% hM4Di occupancy, respectively. Following X administration at a high dose (100 μg/kg), its concentration in cerebrospinal fluid reached a maximum level at 15 min and maintained this level for at least 2 hours without a significant amount of metabolites. To validate the agonist efficacy of X in vivo, we repeatedly performed [18F]FDG-PET imaging with monkeys expressed hM3Dq in the unilateral amygdala. Single dose of X (1 and 100 μg/kg, i.v.) resulted in significantly increased glucose metabolism in the hM3Dq-expressing area (~116% and ~136% of baseline, respectively) but not in the contralateral control area. The same doses of X did not significantly change the regional glucose metabolism in non-DREADD-expressing monkeys. These results demonstrated that compound X is a potent, effective and selective DREADD agonist that enables selective control of neural activity in monkeys., 第41回日本神経科学大会},
 title = {PET imaging of selective control of neural activity with a novel DREADD agonist},
 year = {2018}
}