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PET imaging of selective control of neural activity with a novel DREADD agonist
https://repo.qst.go.jp/records/72882
https://repo.qst.go.jp/records/72882498404f0-cfb0-4cad-9a5d-fc267a00b686
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2018-08-02 | |||||
| タイトル | ||||||
| タイトル | PET imaging of selective control of neural activity with a novel DREADD agonist | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_c94f | |||||
| 資源タイプ | conference object | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Nagai, Yuji
× Nagai, Yuji× Miyakawa, Naohisa× Ji, Bin× Hori, Yukiko× Huang, Xi-Ping× Slocum, Sam× Yan, Xiong× Ono, Maiko× Shimojo, Masafumi× English, Justin× Liu, Jing× Inoue, Ken-Ichi× Kumata, Katsushi× Hirabayashi, Toshiyuki× Seki, Chie× Fujimoto, Atsushi× Mimura, Koki× Oyama, Kei× Zhang, Ming-Rong× Suhara, Tetsuya× Takada, Masahiko× Higuchi, Makoto× Jin, Jian× Roth, Bryan× Minamimoto, Takafumi× 永井 裕司× 宮川 尚久× 季 斌× 堀 由紀子× 小野 麻衣子× 下條 雅文× 熊田 勝志× 平林 敏行× 関 千江× 藤本 淳× 三村 喬生× 小山 佳× 張 明栄× 須原 哲也× 樋口 真人× 南本 敬史 |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | 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. | |||||
| 会議概要（会議名, 開催地, 会期, 主催者等） | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | 第41回日本神経科学大会 | |||||
| 発表年月日 | ||||||
| 日付 | 2018-07-28 | |||||
| 日付タイプ | Issued | |||||
