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A novel PET ligand for visualising cellular and axonal DREADD expression in monkeys
https://repo.qst.go.jp/records/66523
https://repo.qst.go.jp/records/665235edf4f08-46ec-44dd-b0fa-8977cca53469
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2017-11-20 | |||||
| タイトル | ||||||
| タイトル | A novel PET ligand for visualising cellular and axonal DREADD expression in monkeys | |||||
| 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 |
永井, 裕司
× 永井, 裕司× 季, 斌× Xiong, Yan× Liu, Jing× 堀, 由紀子× Inoue, Kenichi× 平林, 敏行× 藤本, 淳× 関, 千江× 熊田, 勝志× 張, 明栄× 須原, 哲也× Takada, Masahiko× 樋口, 真人× L., Roth Bryan× Jin, Jian× 南本, 敬史× 永井 裕司× 季 斌× 堀 由紀子× 平林 敏行× 藤本 淳× 関 千江× 熊田 勝志× 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 temporally and remotely control activity of a target cell population expressing a "designer receptor" by systemic delivery of an agonist compound. Non-invasive visualization of the inhibitory designer receptor, hM4Di, by positron emission tomography (PET) (Nagai et al., 2016) now enables us to monitor the expression and the agonist dose–occupancy relationship that provides the critical information for successful chemogenetic silencing in long-term studies in monkeys as well as for future clinical therapeutics. However, the current PET ligand, 11C-clozapine, has low specificity for DREADDs, thereby the image suffers from a regional difference in "baseline noise". Here we developed a new ligand, a carbon-11-labeled derivative of DREADD agonists (Chen et al., 2015), to improve the sensitivity of DREADD-PET imaging. In vitro assay demonstrated that, unlike clozapine, the derivative did not display high potency for major endogenous G protein coupled receptors. We examined the new PET ligand in a monkey that received injections of an hM4Di-expressing viral vector into the unilateral putamen. As seen with 11C-clozapine, PET imaging localized an increased uptake of the new ligand at the putative hM4Di-expressing site. Compared with 11C-clozapine, the signal-to-noise ratio was largely improved; the ligand uptake at the putative hM4Di-expressing site was enhanced by about 10%, while the baseline uptakes in the striatum or other subcortical areas were reduced by about 30%. Pretreatment with an unlabeled ligand at a dose of 1 mg/kg almost completely diminished the uptake at the injection site, and therefore the ligand uptake appeared to reflect in vivo DREADD expression. Besides the injection site in the putamen, an increased uptake was also found in its projection areas, i.e., the globus pallidus and the substantia nigra, presumably reflecting hM4Di expression at the axon terminal. Two additional monkeys were scanned following bilateral injections of an AAV-hM4Di vector into the rostromedial caudate or the thalamus. In vivo hM4Di expressions in these two subcortical areas were also detected as high ligand uptakes. These results indicate that our new PET ligand provides a high DREADD selectivity in subcortical regions in monkeys, thus being beneficial for quantitative assessment and sensitive detection of DREADD expression even at the axon terminal. | |||||
| 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 | 47th Annual Meeting of Society for Neuroscience | |||||
| 発表年月日 | ||||||
| 日付 | 2017-11-13 | |||||
| 日付タイプ | Issued | |||||
