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Demonstration of intracellular pH-weighting PET imaging using a new-type PET probe responsible for monoacylglycerol lipase activity in the brain
https://repo.qst.go.jp/records/86458
https://repo.qst.go.jp/records/86458ed49da96-f49f-4e7f-8b29-7d1e1fe20139
| Item type | 会議発表論文 / Conference Paper(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2022-05-06 | |||||
| タイトル | ||||||
| タイトル | Demonstration of intracellular pH-weighting PET imaging using a new-type PET probe responsible for monoacylglycerol lipase activity in the brain | |||||
| 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_5794 | |||||
| 資源タイプ | conference paper | |||||
| 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 |
Tomoteru, Yamasaki
× Tomoteru, Yamasaki× Wakana, Mori× Ohkubo, Takayuki× Atsuto, Hiraishi× Kurihara, Yusuke× Nobuki, Nengaki× Zhang, Ming-Rong× Tomoteru, Yamasaki× Wakana, Mori× Ohkubo, Takayuki× Atsuto, Hiraishi× Kurihara, Yusuke× Nobuki, Nengaki× Zhang, Ming-Rong |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Objectives: The brain acidosis is caused by intracellular hyper-accumulation of acidic sources (H+, lactate, and carbonic acid) by switching the cellular energy metabolism from aerobic to anaerobic by the hypoxia. Such intra cellular acidosis give curucial injury to central nurves system of the brain. Therefore, monitoring intracellular pH would be very important to diagnosis neuronal condition. Recently, covalent inhibitors for monoacylglycerol lipase (MAGL), an enzyme intracellur lacated on neuron and astrocyte in the brain and regulates endocannabinoid system, were identified by Bulter et al [1]. Among these inhibitors, 1,1,1,3,3,3-hexafluoropropan-2-yl 3-(1-phenyl-1H-pyrazol-3-yl)azetidine-1-carboxylate (1) showed reversible inhibitory effect to MAGL. The purpose of this study is to establish quantification method of hydrolysis rate of compound 1 mediated by MAGL and to demonstrate pH-weighted PET imaging in the brain of ischemic rat. Methods: To estimate interaction between compound 1 and MAGL, docking simulations were conducted comparing to similar chemical structural irreversible-type inhibitor (2). In addition, to evaluate influents of pH shifts, molecular dynamics (MD) simulations of compound 1 were also performed under the neutral (pH 7) or acidic (pH 6) conditions. Radiosynthesis of [11C]1 and [11C]2 was described in another presentation in this meeting (Mori W, et a1.). To confirm MAGL-hydrolysis of [11C]1, in vitro assessments using rat brain homogenates were conducted. PET imaging with [11C]1 was carried out using middle cerebral artery occlusion (MCAO) rat as an acute hypoxia model and hydrolysis rate (KH) of [11C]1 with MAGL was estimated by monoexponential fitting on time-activity curves of ipsilateral region. Results: MD simulations predicted that azetidine carbamate moiety of 1 was easily hydrolyzed by MAGL due to close distance from water molecule, compared to 2 containing piperidine carbamate. Moreover, the acylated azetidine in 1 has been shown to react differently than piperidine ring size amide in 2 due to decreased planarity in the amide moiety itself, conveyed by the ring strain associated with the azetidine itself. Additionally, it was simulated that the hydrolysis rate of 1 would be slower under the acidic condition because of changing interaction of 1 against water molecule. In vitro assessments showed that generation rate of 11CO2, the final product derived from hydrolysis of [11C]1, would become slower depending on pH shifts. In PET study with [11C]1 using MCAO rat, KH value in ipsilateral region was significantly slower than that in contralateral region. Conclusions: We successfully established the method for quantifying hydrolysis rate of MAGL using new-type PET probe and demonstrated pH-weighted imaging in vivo. |
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| 書誌情報 |
Nuclear Medicine and Biology 発行日 2022-06 |
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| 出版者 | ||||||
| 出版者 | Elsevier Ltd. | |||||
| ISSN | ||||||
| 収録物識別子タイプ | ISSN | |||||
| 収録物識別子 | 0969-8051 | |||||
