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Development of two new PET radiotracers with different brain kinetics for imaging monoacylglycerol lipase in brain
https://repo.qst.go.jp/records/80202
https://repo.qst.go.jp/records/802022bcd5bde-1e37-466d-b5ce-e3af6e4d6969
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2020-07-02 | |||||
| タイトル | ||||||
| タイトル | Development of two new PET radiotracers with different brain kinetics for imaging monoacylglycerol lipase in 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_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 |
Mori, Wakana
× Mori, Wakana× Mori, Wakana |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Objectives: Monoacylglycerol lipase (MAGL) is a serine hydrolase that hydrolyzes 2-arachidonoylglycerol (2-AG) into arachidonic acid (AA) and glycerol in brain. Because 2-AG and AA are endogenous biologically active ligands in brain, inhibition of MAGL is an attractive therapeutic target for brain diseases, such as neuroinflammation. Recently some therapeutic drug candidates have been developed by irreversibly inhibiting MAGL in brain. In this study, to visualize the brain MAGL and provide proof-of-concept for the drug candidates, we developed two new irreversible PET tracers 11C-1 and 11C-2 and evaluated their in vivo potentials in the brain. Methods: The unlabeled compounds 1 and 2 were synthesized by 5-step reactions starting from commercially-available chemicals, respectively. The radiosynthesis of 11C-1 or 11C-2 was performed by reacting alcohol with 11C-phosgene, followed by reaction with the corresponding amine. Small-animal PET scans for rats were conducted to examine the in vivo brain regional distribution of radioactivity. In vitro and in vivo stability tests were also conducted. Results: Compounds 1 and 2 were obtained in total yields of 20-30%, respectively. Radiotracers 11C-1 and 11C-2 were achieved in around 10% isolated radiochemical yields (relative to 11CO2, non-decay corrected). Their radiochemical purity exceeded 98%, and the molar activity was higher than 74 GBq/μmol at the end of synthesis. PET imaging studies showed that the two radiotracers could pass through blood-brain-barrier and the initial uptakes reached 1.5 SUV in the rat brain. Their wide distribution pattern of radioactivity was consistent with the pattern of MAGL in the brain. Pretreatment with MAGL-selective inhibitor JW642 significantly reduced the uptake of radioactivity in the brain. While the radioactivity level for 11C-1 decreased in the brain after the radiotracer injection, the radioactivity for 11C-2 retained a definite level until the end of PET. In vitro stability tests showed that 11C-CO2 was continuously released from the incubated mixture of 11C-1 with brain homogenate, whereas no gaseous radioactivity was formed in the mixture of 11C-2 with the homogenate. Conclusions: Two novel PET tracers 11C-1 and 11C-2 for imaging MAGL were synthesized and obtained with applicable radioactivity yield and enough quality for the evaluation studies. PET imaging studies with 11C-1 and11C-2 showed high brain uptakes and in vivo specific bindings for MAGL in the rat brain. 11C-2 displayed the brain kinetics as a typical irreversible radiotracer while 11C-1 showed a different kinetics from 11C-2. The radiotracers could be used to visualize MAGL in diseased brain models for different purposes. |
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| 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 | SNMMI 2020 Annual Meeting | |||||
| 発表年月日 | ||||||
| 日付 | 2020-07-12 | |||||
| 日付タイプ | Issued | |||||
