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Development of novel 18F-labeled PET tracers for imaging TSPO with insensitivity to rs6971 polymorphism
https://repo.qst.go.jp/records/80201
https://repo.qst.go.jp/records/802012073c480-70ac-4cb1-acbf-7481fa063c06
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2020-07-06 | |||||
| タイトル | ||||||
| タイトル | Development of novel 18F-labeled PET tracers for imaging TSPO with insensitivity to rs6971 polymorphism | |||||
| 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 |
Zhang, Lingling
× Zhang, Lingling× Fujinaga, Masayuki× Ji, Bin× Kuan, Hu× Ye, Weijian× Xie, Lin× Zhang, Yiding× Hou, Lu× Xu, Hao× Ming-Rong, Zhang× Lu, Wang× Fujinaga, Masayuki× Ji, Bin× Kuan, Hu× Xie, Lin× Zhang, Yiding× Ming-Rong, Zhang× Lu, Wang |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Objectives: The translocator protein 18 kDa (TSPO), whose expression is upregulated by the activation of glia cells, is a continuously attractive biomarker for exploring neuroinflammation and neurologic disorders such as AD, PD and multiple sclerosis by PET. However, most TSPO PET tracers are sensitive to rs6971 polymorphism in human. In this study, we aim to identify some potential 18F-labeled PET tracers with high affinities, good brain uptake as well as reasonable insensitivity to rs6971 polymorphism. Methods: Through the structure-activity relationship study, two novel candidates with aryl fluorine moiety, namely LW-1-F and LW-2-F, were screened with high TSPO binding affinities. The corresponding 18F-isotopologues, 18F-LW-1 and 18F-LW-2, were synthesized automatically via spirocyclic iodonium ylide (SCIDY) strategy by CFN-MPS200 module. Dynamic neuroPET imaging were performed on wild-type Sprague-Dawley (SD) rats. The specificities and sensitivities to rs6971 polymorphism were evaluated by autoradiography (ARG) with LAB and HAB postmortem human brain slices. The pharmacokinetics were explored on mice by ex vivo biodistribution (bioD). Results: Both LW-1-F and LW-2-F showed excellent binding affinity with Ki < 0.1 nM. For radiofluorination, the corresponding SCIDY precursors were successfully obtained as colorless solids. The radiochemical yields were 16 ± 5% (n.d.c, n = 4, 18F-LW-1) and 15 ± 7% (n.d.c., n = 4, 18F-LW-2), respectively. The total radiosynthesis time was less than 90 min with good molar activities (> 1 Ci/μmol) and radiochemical purities (> 99%). MicroPET imaging showed that 18F-LW-1 penetrated the blood-brain-barrier (BBB) of SD rat, with the highest whole brain uptake as 1.38 SUV at 2 min post-injection, and gradually washed out to 0.7 SUV after 20 min and remained at this level. The ARG results from human brain slices showed a certain level of sensitivity to rs6971 (ratioHAB/LAB = 1.7) and nonspecific binding. 18F-LW-2 showed reasonable insensitivity (ratioHAB/LAB = 1.1) and excellent in vitro specific binding by ARG study. Ex vivo biodistribution of 18F-LW-2 showed high radioactivity accumulation in the lungs, heart, kidney and adrenal glands, as well as urinary and hepatobiliary excretion. Conclusions: We have efficiently synthesized a series of novel TSPO ligands with aryl fluorine skeleton. Specifically, LW-1-F and LW-2-F showed good binding affinity to TSPO, which were successfully radiolabeled for imaging study. The microPET, in vitro ARG and ex vivo bioD study revealed that 18F-LW-2 showed good specificity, pharmacokinetics as well as reasonable insensitivity to rs6971 polymorphism, which is a potential PET tracer for visualizing TSPO in human. |
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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 | |||||
