WEKO3
アイテム
Development of Novel PET Ligands for Imaging Orexin 2 Receptor
https://repo.qst.go.jp/records/86447
https://repo.qst.go.jp/records/86447f683f10e-5f4c-47f3-9b1f-2be653446e55
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2022-06-20 | |||||
| タイトル | ||||||
| タイトル | Development of Novel PET Ligands for Imaging Orexin 2 Receptor | |||||
| 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 |
Rong, Jian
× Rong, Jian× Tomoteru, Yamasaki× Zhao, Chunyu× Li, Yinlong× Shao, Yihan× Zhe Sun, Phillip× L. Collier, Thomas× Zhang, Ming-Rong× Liang, Steven× Tomoteru, Yamasaki× Zhang, Ming-Rong |
|||||
| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Purpose/Background: The orexin 2 receptor (OX2R) is a G-protein coupled receptor expressed in brain that binds orexin neuropeptides A and B. OX2R is involved in motivation, feeding behaviour, and sleep-wake regulation. Modulation of OX2R with agonists has been found to be a potential treatment towards sleep related disorders. Herein we report [11C]1 and [11C]2 as novel and potential PET ligands for imaging orexin 2 receptor and explore their applications in small animals. Methods: Compounds 1 and 2 were prepared according to a published patent.1 The phenolic precursors were synthesized via demethylation of compounds 1 and 2. The radiosynthesis of [11C]1 and [11C]2 were performed by 11C-methylation of phenolic precursors with [11C]CH3I and Cs2CO3 as the base in DMF at 80 oC for 5 min. The in vitro autoradiography was performed with [11C]1 and [11C]2 on Sprague Dawley rat brain slices. Dynamic PET imaging studies with [11C]1 and [11C]2 were carried out on Sprague Dawley rats with 60 min scans. Results: Compounds 1 (OX2: IC50 = 4 nM, OX1: IC50 > 4000 nM) and 2 (OX2: IC50 = 4 nM, OX1: IC50 > 5000 nM) are selective antagonists at the OX2.1 Compounds 1 and 2 were prepared in 2% and 20% overall yields over four steps, respectively. The phenolic precursors were synthesized via demethylation of compounds 1 and 2 in 41% and 45% yields, respectively. The radiosynthesis of PET ligands [11C]1 and [11C]2 were via 11C-methylation of phenolic precursors with [11C]CH3I and both [11C]1 and [11C]2 were obtained in more than 10% radiochemical yields (decay corrected). Both [11C]1 and [11C]2 had radiochemical purities greater than 99%, and no obvious decompositions of [11C]1 and [11C]2 were found in saline in 90 min. In in vitro autoradiography studies with [11C]1 and [11C]2, high radioactivity accumulation was observed in the hippocampus and cortex. In blocking studies of autoradiography, EMPA (10 μM) rendered diminished radioactivity in OX2R-rich brain regions. In dynamic PET imaging studies with [11C]1, the standard uptake value (SUV) of [11C]1 in hippocampus and cerebellum reached the max value of 0.2 at 2 min and washed out rapidly, and finally reduced to 0.1 at 60 min. PET imaging with [11C]2 showed a similar result. In blocking studies of PET imaging, no significant difference in uptake in the hippocampus and cerebellum was observed for both [11C]1 and [11C]2. Pretreatment with elacridar (3 mg/kg) led to a significant increase of uptake in hippocampus and cerebellum for both [11C]1 and [11C]2. Conclusion: We have developed two novel PET ligand [11C]1 and [11C]2 for imaging OX2R. The PET ligands [11C]1 and [11C]2 were both prepared in more than 10% radiochemical yield (decay corrected). In autoradiography studies, both [11C]1 and [11C]2 showed high binding specificities in hippocampus and cortex in vitro. While in vivo PET imaging with [11C]1 and [11C]2 demonstrated moderate binding affinities towards OX2R, their poor blood-brain barrier permeabilities and rapid clearance from the brain prevent further evaluation. |
|||||
| 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 | SNMMI2022 | |||||
| 発表年月日 | ||||||
| 日付 | 2022-06-11 | |||||
| 日付タイプ | Issued | |||||
