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Synthesis and Evaluation of Novel PET Ligands for Imaging Orexin2 receptor (OX2R)
https://repo.qst.go.jp/records/86452
https://repo.qst.go.jp/records/86452c213c9d3-6936-4436-9ade-3caf142525eb
| Item type | 会議発表論文 / Conference Paper(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2022-06-08 | |||||
| タイトル | ||||||
| タイトル | Synthesis and Evaluation of Novel PET Ligands for Imaging Orexin2 receptor (OX2R) | |||||
| 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 |
Rong, Jian
× Rong, Jian× Tomoteru, Yamasaki× Zhao, Chunyu× Chen, Jiahui× Zhiwei, Xiao× Li, Yinlong× Lee Collier, Thomas× Zhang, Ming-Rong× Liang, Steven× Tomoteru, Yamasaki× Zhang, Ming-Rong |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Objectives: The orexin network mainly relies on two G protein-coupled receptors, orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R), and two neuropeptides, orexin-A (a 33 amino acid peptide) and orexin-B (a 28 amino acid peptide). Orexin-A is a non-selective neuropeptide binding both OX1R and OX2R with similar affinities, while orexin-B has a much higher selectivity towards OX2R against OX1R (> 10 fold). It has been found that OX2R plays a key role in motivation, arousal and sleep-wake regulation. Several OX2R ligands have been developed for OX2R PET imaging, but highly specific PET probes are still lacking. Herein we report [11C]1 and [11C]2 as novel and potential PET ligands for orexin 2 receptor imaging. Methods: Compounds 1 and 2 were synthesized according to patent literature WO2004033418. The phenolic precursors were prepared from demethylation of compounds 1 and 2. The radiosynthesis of [11C]1 and [11C]2 were conducted by 11C-methylation of phenolic precursors precursors with [11C]CH3I and Cs2CO3 as the base in DMF at 80 oC for 5 min. The in vitro autoradiography studies on Sprague Dawley rat brain slices was performed. Results: Compounds 1 was prepared starting from 2-methoxyaniline, which was treated with 3-methylpyridine-2-sulfonyl chloride to obtain N-(2-methoxyphenyl)-3-methylpyridine-2-sulfonamide in 21% yield. The resulting compound was coupled with methyl 2-bromoacetate in 45% yield and then hydrolyzed with NaOH to form carboxylic acid, which was coupled to N-benzylethanamine in the presence of HATU providing compound 1 in 2% overall yield over four steps. Compounds 2 was synthesized in a similar pathway and achieved in 20% overall yield over four steps. The phenolic precursors were prepared from demethylation of compounds 1 and 2 in 41% and 45% yields, respectively. The PET ligands [11C]1 and [11C]2 were prepared via reactions with [11C]CH3I and both achieved in more than 10% radiochemical yields (decay corrected). The radiochemical purities of these tracers were greater than 99%, and both [11C]1 and [11C]2 were stable 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, EMPA (10 μM) rendered diminished radioactivity in OX2R-rich brain regions. 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). High radioactivity accumulation was observed in the hippocampus, and cortex in in vitro autoradiography studies with [11C]1 and [11C]2. These tracers will be evaluated in the PET imaging study for OX2R in rodents and the results will be reported in due course. |
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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 | |||||
