{"created":"2023-05-15T15:03:53.731242+00:00","id":86447,"links":{},"metadata":{"_buckets":{"deposit":"28666851-fbbd-4e03-bba7-ed988f115592"},"_deposit":{"created_by":1,"id":"86447","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"86447"},"status":"published"},"_oai":{"id":"oai:repo.qst.go.jp:00086447","sets":["10:28"]},"author_link":["1055061","1055064","1055066","1055057","1055058","1055063","1055065","1055060","1055062","1055067","1055059"],"item_10005_date_7":{"attribute_name":"発表年月日","attribute_value_mlt":[{"subitem_date_issued_datetime":"2022-06-11","subitem_date_issued_type":"Issued"}]},"item_10005_description_5":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"Purpose/Background:\nThe 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.\n\nMethods:\nCompounds 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.\n\nResults:\nCompounds 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.\n\nConclusion:\nWe 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. \n","subitem_description_type":"Abstract"}]},"item_10005_description_6":{"attribute_name":"会議概要（会議名, 開催地, 会期, 主催者等）","attribute_value_mlt":[{"subitem_description":"SNMMI2022","subitem_description_type":"Other"}]},"item_access_right":{"attribute_name":"アクセス権","attribute_value_mlt":[{"subitem_access_right":"metadata only access","subitem_access_right_uri":"http://purl.org/coar/access_right/c_14cb"}]},"item_creator":{"attribute_name":"著者","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"Rong, Jian"}],"nameIdentifiers":[{"nameIdentifier":"1055057","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Tomoteru, Yamasaki"}],"nameIdentifiers":[{"nameIdentifier":"1055058","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Zhao, Chunyu"}],"nameIdentifiers":[{"nameIdentifier":"1055059","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Li, Yinlong"}],"nameIdentifiers":[{"nameIdentifier":"1055060","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Shao, Yihan"}],"nameIdentifiers":[{"nameIdentifier":"1055061","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Zhe Sun, Phillip"}],"nameIdentifiers":[{"nameIdentifier":"1055062","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"L. Collier, Thomas"}],"nameIdentifiers":[{"nameIdentifier":"1055063","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Zhang, Ming-Rong"}],"nameIdentifiers":[{"nameIdentifier":"1055064","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Liang, Steven"}],"nameIdentifiers":[{"nameIdentifier":"1055065","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Tomoteru, Yamasaki","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"1055066","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Zhang, Ming-Rong","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"1055067","nameIdentifierScheme":"WEKO"}]}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"eng"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"conference object","resourceuri":"http://purl.org/coar/resource_type/c_c94f"}]},"item_title":"Development of Novel PET Ligands for Imaging Orexin 2 Receptor ","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"Development of Novel PET Ligands for Imaging Orexin 2 Receptor "}]},"item_type_id":"10005","owner":"1","path":["28"],"pubdate":{"attribute_name":"公開日","attribute_value":"2022-06-20"},"publish_date":"2022-06-20","publish_status":"0","recid":"86447","relation_version_is_last":true,"title":["Development of Novel PET Ligands for Imaging Orexin 2 Receptor "],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2023-05-15T16:58:16.278323+00:00"}