{"created":"2023-05-15T15:03:53.913084+00:00","id":86451,"links":{},"metadata":{"_buckets":{"deposit":"dc2223fb-feca-4a6d-9898-2815e5364bf8"},"_deposit":{"created_by":1,"id":"86451","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"86451"},"status":"published"},"_oai":{"id":"oai:repo.qst.go.jp:00086451","sets":["2"]},"author_link":["1055152","1055150","1055155","1055157","1055151","1055154","1055153","1055156"],"item_10003_biblio_info_7":{"attribute_name":"書誌情報","attribute_value_mlt":[{"bibliographicIssueDates":{"bibliographicIssueDate":"2022-06","bibliographicIssueDateType":"Issued"},"bibliographic_titles":[{"bibliographic_title":"Nuclear Medicine and Biology"}]}]},"item_10003_description_5":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"Objectives: Transmembrane AMPA receptor regulatory proteins subtype γ8 (TARP γ8) exhibits regiospecific expression in the brain, which could serve as a potential therapeutic target for central nervous system disorders with high selectivity. Based on two potent and selective TARP γ-8 antagonists, 6-(2-cyclobutyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]thiazol-2(3H)-one (compound 8) and (2-cyclobutyl-3-(1H-indazol-5-yl)-5-methyl-3H-imidazo[4,5-b]pyridine (compound 15), we perform the radiosynthesis of its 11C-isotopologue and conduct preliminary evaluation to test the feasibility of imaging  TARP γ-8 dependent receptors in vitro and in vivo.\nMethods: The synthesis of precursor 22 was shown in Scheme 1A. Initially, the preparation of the compound 19 was achieved in 81% through the SN2 coupling reaction between 6-aminobenzo[d] thiazol-2(3H)-one 2 and 2,6-dibromo-3-nitropyridine in the presence of NEt3. As follows, the mild condition of Fe/NH4Cl instead of Pd/C-H2 system was used in the reduction of nitro group to amine in the terms of sensitive bromo-substitution group of 19, which offered 6-((3-Amino-6-bromopyridin-2-yl)amino)benzo[d]thiazol-2(3H)-one 20 with high chemoselectivity in the yield of 76%. The compound 20 then underwent condensation with cyclobutanecarbaldehyde, followed by oxidation, to afford benzothiazolone 21. The subsequent Pd catalyzed Stannylation generated 22 as a precursor in the yield of 36%. Similarly, the other precursor 27 was obtained from commercially available starting material of 1H-indazol-5-amine 10 in 6 steps (Scheme 1B). The radiosynthesis of [11C]8 and [11C]15 from the corresponding precursors were carried out. As a result, [11C]8 and [11C]15 were obtained in an average radiochemical yield (RCY) of 9% and 22%, respectively, with high radiochemical purity (>99%) and excellent molar activity (>150 GBq/μmol). The autoradiography (ARG) studies for [11C]8 were conducted to evaluate target binding in vitro. Figure 1 indicated heterogeneous regional distribution pattern from high to low in the order of hippocampus, cerebral cortex, striatum, thalamus and cerebellum in [11C]8 ARG studies. The distribution profile was consistent with the mRNA expression pattern of TARP γ-8 with the highest signal level in the region of the hippocampus and the lowest level in the cerebellum. For ligand [11C]8, blocking studies by compound 8 (1 µM) led to markedly decrease of the bound radioactivity in the TARP γ8 rich hippocampus.\nResults: The radioligand [11C]8 and [11C]15 were synthesized in 9% and 22% radiochemical yield (RCY) respectively, based on the starting [11C]CO2 at the end-of-synthesis with >99% radiochemical purity (n = 5). Both of their molar activities were greater than 150 GBq/µmol (4.1 Ci/µmol). No sign of radiolysis was observed up to 90 min after re-formulation for both of [11C]8 and [11C]15. In ARG studies, the radioligand [11C]8 exhibited great heterogeneous regional distribution pattern (high uptake in hippocampus while low uptake in cerebellum).\nConclusion: We have evaluated the radiochemical method to prepare 11C-labeled labeled TARP ɣ-8 antagonists based on Stille coupling-based labeling methodology. Ultimately, the desired compounds [11C]8 and [11C]15 were labeled by [11C]CH3I in high radiochemical yield (9% and 22% respectively), high molar activity (>150 GBq/μmol) and high radiochemical purity (>99%).","subitem_description_type":"Abstract"}]},"item_10003_publisher_8":{"attribute_name":"出版者","attribute_value_mlt":[{"subitem_publisher":"Elsevier Ltd."}]},"item_10003_source_id_9":{"attribute_name":"ISSN","attribute_value_mlt":[{"subitem_source_identifier":"0969-8051","subitem_source_identifier_type":"ISSN"}]},"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":"A. Yu, Qingzhen"}],"nameIdentifiers":[{"nameIdentifier":"1055150","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Katsushi, Kumata"}],"nameIdentifiers":[{"nameIdentifier":"1055151","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Lee Collier, Thomas"}],"nameIdentifiers":[{"nameIdentifier":"1055152","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Tomita, Susumu"}],"nameIdentifiers":[{"nameIdentifier":"1055153","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Zhang, Ming-Rong"}],"nameIdentifiers":[{"nameIdentifier":"1055154","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Liang, Steven"}],"nameIdentifiers":[{"nameIdentifier":"1055155","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Katsushi, Kumata","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"1055156","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Zhang, Ming-Rong","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"1055157","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 paper","resourceuri":"http://purl.org/coar/resource_type/c_5794"}]},"item_title":"Radiosynthesis of 6-(2-cyclobutyl-5-(methyl-11C)-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]thiazol-2(3H)-one and (2-cyclobutyl-3-(1H-indazol-5-yl)-5-[11C]methyl-3H-imidazo[4,5-b]pyridine for imaging γ-8 dependent transmembrane AMPA receptor regulatory protein","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"Radiosynthesis of 6-(2-cyclobutyl-5-(methyl-11C)-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]thiazol-2(3H)-one and (2-cyclobutyl-3-(1H-indazol-5-yl)-5-[11C]methyl-3H-imidazo[4,5-b]pyridine for imaging γ-8 dependent transmembrane AMPA receptor regulatory protein"}]},"item_type_id":"10003","owner":"1","path":["2"],"pubdate":{"attribute_name":"公開日","attribute_value":"2022-06-08"},"publish_date":"2022-06-08","publish_status":"0","recid":"86451","relation_version_is_last":true,"title":["Radiosynthesis of 6-(2-cyclobutyl-5-(methyl-11C)-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]thiazol-2(3H)-one and (2-cyclobutyl-3-(1H-indazol-5-yl)-5-[11C]methyl-3H-imidazo[4,5-b]pyridine for imaging γ-8 dependent transmembrane AMPA receptor regulatory protein"],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2023-05-15T16:58:01.234538+00:00"}