{"_buckets": {"deposit": "ea519142-b5db-4366-9bad-b71d572b3c5f"}, "_deposit": {"created_by": 1, "id": "80198", "owners": [1], "pid": {"revision_id": 0, "type": "depid", "value": "80198"}, "status": "published"}, "_oai": {"id": "oai:repo.qst.go.jp:00080198", "sets": ["28"]}, "author_link": ["877984", "877982", "877986", "877981", "877980", "877979", "877983", "877985", "877987"], "item_10005_date_7": {"attribute_name": "発表年月日", "attribute_value_mlt": [{"subitem_date_issued_datetime": "2020-07-12", "subitem_date_issued_type": "Issued"}]}, "item_10005_description_5": {"attribute_name": "抄録", "attribute_value_mlt": [{"subitem_description": "Objectives: We have identified 4-hydroxy-6-(3-methoxyphenethyl)pyridazin-3(2H)-one (1) as a lead molecule for D-amino acid oxidase (DAAO)-specific PET ligand. It has been reported that inhibitory activity of compound 1 for human, mouse and rat DAAOs showed dose-dependent responses with IC50 valves of 8.8, 4.4 and 5.6 nM, respectively. [1] The goal of the project was to synthesize the standard and precursor molecules for this target and perform radiolabeling of compound 1 with carbon-11.\n\nMethods: The leading compound 1 was synthesized in the following procedures. The cyclization of 3,4,6-trichloropyridazine 2 and pyrocatechol 3 led to intermediate 4 in 80% yield. Through the Sonagashira coupling reaction of compound 4 and 1-ethynyl-3-methoxybenzene 5, the alkyne 6 was obtained in 40% yield. Exchanged with phenylmethanol under base, compound 6 was converted to benzyl-protected ether 7 in 58% yield. After Pd-mediated hydrogenation of compound 7, the desired product 1 was obtained in 77% yield (Scheme 1A). The synthesis of the labeling precursor for compound 1 was showed in Scheme 1B. Phenylmethanol was used to react with compound 4 to get benzyl-protected ether 8 in 48% yield. After hydrogenation of compound 8 under hydrogen using palladium/carbon catalysis, 6-chloro-4-hydroxypyridazin-3(2H)-one 9 was obtained in 84% yield. Hydroxy groups were then protected by the treatment with chloromethyl methyl ether to give compound 10 in 40% yield, followed by the Sonagashira coupling reaction with alkyne 12 to produce compound 13 in 38% yield. At the end, benzyl protecting group was removed by palladium hydroxide/carbon catalysis under hydrogen to yield the precursor 14 in 71% yield. Preliminary 11C-labeling was carried out using precursor (14; 1.6 mg) with [11C]methyl iodide in the presence of Cs2CO3 in DMF (0.4 mL) at 80°C for 5 min to generate [11C]15 (Scheme 1C). Then, 4 M HCl in dioxane was added to remove the MOM group and the mixture was neutralized with NaHCO3 aqueous solution to get [11C]1.\n\nResults: The synthesis of candidate compound 1 was obtained from commercially available 3,4,6-trichloropyridazine 2 and pyrocatechol 3 in four steps with overall yield of 14%. The radioligand [11C]1 was synthesized in 13 ± 3% radiochemical yield based on [11C]CH3I (decay corrected). The tracer was obtained at end-of-synthesis (70 min synthesis time) with high radiochemical purity (\u003e99%) and molar activity (\u003e 1.0 Ci/μmol; 37 GBq/μmol). No radiolysis was observed within 90 min.\n\nConclusions: We have successfully prepared one potent and selective DAAO ligand and performed 11C-labeling with a reasonable radiochemical yield and high molar activity. Preliminary in vivo evaluation by PET are underway. References: [1] T. Hondo, M. Warizaya, T. Niimi, I. Namatame, T. Yamaguchi, K. Nakanishi, T. Hamajima, K. Harada, H. Sakashita, Y. Matsumoto, J. Med. Chem. 2013, 56, 3582.", "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": "SNMMI 2020 Annual Meeting", "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": "Deng, Xiaoyun"}], "nameIdentifiers": [{"nameIdentifier": "877979", "nameIdentifierScheme": "WEKO"}]}, {"creatorNames": [{"creatorName": "Shao, Tuo"}], "nameIdentifiers": [{"nameIdentifier": "877980", "nameIdentifierScheme": "WEKO"}]}, {"creatorNames": [{"creatorName": "Shao, Yihan"}], "nameIdentifiers": [{"nameIdentifier": "877981", "nameIdentifierScheme": "WEKO"}]}, {"creatorNames": [{"creatorName": "Josephson, Lee"}], "nameIdentifiers": [{"nameIdentifier": "877982", "nameIdentifierScheme": "WEKO"}]}, {"creatorNames": [{"creatorName": "Hsiao-Ying, Wey"}], "nameIdentifiers": [{"nameIdentifier": "877983", "nameIdentifierScheme": "WEKO"}]}, {"creatorNames": [{"creatorName": "Ming-Rong, Zhang"}], "nameIdentifiers": [{"nameIdentifier": "877984", "nameIdentifierScheme": "WEKO"}]}, {"creatorNames": [{"creatorName": "Liang, Huan"}], "nameIdentifiers": [{"nameIdentifier": "877985", "nameIdentifierScheme": "WEKO"}]}, {"creatorNames": [{"creatorName": "Ming-Rong, Zhang", "creatorNameLang": "en"}], "nameIdentifiers": [{"nameIdentifier": "877986", "nameIdentifierScheme": "WEKO"}]}, {"creatorNames": [{"creatorName": "Liang, Huan", "creatorNameLang": "en"}], "nameIdentifiers": [{"nameIdentifier": "877987", "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": "Synthesis of a11C-labeledD-amino acid oxidase inhibitor for PET imaging", "item_titles": {"attribute_name": "タイトル", "attribute_value_mlt": [{"subitem_title": "Synthesis of a11C-labeledD-amino acid oxidase inhibitor for PET imaging"}]}, "item_type_id": "10005", "owner": "1", "path": ["28"], "permalink_uri": "https://repo.qst.go.jp/records/80198", "pubdate": {"attribute_name": "公開日", "attribute_value": "2020-07-08"}, "publish_date": "2020-07-08", "publish_status": "0", "recid": "80198", "relation": {}, "relation_version_is_last": true, "title": ["Synthesis of a11C-labeledD-amino acid oxidase inhibitor for PET imaging"], "weko_shared_id": -1}