{"created":"2023-05-15T14:59:06.586131+00:00","id":80198,"links":{},"metadata":{"_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":["10:28"]},"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 (>99%) and molar activity (> 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"],"pubdate":{"attribute_name":"公開日","attribute_value":"2020-07-08"},"publish_date":"2020-07-08","publish_status":"0","recid":"80198","relation_version_is_last":true,"title":["Synthesis of a11C-labeledD-amino acid oxidase inhibitor for PET imaging"],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2023-05-15T21:44:50.832659+00:00"}