{"created":"2023-05-15T14:59:06.492425+00:00","id":80196,"links":{},"metadata":{"_buckets":{"deposit":"3d34a4dd-f599-423e-95ee-bdd007108816"},"_deposit":{"created_by":1,"id":"80196","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"80196"},"status":"published"},"_oai":{"id":"oai:repo.qst.go.jp:00080196","sets":["10:28"]},"author_link":["877961","877963","877967","877964","877965","877960","877966","877962"],"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: Transmembrane AMPA receptor regulatory proteins (TARPs) are a recently discovered family of proteins that modulate AMPA receptors activity. TARP subtypes exhibit regiospecific expression in the brain, which could selectively regulate regional brain function. Based on a potent and selective TARP γ-8 antagonist, 6-(methyl(4-(pyridin-2-yl)thiazol-2-yl)amino)benzo[d]thiazol-2(3H)-one (compound 9), we perform the radiosynthesis of its 11C-isotopologue and conduct preliminary PET evaluation to test the feasibility of imaging TARP γ-8 dependent receptors in vivo.\n\nMethods: Radiosynthesis of 1 from compound 16 as the precursor was carried out. To label nitrogenous CH3 of 9, protecting group of benzothiazolone is installed in order to avoid the regioselective problem between two nitrogenous groups during radiolabeling. As shown in Scheme 1, the methoxymethyl (MOM) group was introduced in the first step, which yielded the intermediate 12 in 95%, followed by reduction of nitro group to afford amine 13. Benzoyl isothiocyanate was used to functionalize 13 to afford 14 as a thiourea. After the removal of benzoyl group, condensation reactions between 15 and 2-bromo-1-(pyridin-2-yl)ethan-1-one hydrobromide provided intermediate 16 in 32% yield over 4 steps according to the literature with some modification in this work.[1] Methylation of secondary amine 16 with methyl iodide gave nonradioactive labeling intermediate 17 in 79% yield, which was converted to product 9 by the removal of MOM protecting group at prolonged reaction time. 11C-Methylation occurred smoothly in the presence of sodium hydroxide and [11C]CH3I in DMF for 5 min to afford radioactive intermediate 18. It is noteworthy that TFA[2] is not an ideal acid to remove MOM group for radiosynthesis attributed to low conversion and long reaction time (32% yield over 3 days in reflux). Therefore, our focus turned into the optimization for MOM deprotection in the subsequent radiosynthetic work. We first tested a series of acid-mediated deprotection methods under non-radioactive conditions to provide guidance for the MOM group removal. Of all non-radioactive conditions tested, we selected three representative acids to test their deprotection efficiency under radioactive conditions. Unsurprisingly, TFA failed even though we increased the temperature (80 ºC) and ratio of acid (1:1 ratio of TFA/DMF, Table 1, entry 1). Hydrochloride (6N) gave the similar results as TFA (Table 1, entry 2). Fortunately, TfOH was able to remove the MOM protecting group efficiently, as indicated in non-radioactive tests (Table S1, entry 7) and under radioactive conditions in one-pot manner (Table 1, entry 3). The reaction mixture was then quenched and neutralized by addition of 1M NaOH aqueous solution, and purified by a reverse phase semi-preparative HPLC, followed by reformulation.\n\nResults: Compound 1 was synthesized in 39% decay-corrected radiochemical yield (RCY) based on the starting [11C]CO2 at the end-of-synthesis with >99% radiochemical purity (n = 5). The molar activity was greater than 74 GBq/µmol (2.0 Ci/µmol). No sign of radiolysis was observed up to 90 min after re-formulation. The successful radiosynthesis of 1 with high radiochemical purity and excellent molar activity enabled our subsequent in vitro and in vivo evaluation.\n\nConclusions: We have evaluated the radiochemical method to prepare a 11C-labeled labeled TARP ɣ-8 antagonist (compound 1; also known as TARP-1903, IC50 16 nM) based on a lead drug scaffold LY3130481/CERC-611. Ultimately, the desired compound 1 was labeled by [11C]CH3I in high radiochemical yield (ca. 40%), high molar activity (>74 GBq/μmol) and high radiochemical purity (>99%). Reference: [1] Gao M, Kong D, Clearfield A, et al. Bioorg. Med. Chem. Lett. 2006;16:2229-2233. [2] Gardinier KM, Gernert DL, Porter WJ, et al. J. Med. Chem. 2016;59:4753-4768.","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":"Yu, Qingzhen"}],"nameIdentifiers":[{"nameIdentifier":"877960","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Chen, Zhen"}],"nameIdentifiers":[{"nameIdentifier":"877961","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Shao, Tuo"}],"nameIdentifiers":[{"nameIdentifier":"877962","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Shao, Yihan"}],"nameIdentifiers":[{"nameIdentifier":"877963","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Ming-Rong, Zhang"}],"nameIdentifiers":[{"nameIdentifier":"877964","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Liang, Huan"}],"nameIdentifiers":[{"nameIdentifier":"877965","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Ming-Rong, Zhang","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"877966","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Liang, Huan","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"877967","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":"Radiosynthesis of 6-(11C-methyl(4-(pyridin-2-yl)thiazol-2-yl)amino)benzo[d]thiazol-2(3H)-one as a novel PET tracer towards imaging of γ-8 dependent transmembrane AMPA receptor regulatory protein","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"Radiosynthesis of 6-(11C-methyl(4-(pyridin-2-yl)thiazol-2-yl)amino)benzo[d]thiazol-2(3H)-one as a novel PET tracer towards imaging of γ-8 dependent transmembrane AMPA receptor regulatory protein"}]},"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":"80196","relation_version_is_last":true,"title":["Radiosynthesis of 6-(11C-methyl(4-(pyridin-2-yl)thiazol-2-yl)amino)benzo[d]thiazol-2(3H)-one as a novel PET tracer towards imaging of γ-8 dependent transmembrane AMPA receptor regulatory protein"],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2023-05-15T21:44:59.307795+00:00"}