{"created":"2023-05-15T15:01:04.706927+00:00","id":82857,"links":{},"metadata":{"_buckets":{"deposit":"ec7ed14f-0be1-4f8e-8752-957f010e4e18"},"_deposit":{"created_by":1,"id":"82857","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"82857"},"status":"published"},"_oai":{"id":"oai:repo.qst.go.jp:00082857","sets":["10:29"]},"author_link":["950410","950408","950411","950407","950409"],"item_10005_date_7":{"attribute_name":"発表年月日","attribute_value_mlt":[{"subitem_date_issued_datetime":"2021-05-17","subitem_date_issued_type":"Issued"}]},"item_10005_description_5":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"Objectives: AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor is an important protein in humans that is implicated in the increased risk of neurological diseases including epilepsy and schizophrenia. Transmembrane AMPA Receptor Regulatory Proteins (TARPs) are a recently discovered family of proteins that modulate the activity of AMPA receptors. TARPs exhibit regiospecific expression in the brain, leading to physiological differentiation of the AMPA receptor activity. TARP γ-8 dependent AMPA receptors enrich primarily in the hippocampus. 6-(2-Cyclobutyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]thiazol-2(3H)-one (pIC50 value of 9.6)[1] is one of the most highly potent and selective TARP γ-8 antagonists. Herein we report the synthesis of 6-(5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]thiazol-2(3H)-ones as TARP γ-8 radiotracer candidates and 6-(2-cyclobutyl-5-[11C]methyl-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]thiazol-2(3H)-one as a novel potent PET ligand for imaging of TARP γ-8 for AMPA receptor.\n\nMethods: The standard 6-(2-cyclobutyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]thiazol-2(3H)-one (Compound A), its analogs and the precursor 6-(2-cyclobutyl-5-(tributylstannyl)-3H-imidazo[4,5-b]pyridin-3-yl)benzo[d]thiazol-2(3H)-one (8) were synthesized from 6-nitrobenzo[d]thiazol-2(3H)-one and 2-chloro-6-methyl-3-nitropyridine according to the literature methods with modifications. The target tracer [11C]compound A was prepared from SnBu3-compound A with  [11C]CH3I through Pd-catalyzed methylation under basic condition and isolated by HPLC combined with solid-phase extraction in automated 11C-radiosynthesis module. Generally, 6-aminobenzo[d]thiazol-2(3H)-one 2 was obtained in 93% yield by reducing commercially available reagent 1 in the presence of 10%Pd/C and H2, which generated the key intermediate 3 in 76% through aromatic nucleophilic substitution reaction between 2-chloro-6-methyl-3-nitropyridine and compound 2. The following reduction reaction under Pd/H2 system, as well as the Cu(OAc)2/HOAc mediated condensation and oxidation reactions with cyclobutanecarbaldehyde afforded the standard compound A in 63% over 2 steps. The compounds B-F were prepared in the similar manners.  For the preparation of precursor 8, similarly, the key intermediate 6 was obtained in 76% by the reduction of Fe/NH4Cl instead of Pd/C-H2 system, due to the sensitivity of bromo group of 5. Compound 7 was constructed in 82% yield from 6 and cyclobutanecarbaldehyde by the similar condensation and oxidation reactions as compound A. The subsequent Pd catalyzed stannulation generated 8 as a precursor in 36% yield. The radiosynthesis was carried out by heating a mixture of precursor (1.0 mg), [11C]CH3I, Pd(PPh3)4 (15 mol%), P(o-tol)3 (0.6 mg), CuBr (0.5 mg) and CsF (1.7 mg) in NMP at 100 oC for 10 min.\n\nResults: The standard compound A and precursor were obtained in 45% yield over 4 steps and 17% yield over 6 steps, respectively. The analogs B-F were prepared in the varying yields from 15% to 25%. The desired PET ligand [11C]compound A was achieved in 2% isolated radiochemical yield (relative to [11C]CH3I, non-decay corrected). The radiochemical purity of the tracer was more than 99%, and the molar activity was higher than 37 GBq/µmol at end of synthesis (EOS). [11C]compound A was evaluated in the SD rat brain by PET with a dynamic 0-60 min scan, which showed limited brain uptake and specific binding in the hippocampus region in vivo (Tarp g8 rich region).\n\nConclusion: We have described facile synthetic routes to compound A and its analogs, as well as [11C]compound A, which may facilitate future development and evaluation of TARP γ-8 dependent AMPA tracers.","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":"eSRS","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":"A. Yu, Qingzhen"}],"nameIdentifiers":[{"nameIdentifier":"950407","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Zhang, Ming-Rong"}],"nameIdentifiers":[{"nameIdentifier":"950408","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Liang, Huan"}],"nameIdentifiers":[{"nameIdentifier":"950409","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Zhang, Ming-Rong","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"950410","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Liang, Huan","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"950411","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 a novel PET tracer for imaging of γ-8 dependent transmembrane AMPA receptor regulatory protein","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"Development of a novel PET tracer for imaging of γ-8 dependent transmembrane AMPA receptor regulatory protein"}]},"item_type_id":"10005","owner":"1","path":["29"],"pubdate":{"attribute_name":"公開日","attribute_value":"2021-05-19"},"publish_date":"2021-05-19","publish_status":"0","recid":"82857","relation_version_is_last":true,"title":["Development of a novel PET tracer for imaging of γ-8 dependent transmembrane AMPA receptor regulatory protein"],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2023-05-15T20:09:19.509596+00:00"}