{"created":"2023-05-15T14:53:29.244180+00:00","id":72838,"links":{},"metadata":{"_buckets":{"deposit":"0f741648-d2f9-4edf-8218-fccf296154a1"},"_deposit":{"created_by":1,"id":"72838","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"72838"},"status":"published"},"_oai":{"id":"oai:repo.qst.go.jp:00072838","sets":["10:28"]},"author_link":["717577","717569","717575","717576","717574","717572","717571","717568","717570","717573"],"item_10005_date_7":{"attribute_name":"発表年月日","attribute_value_mlt":[{"subitem_date_issued_datetime":"2018-06-24","subitem_date_issued_type":"Issued"}]},"item_10005_description_5":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"Objectives: Modulating transmembrane AMPA (a-Amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid) receptor regulatory proteins (TARPs) has emerged as a novel and alternative strategy towards pharmacotherapies for neuronal hyperactivity related CNS disorders such as epilepsy, PD, multiple sclerosis and schizophrenia. The development of TARP γ-8 subtype selective AMPA receptor antagonists, such as JNJ55511118 (1), JNJ56022486 (2) and LY3130481, is particularly promising for therapy and diagnosis of pathologic disorders within forebrain.[1][2] The goal of the project was to carry out 11C-isotopologue labeling of two novel TARP γ-8 dependent AMPA receptor antagonists JNJ55511118 and JNJ56022486, and perform preliminary PET studies and in vitro autoradiography in rodents. Methods: The synthesis of labeling precursor 5 was achieved through PdCl2(dtbpf)-catalyzed cross-coupling of aryl boric acid 3 with 4-bromobenzene-1,2-diamine 4. The precursor 8 was assembled via a sequence of PdCl2(dppf)-catalyzed coupling of aryl iodide 6 with 4-amino-3-nitrophenyl borate 7, followed by reduction Fe-mediated reduction in aqueous HCl solution. Subsequent treatment of diamine 5 and 8 with 1,1’-carbonyldiimidazole readily generated the corresponding standard 1 and 2, respectively. Radiosynthesis of [11C]1 and [11C]2 was performed using two 11C-carbonylation labeling strategies from [11C]COCl2 and [11C]CO2, respectively. Dynamic PET scans (60 min) were conducted in Sprague-Dawley rats. In vitro autoradiography (baseline and blocking) were also performed on frozen rat brain tissue to validate the binding specificity. Results: The standard compounds 1 and 2 were achieved in 50% yield over two steps and 61% yield over three steps, respectively, and their corresponding precursor 5 and 8 were obtained in 73% and 68% yields, respectively. Both 11C-carbonylayion strategies readily delivered the isotopologue of [11C]1 and [11C]2 in more than 10% isolated radiochemical yields (ca. 2.22 GBq; non-decay corrected from starting [11C]CO2) with high radiochemical purity (>99%) and high specific activity (greater than 40 GBq/μmol) within 45 min (end of synthesis). The compound [11C]1 synthesized either from [11C]COCl2 or [11C]CO2 showed no signs of radiolysis up to 90 min after formulation (10% ethanol in saline). In preliminary PET studies, while AMPA antagonist [11C]2 showed limited brain uptake (0.3 SUV), [11C]1 is brain permeable with peak uptake of 1 SUV. We further utilize in vitro autoradiography to confirm binding specificity of [11C]2, which showed heterogeneous distribution and reasonable bound radioactivity in the region of hippocampus, in accordance with the brain distribution of TARP γ-8 AMPA receptor. Pretreatment studies with JNJ56022486 (3 mg/kg) showed moderate binding with statistic significance compared to baseline study. \nConclusions: We have successfully radiolabeled two potent TARP γ-8 dependent AMPA receptor antagonists in high radiochemical yields. In vivo PET study demonstrated the brain-penetration of [11C]1 and in vitro autoradiography confirmed the specific binding of [11C]2. Further characterization including blocking studies with structurally-diverse AMPA antagonists, ex vivo whole body distribution and radiometabolite analysis will be performed in order to evaluate and develop potent TARP γ-8 dependent AMPA receptor PET tracers. References: [1] J Pharmacol Exp Ther. 2016, 357, 394-414; [2] Nat Med. 2016, 22, 1496-1501.","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 2018 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":"Chen, Zhen"}],"nameIdentifiers":[{"nameIdentifier":"717568","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Zhang, Xiaofei"}],"nameIdentifiers":[{"nameIdentifier":"717569","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"SHAO, TUO"}],"nameIdentifiers":[{"nameIdentifier":"717570","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Vasdev, Neil"}],"nameIdentifiers":[{"nameIdentifier":"717571","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Shao, Yihan"}],"nameIdentifiers":[{"nameIdentifier":"717572","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Tomita, Susumu"}],"nameIdentifiers":[{"nameIdentifier":"717573","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Zhang, Ming-Rong"}],"nameIdentifiers":[{"nameIdentifier":"717574","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Liang, Huan"}],"nameIdentifiers":[{"nameIdentifier":"717575","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"張 明栄","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"717576","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"梁 歓","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"717577","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":"Preclinical evaluation of 11C-JNJ55511118 and 11C-JNJ56022486 for imaging subtype-selective AMPA receptor","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"Preclinical evaluation of 11C-JNJ55511118 and 11C-JNJ56022486 for imaging subtype-selective AMPA receptor"}]},"item_type_id":"10005","owner":"1","path":["28"],"pubdate":{"attribute_name":"公開日","attribute_value":"2018-06-29"},"publish_date":"2018-06-29","publish_status":"0","recid":"72838","relation_version_is_last":true,"title":["Preclinical evaluation of 11C-JNJ55511118 and 11C-JNJ56022486 for imaging subtype-selective AMPA receptor"],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2023-05-15T19:35:29.883817+00:00"}