{"_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": ["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 (\u003e99%) 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"], "permalink_uri": "https://repo.qst.go.jp/records/72838", "pubdate": {"attribute_name": "公開日", "attribute_value": "2018-06-29"}, "publish_date": "2018-06-29", "publish_status": "0", "recid": "72838", "relation": {}, "relation_version_is_last": true, "title": ["Preclinical evaluation of 11C-JNJ55511118 and 11C-JNJ56022486 for imaging subtype-selective AMPA receptor"], "weko_shared_id": -1}