{"created":"2023-05-15T15:00:33.276367+00:00","id":82180,"links":{},"metadata":{"_buckets":{"deposit":"dfbc058b-d469-4861-b755-3fd13641f338"},"_deposit":{"created_by":1,"id":"82180","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"82180"},"status":"published"},"_oai":{"id":"oai:repo.qst.go.jp:00082180","sets":["1"]},"author_link":["1023617","1023619","1023615","1023620","1023618","1023621","1023613","1023616","1023614"],"item_8_biblio_info_7":{"attribute_name":"書誌情報","attribute_value_mlt":[{"bibliographicIssueDates":{"bibliographicIssueDate":"2021-03","bibliographicIssueDateType":"Issued"},"bibliographicIssueNumber":"3","bibliographicPageStart":"256","bibliographicVolumeNumber":"14","bibliographic_titles":[{"bibliographic_title":"Pharmaceuticals"}]}]},"item_8_description_5":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"Activating double mutations L858R/T790M in the epidermal growth factor receptor\n(EGFR) region are often observed as the cause of resistance to tyrosine kinase inhibitors (TKIs). Third-generation EGFR-TKIs, such as osimertinib and rociletinib (CO-1686), was developed to target such resistance mutations. The detection of activating L858R/T790M mutations is necessary to select sensitive patients for therapy. Hence, we aimed to develop novel radiobromine-labeled CO-1686 as a\npositron emission tomography (PET) imaging probe for detecting EGFR L858R/T790M mutations. Nonradioactive brominated-CO1686 (BrCO1686) was synthesized by the condensation of N-(3-[{2-chloro-5-(trifluoromethyl)pyrimidin-4-yl}amino]-5-bromophenyl) acrylamide with the corresponding substituted 1-(4-[4-amino-3-methoxyphenyl]piperazine-1-yl)ethan-1-one. The radiobrominated [77Br]BrCO1686 was prepared through bromodestannylation of the corresponding tributylstannylated precursor with [77Br]bromide and N-chlorosuccinimide. Although we aimed to provide a novel PET imaging probe, 77Br was used as an alternative radionuclide for 76Br. We fundamentally evaluated the potency of [77Br]BrCO1686 as a molecular probe for detecting EGFR L858R/T790M using human non-small-cell lung cancer (NSCLC) cell lines: H1975 (EGFR L858R/T790M), H3255 (EGFR L858R), and H441 (wild-type EGFR). The BrCO1686 showed high cytotoxicity toward H1975 (IC50 0.18  0.06 M) comparable to that of CO-1686 (IC50 0.14  0.05 M). In cell uptake experiments, the level of accumulation of [77Br]BrCO1686 in H1975 was significantly higher than those in H3255 and H441 upon 4 h of incubation. The radioactivity of [77Br]BrCO1686 (136.3% dose/mg protein) was significantly reduced to 56.9% dose/mg protein by the pretreatment with an excess CO-1686. These results indicate that the binding site of the radiotracers should be identical to that of CO-1686. The in vivo accumulation of radioactivity of [77Br]BrCO1686 in H1975 tumor (4.51  0.17) was higher than that in H441 tumor (3.71  0.13) 1 h postinjection. Our results suggested that [77Br]BrCO1686 has specificity toward NSCLC cells with double mutations EGFR L858R/T790M compared to those in EGFR L858R and wild-type EGFR. However, the in vivo accumulation of radioactivity in the targeted tumor needs to be optimized by structural modification.","subitem_description_type":"Abstract"}]},"item_8_relation_14":{"attribute_name":"DOI","attribute_value_mlt":[{"subitem_relation_type_id":{"subitem_relation_type_id_text":"10.3390/ph14030256","subitem_relation_type_select":"DOI"}}]},"item_8_relation_17":{"attribute_name":"関連サイト","attribute_value_mlt":[{"subitem_relation_type_id":{"subitem_relation_type_id_text":"https://www.mdpi.com/1424-8247/14/3/256#cite","subitem_relation_type_select":"URI"}}]},"item_8_source_id_9":{"attribute_name":"ISSN","attribute_value_mlt":[{"subitem_source_identifier":"1424-8247","subitem_source_identifier_type":"ISSN"}]},"item_creator":{"attribute_name":"著者","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"M, Fawwaz"}],"nameIdentifiers":[{"nameIdentifier":"1023613","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"K, Mishiro"}],"nameIdentifiers":[{"nameIdentifier":"1023614","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Ryuichi, Nishii"}],"nameIdentifiers":[{"nameIdentifier":"1023615","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"A, Makino"}],"nameIdentifiers":[{"nameIdentifier":"1023616","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Y, Kiyono"}],"nameIdentifiers":[{"nameIdentifier":"1023617","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"K, Shiba"}],"nameIdentifiers":[{"nameIdentifier":"1023618","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"S, Kinuya"}],"nameIdentifiers":[{"nameIdentifier":"1023619","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"K, Ogawa"}],"nameIdentifiers":[{"nameIdentifier":"1023620","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Ryuichi, Nishii","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"1023621","nameIdentifierScheme":"WEKO"}]}]},"item_files":{"attribute_name":"ファイル情報","attribute_type":"file","attribute_value_mlt":[{"accessrole":"open_date","date":[{"dateType":"Available","dateValue":"2022-03-28"}],"displaytype":"detail","filename":"517af860d68a961a4ee86a7cb5d0ca28.pdf","filesize":[{"value":"747.1 kB"}],"format":"application/pdf","licensetype":"license_note","mimetype":"application/pdf","url":{"label":"pharmaceuticals-14-00256-v2.pdf","url":"https://repo.qst.go.jp/record/82180/files/517af860d68a961a4ee86a7cb5d0ca28.pdf"},"version_id":"2ddc67d7-89fe-44eb-a8ab-23429220da2d"}]},"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":"journal article","resourceuri":"http://purl.org/coar/resource_type/c_6501"}]},"item_title":"A Radiobrominated Tyrosine Kinase Inhibitor for EGFR with L858R/T790M Mutations in Lung Carcinoma","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"A Radiobrominated Tyrosine Kinase Inhibitor for EGFR with L858R/T790M Mutations in Lung Carcinoma"}]},"item_type_id":"8","owner":"1","path":["1"],"pubdate":{"attribute_name":"公開日","attribute_value":"2021-03-16"},"publish_date":"2021-03-16","publish_status":"0","recid":"82180","relation_version_is_last":true,"title":["A Radiobrominated Tyrosine Kinase Inhibitor for EGFR with L858R/T790M Mutations in Lung Carcinoma"],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2023-05-15T18:09:27.636819+00:00"}