{"created":"2023-05-15T15:03:51.926636+00:00","id":86413,"links":{},"metadata":{"_buckets":{"deposit":"0d0d4287-ad8a-476a-b2ba-156f53b72388"},"_deposit":{"created_by":1,"id":"86413","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"86413"},"status":"published"},"_oai":{"id":"oai:repo.qst.go.jp:00086413","sets":["10:28"]},"author_link":["1054667","1054674","1054669","1054673","1054671","1054668","1054672","1054670"],"item_10005_date_7":{"attribute_name":"発表年月日","attribute_value_mlt":[{"subitem_date_issued_datetime":"2022-06-14","subitem_date_issued_type":"Issued"}]},"item_10005_description_5":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"Purpose/Background:\nAtherosclerosis is the process that underlies heart attack and stroke and has remained the leading cause of death in many countries. Macrophages play critical roles in atherogenesis and represent attractive targets for the\ndevelopment of antiatherosclerotic therapy and the diagnosis of atherosclerosis. Stabilin-2 was identified to be highly expressed on macrophages and smooth muscle and endothelial cells; and therefore has been considered a promising\nbiomarker for vulnerable atherosclerotic plaques. The objective of this study was to develop a peptide-based, stabilin-2 ‒targeted positron-emission tomography (PET) radiotracer and validate its application to the noninvasive detection of atherosclerotic plaque in a mouse model. \nMethods:\nA stabilin-2 binding peptide S2P with a sequence of CRTLTVRKC was synthesized by a SPPS strategy. DOTA, a commonly used chelator for 64Cu complexation, was conjugated to the N-terminus of S2P peptides. A tetrameric\nversion of S2P-DOTA, which was linked together by a 4-arm branched PEG (M.W.=5 kDa), was synthesized employing the thiol-maleimide Michael addition reaction. Next, both S2P-DOTA and 4armPEG-(S2P-DOTA)4 were labeled with 64Cu under ambient conditions. The radiolabeling yield, specific activity, and radiochemical purity were analyzed using radio HPLC. The stability of [64Cu]Cu-S2P-DOTA and [64Cu]Cu-4armPEG-(S2P-DOTA)4 was assayed in freshly prepared mouse serum. The specific binding and uptake of the radiotracers to activated macrophages were investigated. Micro-PET/CT imaging was performed at a series of time points for longitudinal tracking of tracers\nin APOE-/- mice (15-25 weeks on a high-fat diet) and wild-type C57BL/6J mice in normal mice. Ex vivo ARG and biodistribution studies were conducted to verify the specificity of the radiotracers. The plaque distribution and morphology of the plaques were assessed by Oil Red. HE, Masson staining, and immunohistology. \nResults:\n[64Cu]Cu-S2P-DOTA and [64Cu]Cu-4armPEG-(S2P-DOTA)4 were obtained with decay-correlated radiochemical yields\nof >99% and >95%, specific activities of >70 and >50 GBq/μmoL (n=10), and radiochemical purities of >99% and 96%, respectively. Both radiotracers showed excellent stability in vitro. Compared to [ 64Cu]Cu-S2P-DOTA, [64Cu]Cu-4armPEG-(S2P-DOTA)4 showed significantly higher cellular uptake to macrophages and a 1.5-fold increase in binding affinity for stabilin-2. The prolonged blood elimination half-life (t1/2) of [64Cu]Cu-4armPEG-(S2P-DOTA)4\nwas observed in a pharmacokinetic study of normal mice, which was significantly longer than that of [64Cu]Cu-S2P-DOTA. As expected, PET imaging with [64Cu]Cu-4armPEG-(S2P-DOTA)4 showed higher uptake in advanced plaques than that with [ 64Cu]Cu-S2P-DOTA. Moreover, we observed stable and durable retention of [64Cu]Cu-4armPEG-(S2P-DOTA)4 in the aortas of atherosclerotic mice from 12 hours to 48 hours postinjection. In contrast, [64Cu]Cu-S2P-DOTA showed a fast clearance in aortas from 30 min to 60 min postinjection. Block PET using unlabeled peptide as a blocking agent verified a notable decrease in radiotracer uptake in the aortas, indicating the specificity to stabilin-2. Radioactivity in excised aortas examined by ex vivo autoradiography further confirmed the specific uptake of [64Cu]Cu-4armPEG-(S2P-DOTA)4 in high-risk AS plaques. ELISA and histological analysis correlated well with the observation. \nwell with the observation. \nConclusion:\nIn summary, we reported a proof-of-concept study of peptide-based, stabilin-2 targeting PET tracers for macrophage imaging in atherosclerosis. The tetrameric peptide tracer, [64Cu]Cu-4armPEG-(S2P-DOTA)4, significantly prolongs the\nplasma elimination half-life and has the potential for the monitoring of AS plaques. Our study also provides a potential powerful non-invasive method for the diagnosis of atherosclerotic lesions and a companion diagnostic tool\nfor new drug screening for antiatherosclerosis therapy. ","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":"SNMMI2022","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":"Kuan, Hu"}],"nameIdentifiers":[{"nameIdentifier":"1054667","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Lin, Xie"}],"nameIdentifiers":[{"nameIdentifier":"1054668","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Zhang, Yiding"}],"nameIdentifiers":[{"nameIdentifier":"1054669","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Masayuki, Hanyu"}],"nameIdentifiers":[{"nameIdentifier":"1054670","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Kuan, Hu","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"1054671","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Lin, Xie","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"1054672","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Zhang, Yiding","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"1054673","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Masayuki, Hanyu","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"1054674","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":"Stabilin-2-specific peptide-based radiotracers for atherosclerosis plaque PET imaging","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"Stabilin-2-specific peptide-based radiotracers for atherosclerosis plaque PET imaging"}]},"item_type_id":"10005","owner":"1","path":["28"],"pubdate":{"attribute_name":"公開日","attribute_value":"2022-04-28"},"publish_date":"2022-04-28","publish_status":"0","recid":"86413","relation_version_is_last":true,"title":["Stabilin-2-specific peptide-based radiotracers for atherosclerosis plaque PET imaging"],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2023-05-15T16:59:18.773853+00:00"}