Synthesis of DOTA-Pyridine Chelates for 64Cu Coordination and Radiolabeling of αMSH Peptide

Synthesis of DOTA-Pyridine Chelates for 64Cu Coordination and Radiolabeling of αMSH Peptide | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Synthesis of DOTA-Pyridine Chelates for 64 Cu Coordination and Radiolabeling of αMSH Peptide Hua Yang, Feng Gao, Brooke McNeil, Chengcheng Zhang, Stefan Zeisler, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-76625/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Jan, 2021 Read the published version in EJNMMI Radiopharmacy and Chemistry → Version 1 posted 10 You are reading this latest preprint version Abstract Background : 64 Cu is one of the few radioisotopes that can be used for both imaging and therapy, enabling theranostics with identical chemical composition. Development of stable chelators is essential to harness the potential of this isotope, challenged by the presence of endogenous copper chelators. Pyridyl type chelators show good coordination ability with copper, prompting the present study of a series of chelates DOTA-xPy (x=1-4) that sequentially substitute carboxyl moieties with pyridyl moieties on a DOTA backbone. Results : We found that the presence of pyridyl groups significantly increases 64 Cu labeling yield, with DOTA-2Py, -3Py and -4Py quantitatively complexing 64 Cu at room temperature within 5 min (10 -4 M). [ 64 Cu]Cu-DOTA-xPy (x=2-4) exhibited good stability in human serum up to 24 hours. When challenged with 1000 eq. of NOTA, no transmetallation was observed for all three 64 Cu complexes. DOTA-xPy (x=1-3) were conjugated to a cyclized α-melanocyte-stimulating hormone (αMSH) peptide by using one of the pendant carboxyl groups as a bifunctional handle. [ 64 Cu]Cu-DOTA-xPy-αMSH retained good serum stability (>96% in 24 hours) and showed high binding affinity (Ki=2.1-3.7 nM) towards the melanocortin 1 receptor. Conclusion : DOTA-xPy (x=1-3) are promising chelators for 64 Cu. Further in vivo evaluation is necessary to assess the full potential of these chelators as a tool to enable further theranostic radiopharmaceutical development. Nuclear Chemistry Copper-64 Chelating ligands Radiolabeling α-Melanocyte-stimulating hormone Pyridyl DOTA Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Full Text Supplementary Files Cu64DOTAPySupportingInformation.pdf Cite Share Download PDF Status: Published Journal Publication published 13 Jan, 2021 Read the published version in EJNMMI Radiopharmacy and Chemistry → Version 1 posted Review # 2 received at journal 26 Oct, 2020 Editorial decision: Major revision 26 Oct, 2020 Review # 1 received at journal 12 Oct, 2020 Reviewer # 2 agreed at journal 05 Oct, 2020 Reviewer # 1 agreed at journal 02 Oct, 2020 Reviewers invited by journal 30 Sep, 2020 Editor assigned by journal 29 Sep, 2020 Editor invited by journal 28 Sep, 2020 Submission checks completed at journal 17 Sep, 2020 First submitted to journal 11 Sep, 2020 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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10:14:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-76625/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-76625/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s41181-020-00119-4","type":"published","date":"2021-01-13T15:02:27+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":2539450,"identity":"a7998738-2e5a-46c2-b9f6-4b893825dd0a","added_by":"auto","created_at":"2020-09-22 17:02:50","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":42357,"visible":true,"origin":"","legend":"Examples of commonly used 64Cu chelators.","description":"","filename":"Fig1.JPG","url":"https://assets-eu.researchsquare.com/files/rs-76625/v1/Fig1.JPG"},{"id":2539451,"identity":"f4b8ebeb-d00e-4848-879b-07ffe2ca51bb","added_by":"auto","created_at":"2020-09-22 17:02:50","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":24625,"visible":true,"origin":"","legend":"Radio-HPLC chromatogram showing the quantitative 64Cu labeling of (a) DOTA-1Py (retention time, tR = 12.5 min), (b) DOTA-2Py (tR = 12.7 min), (c) DOTA-3Py (tR = 14.5 min), and (d) DOTA-4Py (tR = 16.7 min) at ligand concentration 10-3M and ambient temperature.","description":"","filename":"Fig2.JPG","url":"https://assets-eu.researchsquare.com/files/rs-76625/v1/Fig2.JPG"},{"id":2539452,"identity":"3206964e-79a3-4a17-9db2-52e4d6b96c87","added_by":"auto","created_at":"2020-09-22 17:02:50","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":44426,"visible":true,"origin":"","legend":"64Cu labeling yield at various ligand concentrations for DOTA, DOTA-1Py, DOTA-2Py, DOTA-3Py, and DOTA-4Py (n=3) at ambient temperature and 5 min reaction time.","description":"","filename":"Fig3.JPG","url":"https://assets-eu.researchsquare.com/files/rs-76625/v1/Fig3.JPG"},{"id":2539453,"identity":"a8f4dcb3-7f24-4fcd-a036-b7d3fc1c1c1a","added_by":"auto","created_at":"2020-09-22 17:02:50","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":37206,"visible":true,"origin":"","legend":"64Cu labeling yield of DOTA-2Py, DOTA-3Py and DOTA-4Py at 1, 5, 10, 20 and 30 min performed with ligand concentration of 10-4 M and ambient temperature (n = 3).","description":"","filename":"Fig4.JPG","url":"https://assets-eu.researchsquare.com/files/rs-76625/v1/Fig4.JPG"},{"id":2539454,"identity":"a4fbebfc-72c8-4c39-a78c-732cf07b242c","added_by":"auto","created_at":"2020-09-22 17:02:50","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":40374,"visible":true,"origin":"","legend":"Chemical structure of DOTA-3Py-αMSH","description":"","filename":"Fig5.JPG","url":"https://assets-eu.researchsquare.com/files/rs-76625/v1/Fig5.JPG"},{"id":2539455,"identity":"2b3b0c17-80cf-4b17-9ac9-07777c023011","added_by":"auto","created_at":"2020-09-22 17:02:51","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":24613,"visible":true,"origin":"","legend":"Radio-HPLC chromatograms of (a) [64Cu]Cu-DOTA-1Py-αMSH (RCY=66%), (b) [64Cu]Cu-DOTA-2Py-αMSH, and (c) [64Cu]Cu-DOTA-3Py-αMSH.","description":"","filename":"Fig6.JPG","url":"https://assets-eu.researchsquare.com/files/rs-76625/v1/Fig6.JPG"},{"id":2539456,"identity":"9b848046-e363-4830-9280-dc76a008fed1","added_by":"auto","created_at":"2020-09-22 17:02:51","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":72517,"visible":true,"origin":"","legend":"Scheme 1. Synthesis of cyclen-xPy (x=1-4, compounds 1-4) and DOTA pyridine derivatives DOTA-xPy (x=1-3, compounds 5-7).","description":"","filename":"Scheme1.JPG","url":"https://assets-eu.researchsquare.com/files/rs-76625/v1/Scheme1.JPG"},{"id":15669005,"identity":"60971b90-91a4-4c14-9bfe-4161d9f489e5","added_by":"auto","created_at":"2021-11-18 13:51:12","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":747835,"visible":true,"origin":"","legend":"","description":"","filename":"Cu64DOTAPymanuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-76625/v1_covered.pdf"},{"id":13533828,"identity":"a6ae84ac-0734-4df0-94b4-d51557b2a6e1","added_by":"auto","created_at":"2021-09-17 01:22:24","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":747679,"visible":true,"origin":"","legend":"","description":"","filename":"Cu64DOTAPymanuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-76625/v1_covered.pdf"},{"id":2539459,"identity":"a2363622-7da4-4357-a28b-2d690c90de34","added_by":"auto","created_at":"2020-09-22 17:02:53","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":506152,"visible":true,"origin":"","legend":"","description":"","filename":"Cu64DOTAPymanuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-76625/v1_stamped.pdf"},{"id":2539457,"identity":"ff3fde4f-0c18-4f6b-8170-fd56961edff1","added_by":"auto","created_at":"2020-09-22 17:02:51","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":434680,"visible":true,"origin":"","legend":"","description":"","filename":"Cu64DOTAPymanuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-76625/v1/Cu64DOTAPymanuscript.pdf"},{"id":2539458,"identity":"6da3899f-0e5c-4517-88fe-fe4816111b13","added_by":"auto","created_at":"2020-09-22 17:02:51","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":855927,"visible":true,"origin":"","legend":"","description":"","filename":"Cu64DOTAPySupportingInformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-76625/v1/Cu64DOTAPySupportingInformation.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eSynthesis of DOTA-Pyridine Chelates for \u003csup\u003e64\u003c/sup\u003eCu Coordination and Radiolabeling of αMSH Peptide\u003c/p\u003e","fulltext":[{"header":"Full Text","content":"\u003cp\u003eThis preprint is available for \u003ca href='/article/rs-76625/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-radiopharmacy-and-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"erpc","sideBox":"Learn more about [EJNMMI Radiopharmacy and Chemistry](http://ejnmmipharmchem.springeropen.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/erpc/default.aspx","title":"EJNMMI Radiopharmacy and Chemistry","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Copper-64, Chelating ligands, Radiolabeling, α-Melanocyte-stimulating hormone, Pyridyl, DOTA","lastPublishedDoi":"10.21203/rs.3.rs-76625/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-76625/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003e: \u003csup\u003e64\u003c/sup\u003eCu is one of the few radioisotopes that can be used for both imaging and therapy, enabling theranostics with identical chemical composition. Development of stable chelators is essential to harness the potential of this isotope, challenged by the presence of endogenous copper chelators. Pyridyl type chelators show good coordination ability with copper, prompting the present study of a series of chelates DOTA-xPy (x=1-4) that sequentially substitute carboxyl moieties with pyridyl moieties on a DOTA backbone. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: We found that the presence of pyridyl groups significantly increases 64 Cu labeling yield, with DOTA-2Py, -3Py and -4Py quantitatively complexing 64 Cu at room temperature within 5 min (10 -4 M). [ 64 Cu]Cu-DOTA-xPy (x=2-4) exhibited good stability in human serum up to 24 hours. When challenged with 1000 eq. of NOTA, no transmetallation was observed for all three 64 Cu complexes.\u0026nbsp;DOTA-xPy (x=1-3) were conjugated to a cyclized α-melanocyte-stimulating hormone (αMSH) peptide by using one of the pendant carboxyl groups as a bifunctional handle. [ 64 Cu]Cu-DOTA-xPy-αMSH retained good serum stability (\u0026gt;96% in 24 hours) and showed high binding affinity (Ki=2.1-3.7 nM) towards the melanocortin 1 receptor.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion \u003c/strong\u003e: DOTA-xPy (x=1-3) are promising chelators for 64 Cu. Further in vivo evaluation is necessary to assess the full potential of these chelators as a tool to enable further theranostic radiopharmaceutical development.\u003c/p\u003e","manuscriptTitle":"Synthesis of DOTA-Pyridine Chelates for 64Cu Coordination and Radiolabeling of αMSH Peptide","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-09-22 17:02:48","doi":"10.21203/rs.3.rs-76625/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2020-10-26T12:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"decision","content":"Major revision","date":"2020-10-26T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-10-12T12:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2020-10-05T12:00:00+00:00","index":2,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-10-02T12:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-09-30T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-09-29T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-09-28T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-09-17T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-09-11T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-radiopharmacy-and-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"erpc","sideBox":"Learn more about [EJNMMI Radiopharmacy and Chemistry](http://ejnmmipharmchem.springeropen.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/erpc/default.aspx","title":"EJNMMI Radiopharmacy and Chemistry","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bd6d1342-66a3-4bad-b147-ddfd4088877f","owner":[],"postedDate":"September 22nd, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":579154,"name":"Nuclear Chemistry"}],"tags":[],"updatedAt":"2021-01-17T15:03:06+00:00","versionOfRecord":{"articleIdentity":"rs-76625","link":"https://doi.org/10.1186/s41181-020-00119-4","journal":{"identity":"ejnmmi-radiopharmacy-and-chemistry","isVorOnly":false,"title":"EJNMMI Radiopharmacy and Chemistry"},"publishedOn":"2021-01-13 15:02:27","publishedOnDateReadable":"January 13th, 2021"},"versionCreatedAt":"2020-09-22 17:02:48","video":"","vorDoi":"10.1186/s41181-020-00119-4","vorDoiUrl":"https://doi.org/10.1186/s41181-020-00119-4","workflowStages":[]},"version":"v1","identity":"rs-76625","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-76625","identity":"rs-76625","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}