[11C]MODAG 005 – a novel PET tracer targeting alpha-synuclein aggregates in the brain

[11C]MODAG 005 – a PET tracer targeting alpha-synuclein aggregates in the brain | 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 [ 11 C]MODAG 005 – a PET tracer targeting alpha-synuclein aggregates in the brain Ran Sing Saw, Sabrina Buss, Felix Schmidt, Sergey Ryazanov, Andrei Leonov, and 24 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2189800/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Synucleinopathies are neurodegenerative diseases characterized by the presence of brain inclusions containing the pathologically aggregated protein α-synuclein (αSYN). The development of a positron emission tomography tracer to detect aggregates of misfolded αSYN would revolutionize early diagnosis, disease monitoring and the evaluation of therapeutic efficacy. Here we present the development and preclinical in vitro and in vivo validation of [11C]MODAG-005. In vitro binding experiments demonstrate sub-nanomolar binding affinity to recombinant αSYN fibrils as well as to αSYN inclusions in human brain tissue. Specific binding in multiple system atrophy (MSA) brain tissue was detected using autoradiography and microautoradiography, and was validated through immunostaining. In vivo, [11C]MODAG-005 shows good brain penetration, rapid clearance from brain tissue and low metabolite formation in rodents and non-human primates. In addition, a pronounced binding and a good signal-to-noise ratio were achieved in an αSYN fibril-injected rat model and in an αSYN(A30P) transgenic mouse model in correlation to the pathological load. To validate its value for therapeutic development, we show target engagement of the drug candidate anle138b in the brain tissues from αSYN(A30P) mouse and MSA as well as in vivo in αSYN fibril-injected rats. Finally, our translational approach in first-in-human patients with clinically established MSA-C, MSA-C/P and PD, revealed a marked tracer binding in regions affected by αSYN pathology. Health sciences/Health care/Medical imaging/Brain imaging Biological sciences/Biological techniques/Imaging/Positron-emission tomography Health sciences/Diseases/Neurological disorders/Neurodegenerative diseases PET imaging alpha-synuclein pathology Full Text Additional Declarations The authors declare potential competing interests as follows: A patent has been filed (PCT/EP2020/082778) that includes MODAG-005. Armin Giese, Felix Schmidt, Andrei Leonov, Sergey Ryazanov and Johannes Levin are employed by MODAG GmbH, which retains ownership of MODAG-005, Armin Giese and Christian Griesinger are shareholders of MODAG GmbH. The other authors declare no competing interests. Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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competing interests as follows: A patent has been filed (PCT/EP2020/082778) that includes MODAG-005.\nArmin Giese, Felix Schmidt, Andrei Leonov, Sergey Ryazanov and Johannes Levin are employed by MODAG GmbH, which retains ownership of MODAG-005, Armin Giese and Christian Griesinger are shareholders of MODAG GmbH. The other authors declare no competing interests.","formattedTitle":"\u003cp\u003e[\u003csup\u003e11\u003c/sup\u003eC]MODAG 005 – a PET tracer targeting alpha-synuclein aggregates in the brain\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"PET imaging, alpha-synuclein pathology","lastPublishedDoi":"10.21203/rs.3.rs-2189800/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2189800/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSynucleinopathies are neurodegenerative diseases characterized by the presence of brain inclusions containing the pathologically aggregated protein α-synuclein (αSYN). The development of a positron emission tomography tracer to detect aggregates of misfolded αSYN would revolutionize early diagnosis, disease monitoring and the evaluation of therapeutic efficacy. Here we present the development and preclinical in vitro and in vivo validation of [11C]MODAG-005. In vitro binding experiments demonstrate sub-nanomolar binding affinity to recombinant αSYN fibrils as well as to αSYN inclusions in human brain tissue. Specific binding in multiple system atrophy (MSA) brain tissue was detected using autoradiography and microautoradiography, and was validated through immunostaining. In vivo, [11C]MODAG-005 shows good brain penetration, rapid clearance from brain tissue and low metabolite formation in rodents and non-human primates. In addition, a pronounced binding and a good signal-to-noise ratio were achieved in an αSYN fibril-injected rat model and in an αSYN(A30P) transgenic mouse model in correlation to the pathological load. To validate its value for therapeutic development, we show target engagement of the drug candidate anle138b in the brain tissues from αSYN(A30P) mouse and MSA as well as in vivo in αSYN fibril-injected rats. Finally, our translational approach in first-in-human patients with clinically established MSA-C, MSA-C/P and PD, revealed a marked tracer binding in regions affected by αSYN pathology.\u003c/p\u003e","manuscriptTitle":"[11C]MODAG 005 – a PET tracer targeting alpha-synuclein aggregates in the brain","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2025-10-28 22:01:36","doi":"10.21203/rs.3.rs-2189800/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2024-03-21 03:33:55","doi":"10.21203/rs.3.rs-2189800/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b8483ffb-bf84-469c-9d3f-838657543dfd","owner":[],"postedDate":"October 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":57048590,"name":"Health sciences/Health care/Medical imaging/Brain imaging"},{"id":57048591,"name":"Biological sciences/Biological techniques/Imaging/Positron-emission tomography"},{"id":57048592,"name":"Health sciences/Diseases/Neurological disorders/Neurodegenerative diseases"}],"tags":[],"updatedAt":"2025-10-27T11:02:03+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-28 22:01:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-2189800","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2189800","identity":"rs-2189800","version":["v2"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}