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Transl. Med."],"published-print":{"date-parts":[[2026,5,27]]},"abstract":"<jats:p>\n                    Synucleinopathies are neurodegenerative diseases characterized by the presence of brain inclusions containing the pathologically aggregated protein \u03b1-synuclein. The development of a positron emission tomography tracer to detect aggregates of misfolded \u03b1-synuclein could revolutionize early diagnosis, disease monitoring, and the evaluation of therapeutic efficacy. Here, we present the development, preclinical validation, and first-in-human evaluation of [\n                    <jats:sup>11<\/jats:sup>\n                    C]MODAG-005. In vitro binding experiments demonstrated subnanomolar binding affinity to recombinant \u03b1-synuclein fibrils and to \u03b1-synuclein 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, [\n                    <jats:sup>11<\/jats:sup>\n                    C]MODAG-005 showed good brain penetration, rapid clearance from brain tissue, and low metabolite formation in rodents and nonhuman primates. In addition, a pronounced binding and a good signal-to-noise ratio were achieved in an \u03b1-synuclein fibril\u2013injected rat model and in an \u03b1-synuclein (A30P) transgenic mouse model in correlation to the pathological load. To validate the potential of [\n                    <jats:sup>11<\/jats:sup>\n                    C]MODAG-005 for therapeutic development, we showed target engagement of the drug candidate anle138b in the brain tissues from \u03b1-synuclein (A30P) mice and patients with multiple system atrophy as well as in vivo in \u03b1-synuclein fibril\u2013injected rats. Last, first-in-human imaging demonstrated [\n                    <jats:sup>11<\/jats:sup>\n                    C]MODAG-005 binding in brain regions affected by \u03b1-synuclein pathology in patients with clinically established MSA cerebellar type, MSA cerebellar and parkinsonian type, and Parkinson\u2019s disease.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.aec0813","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T17:58:36Z","timestamp":1779904716000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":6,"title":["The PET tracer [\n                    <sup>11<\/sup>\n                    C]MODAG-005 targets alpha-synuclein aggregates in the brain"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1787-6992","authenticated-orcid":true,"given":"Ran Sing","family":"Saw","sequence":"first","affiliation":[{"name":"Werner Siemens Imaging Center, 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Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5586-9382","authenticated-orcid":true,"given":"Andrei","family":"Leonov","sequence":"additional","affiliation":[{"name":"MODAG GmbH, 55234 Wendelsheim, Germany."},{"name":"Department of NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, 37077 Goettingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2216-2524","authenticated-orcid":true,"given":"Daniel","family":"Bleher","sequence":"additional","affiliation":[{"name":"Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tuebingen, 72076 Tuebingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2717-0723","authenticated-orcid":true,"given":"Ann-Kathrin","family":"Grotegerd","sequence":"additional","affiliation":[{"name":"Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tuebingen, 72076 Tuebingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Kuebler","sequence":"additional","affiliation":[{"name":"Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tuebingen, 72076 Tuebingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4905-8698","authenticated-orcid":true,"given":"Benjamin","family":"Roeben","sequence":"additional","affiliation":[{"name":"Department of Neurology, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany."},{"name":"Hertie Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany."},{"name":"German Center for Neurodegenerative Diseases, 72076 Tuebingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1886-4803","authenticated-orcid":true,"given":"Fabian","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tuebingen, 72076 Tuebingen, Germany."},{"name":"Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, University Hospital Tuebingen, 72076 Tuebingen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1314-1932","authenticated-orcid":true,"given":"Matthias","family":"Reimold","sequence":"additional","affiliation":[{"name":"Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, University Hospital Tuebingen, 72076 Tuebingen, 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