The PET tracer [ <sup>11</sup> C]MODAG-005 targets alpha-synuclein aggregates in the brain
Synucleinopathies are neurodegenerative diseases characterized by the presence of brain inclusions containing the pathologically aggregated protein α-synuclein. The development of a positron emission tomography tracer to detect aggregates of misfolded α-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 [ 11 C]MODAG-005. In vitro binding experiments demonstrated subnanomolar binding affinity to recombinant α-synuclein fibrils and to α-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, [ 11 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 α-synuclein fibril–injected rat model and in an α-synuclein (A30P) transgenic mouse model in correlation to the pathological load. To validate the potential of [ 11 C]MODAG-005 for therapeutic development, we showed target engagement of the drug candidate anle138b in the brain tissues from α-synuclein (A30P) mice and patients with multiple system atrophy as well as in vivo in α-synuclein fibril–injected rats. Last, first-in-human imaging demonstrated [ 11 C]MODAG-005 binding in brain regions affected by α-synuclein pathology in patients with clinically established MSA cerebellar type, MSA cerebellar and parkinsonian type, and Parkinson’s disease.
Authors
- Ann-Kathrin Grotegerd
- Gerald Reischl (ORCID: https://orcid.org/0000-0003-3961-116X)
- Sergey Ryazanov (ORCID: https://orcid.org/0000-0002-2685-7956)
- Federica Bonanno
- M SCHALLER
- Christian Griesinger (ORCID: https://orcid.org/0000-0002-1266-4344)
- Christine Sandiego (ORCID: https://orcid.org/0000-0001-7490-2494)
- Laura Kuebler (ORCID: https://orcid.org/0000-0002-6986-403X)
- Kelly E. Henry (ORCID: https://orcid.org/0000-0002-8492-9364)
- Daniel Bleher (ORCID: https://orcid.org/0000-0002-2216-2524)
- Benjamin Röeben (ORCID: https://orcid.org/0000-0002-4905-8698)
- Ran Sing Saw
- Matthias Reimold
- Philipp J. Kahle (ORCID: https://orcid.org/0000-0002-8587-1731)
- Kristina Herfert (ORCID: https://orcid.org/0000-0003-0231-7717)
- Bernadette Dahl
- Ioannis Papadopoulos
- Felix Schmidt
- Sabrina Haas (ORCID: https://orcid.org/0009-0006-9003-8708)
- Fabian Schmidt
- B Pichler
- V Ruf
- Johannes Levin (ORCID: https://orcid.org/0000-0001-5092-4306)
- Kathrin Brockmann (ORCID: https://orcid.org/0000-0002-7515-8596)
- Andrei Leonov (ORCID: https://orcid.org/0000-0002-5586-9382)
- Thomas Gasser (ORCID: https://orcid.org/0000-0002-1069-1146)
- Christian la Fougère (ORCID: https://orcid.org/0000-0001-7519-0417)
- Andreas Maurer (ORCID: https://orcid.org/0000-0003-2412-5361)
- Armin Giese (ORCID: https://orcid.org/0000-0002-8238-4102)
Institutions
- Siemens (Germany) (DE)
- German Center for Neurodegenerative Diseases (DE)
- Munich Cluster for Systems Neurology (DE)
- Invicro (United States) (US)
- Hertie Institute for Clinical Brain Research (DE)
- Max Planck Institute for Multidisciplinary Sciences (DE)
- University of Göttingen (DE)
- University of Tübingen (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2026-05-27
- DOI
- https://doi.org/10.1126/scitranslmed.aec0813
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Carl-Zeiss-Stiftung
- Deutsche Forschungsgemeinschaft