The PET tracer [11C]MODAG-005 targets alpha-synuclein aggregates in the brain PMID: 42202047

ADC Targets in Oncology

2026-04-10

The PET tracer [11C]MODAG-005 targets alpha-synuclein aggregates in the brain

Sci Transl Med. 2026 May 27;18(851):eaec0813. doi: 10.1126/scitranslmed.aec0813.

Ran Sing Saw ¹ , Sabrina Haas ¹ , Felix Schmidt ² , Sergey Ryazanov ² ³ , Andrei Leonov ² ³ , Daniel Bleher ¹ , Ann-Kathrin Grotegerd ¹ , Laura Kuebler ¹ , Benjamin Roeben ⁴ ⁵ ⁶ , Fabian Schmidt ¹ ⁷ , Matthias Reimold ⁷ , Federica Bonanno ¹ , Viktoria C Ruf ⁸ , Bernadette Dahl ⁵ ⁶ ⁹ , Christine M Sandiego ¹⁰ , Kelly E Henry ¹⁰ , Ioannis Papadopoulos ¹ , Martin Schaller ¹¹ , Philipp J Kahle ⁵ ⁶ , Johannes Levin ² ¹² ¹³ ¹⁴ , Thomas Gasser ⁴ ⁵ , Kathrin Brockmann ⁴ ⁵ ⁶ , Gerald Reischl ¹ ¹⁵ , Christian la Fougère ⁷ ¹⁵ , Bernd J Pichler ¹ ¹⁵ , Andreas Maurer ¹ ¹⁵ , Christian Griesinger ³ ¹⁶ , Armin Giese ² , Kristina Herfert ¹

Affiliations

1. Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tuebingen, 72076 Tuebingen, Germany.
2. MODAG GmbH, 55234 Wendelsheim, Germany.
3. Department of NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, 37077 Goettingen, Germany.
4. Department of Neurology, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany.
5. Hertie Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany.
6. German Center for Neurodegenerative Diseases, 72076 Tuebingen, Germany.
7. Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, University Hospital Tuebingen, 72076 Tuebingen, Germany.
8. Ludwig Maximilians University, Center for Neuropathology and Prion Research, 81377 Munich, Germany.
9. Graduate School of Cellular and Molecular Neuroscience, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany.
10. Invicro LLC, Needham, MA 02494, USA.
11. Department of Dermatology, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany.
12. Department of Neurology, Ludwig-Maximilians-University Munich, Munich, Germany.
13. German Center for Neurodegenerative Diseases (DZNE), site Munich, Munich, Germany.
14. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
15. Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany.
16. Cluster of Excellence "Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells" (MBExC), University of Goettingen; 37075 Goettingen, Germany.

Abstract

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 [¹¹C]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, [¹¹C]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 [¹¹C]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 [¹¹C]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.