Authors
Saw RS, Haas S, Schmidt F, Ryazanov S, Leonov A, Bleher D, Grotegerd AK, Kuebler L, Roeben B, Schmidt F, Reimold M, Bonanno F, Ruf VC, Dahl B, Sandiego CM, Henry KE, Papadopoulos I, Schaller M, Kahle PJ, Levin J, Gasser T, Brockmann K, Reischl G, la Fougère C, Pichler BJ, Maurer A, Griesinger C, Giese A, Herfert K
Journal
Science Translational Medicine
Citation
Sci Transl Med. 2026 May 27;18(851):eaec0813.
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.
