Journal Article

DZNE-2026-00569

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The PET tracer [11C]MODAG-005 targets alpha-synuclein aggregates in the brain.

Saw, R. S. ; Haas, S. ; Schmidt, F. ; Ryazanov, S. ; Leonov, A. ; Bleher, D. ; Grotegerd, A.-K. ; Kuebler, L. ; Roeben, B.DZNE* ; Schmidt, F. ; Reimold, M. ; Bonanno, F. ; Ruf, V. C. ; Dahl, B.DZNE* ; Sandiego, C. M. ; Henry, K. E. ; Papadopoulos, I. ; Schaller, M. ; Kahle, P. J.DZNE* ; Levin, J.DZNE* ; Gasser, T.Extern* ; Brockmann, K.DZNE* ; Reischl, G. ; la Fougère, C. ; Pichler, B. J. ; Maurer, A. ; Griesinger, C. ; Giese, A. ; Herfert, K.

2026
AAAS Washington, DC

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Please use a persistent id in citations: doi:10.1126/scitranslmed.aec0813

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.

Keyword(s): alpha-Synuclein: metabolism (MeSH) ; Animals (MeSH) ; Positron-Emission Tomography: methods (MeSH) ; Humans (MeSH) ; Brain: metabolism (MeSH) ; Brain: diagnostic imaging (MeSH) ; Brain: pathology (MeSH) ; Carbon Radioisotopes: chemistry (MeSH) ; Mice, Transgenic (MeSH) ; Male (MeSH) ; Multiple System Atrophy: diagnostic imaging (MeSH) ; Multiple System Atrophy: pathology (MeSH) ; Multiple System Atrophy: metabolism (MeSH) ; Protein Aggregates (MeSH) ; Mice (MeSH) ; Female (MeSH) ; Rats (MeSH) ; alpha-Synuclein ; Carbon Radioisotopes ; Protein Aggregates ; Carbon-11

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser)
2. Clinical Research (Munich) (Clinical Research (Munich))
3. Clinical Neurodegeneration (AG Levin)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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