[11C]MODAG 005 – a PET tracer targeting alpha-synuclein aggregates in the brain

Synucleinopathies are neurodegenerative diseases characterized by the presence of brain inclusions containing the pathologically aggregated protein α-synuclein (αSYN). The development of a positron emission tomography tracer to detect aggregates of misfolded αSYN would revolutionize early diagnosis, disease monitoring and the evaluation of therapeutic efficacy. Here we present the development and preclinical in vitro and in vivo validation of [11C]MODAG-005. In vitro binding experiments demonstrate sub-nanomolar binding affinity to recombinant αSYN fibrils as well as to αSYN 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 shows good brain penetration, rapid clearance from brain tissue and low metabolite formation in rodents and non-human primates. In addition, a pronounced binding and a good signal-to-noise ratio were achieved in an αSYN fibril-injected rat model and in an αSYN(A30P) transgenic mouse model in correlation to the pathological load. To validate its value for therapeutic development, we show target engagement of the drug candidate anle138b in the brain tissues from αSYN(A30P) mouse and MSA as well as in vivo in αSYN fibril-injected rats. Finally, our translational approach in first-in-human patients with clinically established MSA-C, MSA-C/P and PD, revealed a marked tracer binding in regions affected by αSYN pathology.