α-synuclein PET imaging: early human evidence and the path toward clinical proof-of-concept

Introduction: Aggregation of misfolded α-synuclein is the defining pathological hallmark of synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy (MSA). Despite major advances in the field of molecular neuroimaging, the in vivo detection of α-synuclein remains one of the most challenging goals in positron emission tomography (PET), largely due to the low abundance of aggregates, structural heterogeneity of fibrillar strains, and the need for high selectivity over other amyloid proteins. Areas covered: This Special Report summarizes advances in the development of small-molecule PET tracers targeting α-synuclein aggregates, with particular emphasis on the transition from preclinical radiotracer discovery to early clinical imaging studies. The article discusses key methodological challenges in tracer development, emerging chemical scaffolds, and the first translational efforts enabling initial human PET investigations. Expert opinion: Although no tracer is yet clinically validated, emerging evidence is consistent but still preliminary, particularly in MSA, where several compounds show regionally specific signals. However, important challenges remain, including limited sensitivity in early or prodromal disease and the need to further establish tracer specificity and biological interpretability in vivo. Further multicenter studies will be essential to establish α-synuclein PET as a reliable biomarker for diagnosis, patient stratification, and therapeutic monitoring.