Review of technical advances, validation, and clinical application of tau and α-synuclein PET tracers—highlighting second-generation tau tracers (e.g., [18F]PI-2620) and emerging α-synuclein tracer [18F]ACI-12589—that improve differentiation of atypical parkinsonian syndromes.

Provides high translational value by describing biomarkers that can improve differential diagnosis, patient stratification, and therapy monitoring in disease‑modifying Parkinson's trials, though it is a review rather than primary therapeutic discovery work.

The differential diagnosis of neurodegenerative diseases, particularly Parkinsonian syndromes, remains a major challenge despite improved clinical criteria. Positron emission tomography enables the in vivo visualization of pathological protein aggregates and has therefore become an important tool in molecular imaging. While amyloid PET is already clinically established, tau and α-synuclein PET are increasingly gaining attention in translational research and clinical applications. This review provides a current overview of the development, validation, and clinical application of tau and α-synuclein PET tracers, with a particular focus on atypical Parkinsonian syndromes. For tau-PET, isoform-specific aspects of tracer binding, differences between first- and second-generation tracers, as well as in vitro, autoradiographic, and in vivo validation data are discussed. Special emphasis is placed on second-generation tracers such as [18F]PI-2620, which exhibit improved binding properties for 4R tauopathies. In addition, methodological aspects of quantitative analysis, including reference regions, target regions, and dynamic acquisition protocols, are addressed. In the second part of the article, the current status of α-synuclein PET is summarized. Initial preclinical and clinical data on the tracer [18F]ACI-12589 demonstrate specific binding to pathological α-synuclein and enable a clear differentiation of multiple system atrophy from Parkinson's disease and healthy controls. Furthermore, early preclinical developments of TDP-43 PET tracers are discussed as a prospective extension of molecular imaging.In summary, this review highlights the potential of tau- and α-synuclein PET as complementary molecular imaging techniques to improve the differential diagnosis of atypical Parkinsonian syndromes and as future biomarkers for patient stratification and therapy monitoring in disease-modifying clinical trials.