α-Synuclein Radiotracer Development and In Vivo Imaging: Recent Advancements and New Perspectives

alpha-Synucleinopathies including idiopathic Parkinson's disease, dementia with Lewy bodies and multiple systems atrophy share overlapping symptoms and pathological hallmarks. Selective neurodegeneration and Lewy pathology are the main hallmarks of alpha-synucleinopathies. Currently, there is no imaging biomarker suitable for a definitive early diagnosis of alpha-synucleinopathies. Although dopaminergic deficits detected with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) radiotracers can support clinical diagnosis by confirming the presence of dopaminergic neurodegeneration, dopaminergic imaging cannot visualize the preceding disease process, nor distinguish alpha-synucleinopathies from tauopathies with dopaminergic neurodegeneration, especially at early symptomatic disease stage when clinical presentation is often overlapping. Aggregated alpha-synuclein (alpha-Syn) could be a suitable imaging biomarker in alpha-synucleinopathies, because alpha-Syn- aggregation and therefore, Lewy pathology is evidently an early driver of alpha-synucleinopathies pathogenesis. Additionally, several antibodies and small molecule compounds targeting aggregated alpha Syn are in development for therapy. However, there is no way to directly measure if or how much they lower the levels of aggregated alpha Syn in the brain. There is clearly a paramount diagnostic and therapeutic unmet medical need. To date, aggregated alpha Syn and Lewy pathology inclusion bodies cannot be assessed ante-mortem with SPECT or PET imaging because of the suboptimal binding characteristics and/or physicochemical properties of current radiotracers. The aim of this narrative review is to highlight the suitability of aggregated alpha Syn as an imaging biomarker in alpha-synucleinopathies, the current limitations with and lessons learned from alpha Syn radiotracer development, and finally to propose antibody-based ligands for imaging alpha Syn aggregates as a complementary tool rather than an alternative to small molecule ligands. (C) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.