Development of an ?-synuclein fibril and oligomer specific tracer for diagnosis of Parkinson?s disease, dementia with Lewy bodies and multiple system atrophy

The development of specific disease-associated PET tracers is one of the major challenges, the realization of which in neurodegenerative diseases would enable not only the efficiency of diagnosis but also support the development of disease-modifying therapeutics. Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized by neuronal fibrillary inclusions composed of aggregated alpha-synuclein (alpha-syn). However, these deposits are not only found in PD, but also in other related diseases such as multiple system atrophy (MSA) and dementia with Lewy bodies (DLB), which are grouped under the term synucleinopathies. In this study, we used NGS-guided phage display selection to identify short peptides that bind aggregated alpha-syn. By surface plasmon resonance (SPR)-based affinity screening, we identified the peptide SVLfib-5 that recognizes aggregated alpha-syn with high complex stability and sequence specificity. Further analysis SPR showed that SVLfib-5 is not only specific for aggregated alpha-syn, but in particular recognizes fibrillary and oligomeric structures. Moreover, fluorescence microscopy of human brain tissue sections from PD, MSA, and DLB patients with SVLfib-5 allowed specific recognition of alpha-syn and a clear discrimination between diseased and nondiseased samples. These findings provide the basis for the further development of an alpha-syn PET tracer for early diagnosis and monitoring of disease progression and therapy progress.