Study Rationale: Aggregation of the protein alpha-synuclein into fibrils in Lewy bodies and Lewy neurites is the key pathological feature of Parkinson's disease (PD) and related synucleinopathies. Despite advancements in detecting alpha-synuclein pathology in samples of cerebrospinal fluid and skin, current measures are inadequate for use in clinical trials. PET scanning has been used to successfully identify amyloid beta and tau protein pathologies in Alzheimer's disease, an advance that has been critical for developing new therapies. In contrast, identifying novel PET probes that selectively recognize alpha-synuclein has been challenging and has limited early diagnosis of PD and clinical trial design.
Hypothesis: We recently screened billions of compounds for their ability to specifically bind alpha-synuclein versus amyloid beta or tau. We hypothesize that the top hits from this screen will produce highly selective PET tracers for alpha-synuclein fibrils, improving diagnosis and treatment of PD.
Study Design: We will screen and optimize compounds based on 16 distinct chemical scaffolds identified by our screen, aiming for compounds that bind alpha-synuclein strongly and with a high degree of specificity. We will add a radioactive label to selected candidates and test them in human stem-cell models engineered to replicate alpha-synuclein pathologies. We will conduct additional testing on postmortem human brain tissue to assess the probes’ specificity for alpha-synuclein aggregates. Lastly, we will study the chemical properties of lead compounds in preclinical PD models.
Impact on Diagnosis/Treatment of Parkinson’s Disease: The Development of PET probes specific for alpha-synuclein fibrils could transform how PD is diagnosed, allowing for earlier detection and precise monitoring of disease progression and treatment efficacy.
Next Steps for Development: If successful, the next steps include clinical testing of lead compounds in people with PD and expanding these compounds' use for diagnosing other synucleinopathies, such as dementia with Lewy bodies and multiple system atrophy. Some of these compounds could even be good candidates to adapt for therapeutic application.