Study Rationale:
Parkinson’s disease (PD), Alzheimer’s disease and progressive supranuclear palsy are all characterized by the presence of abnormal aggregations of two proteins in the brain: alpha-synuclein and tau. Currently, the diagnosis of these diseases only takes place after the appearance of symptoms or signs of motor dysfunction. The development of highly specific and sensitive imaging agents for these abnormal aggregations would enable early detection and the accurate monitoring of disease progression, which would improve our understanding of the underlying disease mechanisms and potentially lead to the discovery of more effective therapeutics.
Hypothesis:
This project will extend the use of a recently developed class of chemically synthesized molecules, called peptoids, to produce PET imaging agents that can detect alpha-synuclein and tau aggregates.
Study Design:
This project employs a unique approach that leverages the inherent versatility and stability of chemically synthesized peptoids and a structural understanding of peptoids that have previously shown very high specificity for protein aggregations such as alpha-synuclein and tau. We will synthesize radioactively labeled variations of these previously engineered peptoids and test their ability to bind selectively to alpha-synuclein and tau when exposed to a diverse array of proteins meant to simulate the native environment of the brain. Successive iterations will be used to refine the peptoid variations and identify those with the greatest affinity and specificity for alpha-synuclein and tau.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Development of PET imaging agents that are highly specific and sensitive for alpha-synuclein and tau may enable early detection and should help diagnose disease status more accurately. Researchers can also use these tools to explore disease mechanisms, which could lead to the development of effective therapeutics.
Next Steps for Development:
PET tracers for alpha-synuclein and tau can be optimized for absorption and retention time in the brain to enhance image quality. These peptoids can also be exploited to reveal unique binding sites in alpha-synuclein and tau aggregates, which could offer promising alternatives for the development of improved diagnostics and therapeutics.