The ultimate goal of this project is develop a positron emission tomography (PET) radiotracer to image the distribution of alpha-synuclein in the brain. Alpha-synuclein imaging would be a valuable biomarker that could be used for diagnosis (potentially pre-symptomatic), drug development, and monitoring of disease progression and therapeutic effects.
Four groups have been selected by The Michael J. Fox Foundation to participate in this project including two academic groups, a radiopharmaceutical company, and a contract research organization. They sought to uncover new compounds that bound with high affinity and high selectivity to alpha-synuclein protein deposits using high throughput screens (HTS). The HTS revealed more than ten structurally diverse compounds that are promising as potential alpha-synuclein-selective ligands. Laboratory analyses indicated that many of the lead compounds bound with high affinity and selectivity to alpha-synuclein aggregates and bound much less avidly to deposits of other proteins, amyloid-beta and tau. This project has been supported by multiple follow-on grants. They are now radiolabeling (attaching a kind of atom that can be visualized with imaging) the top three candidate compounds and testing brain uptake.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The accumulation of aggregated alpha-synuclein in the brain is the pathological hallmark of Parkinson’s disease (PD) and is a target for drugs being developed to treat PD. The ability to visualize alpha-syncuclein in the brain could be useful both as a biomarker of the presence of disease and disease progression and as a tool for drug development.
Researchers hope to identify and radiolabel compounds that selectively bind alpha-synuclein for use as PET imaging agents.
This project was supported with a 2014 supplemental grant to continue work outlined above.