Study Rationale: In Parkinson’s disease (PD) and related disorders, a protein called alpha-synuclein (asyn) forms harmful deposits in the brain. Doctors can’t see these changes in living people, making diagnosis slow and uncertain. Positron Emission Tomography (PET) uses tiny amounts of safe, radioactive “tracers” that bind to target proteins, in this case, asyn. A PET scan could reveal asyn and help track disease over time. Many teams have tried to create an asyn tracer, but past versions either didn’t bind tightly enough or stuck to the wrong brain proteins. We propose a faster, smarter design strategy to deliver a highly selective, strong-binding asyn tracer.
Hypothesis: By building many new molecules quickly with “click chemistry,” testing them directly on PD brain tissue, and screening out any that stick to the wrong targets, we can identify a molecule that binds very strongly to asyn, while not binding to other targets, so that it is potentially useful as a PET tracer for asyn.
Study Design: In year 1, we will use click chemistry to make about 1,500 candidate molecules and test them on PD brain tissue to find strong binders. We will do follow up tests to remove molecules that also bind to other brain proteins and check how these molecules behave in the body, including how well they get into the brain, how fast they leave, and how the body breaks them down.
In year 2, we will improve the best molecules to make them bind more strongly and more selectively. We will add a positron emitter, so they can be seen on PET scans, and then test them to confirm clear brain signals. Based on these experiments, we will pick one lead tracer that meets all goals for binding strength, selectivity, and safety.
Impact on Diagnosis/Treatment of Parkinson’s disease: A reliable asyn PET tracer would make PD diagnosis faster and more accurate. It could help tell PD apart from similar diseases, measure how much asyn is in the brain and show whether a new drug is working. This would speed up treatment trials and help doctors choose better treatments for patients.
Next Steps for Development: Once we have found a promising asyn PET tracer candidate, we will test it for safety and work on the manufacturing and quality control procedures, so we can test it in PD patients.