Study Rationale: One of the hallmarks of Parkinson’s disease (PD) is neuroinflammation. During this dynamic process, the brain’s immune cells, called microglia, become activated and can either prolong or reduce the inflammation. When microglia are in a neuroprotective state, they boost the levels of a receptor called P2Y12 on their surface. We propose using Positron Emission Tomography (PET) to measure the P2Y12 receptor and monitor the activation of microglia in people with PD. In this study, we will develop a radiolabeled compound, or PET tracer, that will bind to the P2Y12 receptor and allow us to track it by PET imaging.
Hypothesis: We hypothesize that, with the aid of computational methods, we can find compounds that can enter the brain and bind to the P2Y12 receptor. These compounds will then be used as starting points for developing a PET tracer.
Study Design: To find new compounds that bind to the P2Y12 receptor, we will screen large databases containing more than 11 billion compounds using computerized systems. Next, we will assess the ability of these compounds to bind to the P2Y12 receptor in test tubes; promising compounds will be further explored and optimized. A few selected optimized compounds will be radioactively labeled and evaluated as PET tracers in animals to demonstrate that the P2Y12 receptor can be measured in the living brain with PET.
Impact on Diagnosis/Treatment of Parkinson’s disease: PET imaging of the P2Y12 receptor will allow measurement of the changes in microglia activity at different stages of PD. This insight can pave the way for improved monitoring and diagnosis, as well as facilitating the development of drugs that will bring us closer to slowing or reversing PD progression.
Next Steps for Development: A successful PET tracer for the P2Y12 receptor will first be tested for safety in animals. If deemed safe, the tracer will be studied in people with PD to assess whether it can be used to monitor microglia activation in humans.