Grant: Project Grant

Multiple sclerosis (MS) is a chronic disease that predominantly affects young adults and causes problems with movement, coordination, and cognition. Canada has one of the highest rates of MS in the world, with more than 133,000 cases expected by 2031. Globally, over 2.8 million people live with MS, placing a heavy burden on patients, families, and healthcare systems. Despite this impact, the exact cause of MS remains unknown, and there is currently no cure or simple test for diagnosis. In the brain, proteins called AMPA receptors (AMPARs) play a key role in how nerve cells communicate. Changes in AMPAR signaling have been linked to MS, particularly in the later stages of the disease, making AMPARs a promising target for new treatments. A major challenge in developing therapies for the brain is whether the drug reaches the brain and binds to its intended target at the right dose. Our project aims to address this gap by developing positron emission tomography (PET) imaging tools that can measure target engagement (whether a drug binds its target in the brain) and dose-occupancy (how much of the target is bound at a given dose). These measurements are critical for selecting dose ranges, comparing drug candidates, and making early decisions in therapeutic development. We have developed an AMPA-targeting compound, ZCAN262, and will build on this compound in three steps: (1) optimize and validate PET imaging tools that can measure AMPARs in the living brain; (2) confirm binding patterns using postmortem brain tissue from individuals with MS and controls; and (3) use an MS mouse model to quantify brain target engagement and dose-occupancy and to explore how AMPAR-related signals change over the course of disease. Together, this work will deliver a first-in-class imaging toolkit to accelerate AMPAR-focused drug discovery and improve evaluation of emerging MS therapies, with the long-term goal of enabling more effective treatment strategies for people living with MS.