Project Summary Demyelination represents the hallmark of multiple sclerosis (MS) and is also present in other diseases including brain ischemia, traumatic brain injury and even Alzheimer’s disease. Currently, demyelinating diseases are primarily imaged using MRI. Even though MRI is highly sensitive to demyelination, it is not quantitative and it cannot distinguish demyelination from other potentially coexisiting pathological processes such as inflammation or axonal loss. Positron Emission Tomography (PET) can provide quantitative and biochemically specific information to complement MRI. We recently developed a PET radiotracer for demyelination based on the FDA-approved drug for MS 4- aminopyridine (4AP) called [18F]3F4AP. We showed that this tracer be used to detect demyelination in rodent models of MS and that it has good properties for imaging the brain in monkeys. In this project, we seek to investigate the potential of this tracer for imaging demyelination in a model of traumatic brain injury and to validate it in nonhuman primates and humans. The information gathered here will be crucial for the design and interpretation of future human studies. Once validated, this tracer and could contribute to better monitoring of demyelinating diseases and to the development of therapies to reverse demyelination.