Neuroinflammation is a key early event in the development of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Predominately driven by innate immunity mediated by microglia and macrophages, aberrant activation of the neuroinflammatory response can generate oxidative stress to directly damage neurons and axons, cause demyelination, and break down the blood-brain barrier. Inflammation has been found in patients with early stage AD, PD, and multiple system atrophy (MSA). As such, neuroinflammation is also emerging to be a potential treatment target. Thus, a non-invasive imaging method to specifically and sensitively assess early damaging neuroinflammation would be able to detect incipient disease before irreversible damage occurs, and enable monitoring of disease progression and treatment response of current and emerging therapies. Through transcriptome profiling we have identified myeloperoxidase (MPO) to be highly expressed by pro-inflammatory cells but not by reparative cells. MPO is a key generator of oxidative stress and has been found to be associated with many neurological diseases. Increased number of MPO immunoreactive cells have been found in the brains of early AD and PD patients, but not in the brains of normal patients. As such, MPO is a treatment target for neurodegenerative diseases, and an MPO inhibitor (verdiperstat) is currently undergoing phase 2/3 clinical trial for MSA and amyotrophic lateral sclerosis (ALS). We and others have found that MRI agents targeting MPO (“MPO-Gd”) can detect neuroinflammation and track the infiltration of myeloid immune cells into the CNS non-invasively. However, MPO-Gd suffers from lower detection sensitivity inherent in the MRI technique and cannot cross the blood- brain barrier (BBB), and is unable to detect the smaller amount of MPO activity in most neurodegenerative diseases such as AD. To overcome these limitations, we propose to develop a PET agent that is not only more specific and sensitive for MPO activity than current MPO imaging agents, but also capable of crossing the BBB, to enable imaging of damaging inflammation in neurodegenerative diseases. This agent can also provide complementary information to emerging imaging technologies that focus on cells (translocator protein imaging) and abnormal proteins (β-amyloid, tau) in neurodegenerative diseases. Specifically, we will 1) systematically design and screen potential PET agents for detecting MPO activity in the brain, 2) characterize and validate candidate MPO PET agents in vivo, and 3) demonstrate utility of MPO PET imaging to identify and track neuroinflammation in a mouse model of AD, and characterize safety elements of the optimized PET probe for regulatory filing. The output of this research will be a novel MPO-targeting PET imaging probe with demonstrated high efficacy and specificity, pharmacokinetic characterization, and preclinical dosimetry data to enable rapid translation for human use. Thi...