Phase 0 Study to Evaluate the in vivo Characteristics of a Myeloperoxidase-Targeting PET Agent in Healthy Volunteers and Early AD Patients

Alzheimer’s disease (AD) is a devastating and progressive disease without a cure. Long thought to be a consequence of AD, neuroinflammation is now recognized as a key early event in the development of neurodegenerative diseases such as AD. Aberrant neuroinflammatory response activates immune cells that can increase oxidative stress, and oxidative stress can directly damage neurons and axons, cause demyelination, and break down the blood-brain barrier (BBB), and has been found in patients with early-stage AD. However, current clinical imaging technologies do not specifically assess oxidative stress and cannot distinguish between damaging and reparative inflammation. We have found that the enzyme myeloperoxidase (MPO) is highly expressed by pro-inflammatory cells but not by reparative cells. MPO is a key mediator of oxidative inflammation and has been found to be associated with AD. An increased number of MPO immunoreactive cells have been found in the brains of AD patients, but not in the brains of normal patients. We and others have found that an MRI agent targeting MPO (“MPO-Gd”) can detect neuroinflammation non- invasively, from early to advanced stages, in stroke and multiple sclerosis, and can accurately track the infiltration of early pro-inflammatory myeloid cells into the CNS non-invasively. However, MPO-Gd suffers from the lower detection sensitivity of MRI techniques and cannot cross the blood-brain barrier (BBB). As such, MPO-Gd is unable to detect the smaller amount of MPO activity found in AD. A PET imaging agent can overcome these limitations. We have developed an activatable MPO-PET imaging agent (18F-EH301) that can cross the BBB to enable imaging of MPO activity in AD. Under a funded SBIR, we have validated in rodents that 18F-EH301 is highly stable without interfering metabolites, and 18F-EH301 PET imaging is specific to MPO activity, crosses the blood-brain barrier, and can detect early neuroinflammation in the 5XFAD mouse model of AD. Furthermore, an acute single-dose toxicology study in rats at 100X of the expected clinical dose revealed no evidence of adverse effects, setting the stage for translation. The goal of this proposal is to perform a first- in-human Phase 0 clinical study of 18F-EH301 to assess 18F-EH301’s in vivo characteristics, including the ability to cross the human blood-brain barrier and validate its ability to be activated by human MPO in the AD brain. Ultimately, we hope to provide a tool to image and track oxidative damaging neuroinflammation in AD and other neurological disease. In this phase 1 SBIR application, we aim to 1) assemble and file an exploratory investigational new drug (eIND) application and 2) conduct a first-in-human Phase 0 clinical study to study and confirm the in vivo characteristics (pharmacokinetics, mechanism/pharmacodynamics, elimination, dosimetry, metabolite, and biodistribution) in both healthy volunteers and early-stage AD patients. These studies will provide us with valuable information not only on the behavior of 18F-EH301 in human subjects but also establish feasibility and guide future clinical development of 18F-EH301 for AD patients.