Project Abstract We intend to validate [18F]FNDP for PET imaging of soluble epoxide hydrolase (sEH) in healthy human subjects. sEH is important in cerebrovascular pathophysiology in the context of mild cognitive impairment, vascular cognitive impairment (VCI), Alzheimer’s disease, stroke and other conditions. Post-mortem studies have shown highly increased expression of cerebral sEH in patients with VCI, stroke and other disorders of the central nervous system. We developed [18F]FNDP to understand better and to quantify the vascular and potentially inflammatory components to these disorders non-invasively and to promote the development of new drugs targeting sEH, which are beginning to proliferate. Notably [18F]FNDP is the first and only radioligand highly specific for PET imaging of sEH, as we now show in rodent and non-human primate brain. The proposed imaging project addresses measurement of the availability and distribution of sEH throughout the human brain with fewer confounding variables than the post- mortem studies, and could be done repeatedly according to a variety of scenarios. Consonant with the format of the R21/R33 we will complete pre-clinical studies with [18F]FNDP during the R21 (eIND enabling) phase, including optimization and automation of the radiosynthesis, assessment of radiometabolites, calculation of dosimetry estimates, and determination of binding specificity in baboon brain. The R33 portion will involve first-in-human brain kinetic analysis, test- retest and whole body PET/CT-based human dosimetry. We have obtained independent funding for the toxicology studies also needed for the eIND. At the end of this project we will have a validated radiotracer targeting sEH, increasingly recognized as a key regulator of vasoactive phenomena within the brain, ready to be applied to a wide variety of conditions not heretofore studied directly and non-invasively in human subjects.