Abstract
PurposeSoluble epoxide hydrolase (sEH) is a promising candidate positron emission tomography (PET) imaging biomarker altered in various disorders, including vascular cognitive impairment (VCI), Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, and depression, known to regulate levels of epoxyeicosatrienoic acids (EETs) and play an important role in neurovascular coupling. [18F]FNDP, a PET radiotracer for imaging sEH, was evaluated through quantitative PET imaging in the baboon brain, radiometabolite analysis, and radiation dosimetry estimate.MethodsBaboon [18F]FNDP dynamic PET studies were performed at baseline and with blocking doses of the selective sEH inhibitor AR-9281 to evaluate sEH binding specificity. Radiometabolites of [18F]FNDP in mice and baboons were measured by high-performance liquid chromatography. Regional brain distribution volume (VT) of [18F]FNDP was computed from PET using radiometabolite-corrected arterial input functions. Full body distribution of [18F]FNDP was studied in CD-1 mice, and the human effective dose was estimated using OLINDA/EXM software.Results[18F]FNDP exhibited high and rapid brain uptake in baboons. AR-9281 blocked [18F]FNDP uptake dose-dependently with a baseline VT of 10.9 ± 2.4 mL/mL and a high-dose blocking VT of 1.0 ± 0.09 mL/mL, indicating substantial binding specificity (91.70 ± 1.74%). The VND was estimated as 0.865 ± 0.066 mL/mL. The estimated occupancy values of AR-9281 were 99.2 ± 1.1% for 1 mg/kg, 88.6 ± 1.3% for 0.1 mg/kg, and 33.8 ± 3.8% for 0.02 mg/kg. Murine biodistribution of [18F]FNDP enabled an effective dose estimate for humans (0.032 mSv/MBq). [18F]FNDP forms hydrophilic radiometabolites in murine and non-human primate plasma. However, only minute amounts of the radiometabolites entered the animal brain (< 2% in mice).Conclusions[18F]FNDP is a highly sEH-specific radiotracer that is suitable for quantitative PET imaging in the baboon brain. [18F]FNDP holds promise for translation to human subjects.
Highlights
Soluble epoxide hydrolase catalyzes the hydrolysis of epoxyeicosatrienoic acids (EETs) to the corresponding diols with reduced biological activity
positron emission tomography (PET) imaging of Soluble epoxide hydrolase (sEH) may enhance our understanding of the pathophysiology of vascular disease that occurs in MCI and Alzheimer’s disease (AD) [16]
Baboon PET studies Plasma and tissue time−activity curves In plasma, the amount of [18F]FNDP gradually decreased after injection while radiometabolites gradually increased (Fig 2a)
Summary
Soluble epoxide hydrolase (sEH) catalyzes the hydrolysis of epoxyeicosatrienoic acids (EETs) to the corresponding diols with reduced biological activity. SEH is important in cerebrovascular pathophysiology in the context of mild cognitive impairment, vascular cognitive impairment (VCI), Alzheimer’s disease (AD), stroke, stress, depression, and other conditions [4, 5]. Post-mortem and animal studies have shown increased levels of expression of cerebral sEH in age-related VCI [4], anorexia [6], depression [5, 7], bipolar disorder [5], schizophrenia [5], Parkinson’s disease [5, 8, 9], and dementia with Lewy bodies [5, 10, 11]. PET imaging of sEH may enhance our understanding of the pathophysiology of vascular disease that occurs in MCI and AD [16]. Combined with existing imaging agents for amyloid and tau, PET imaging of sEH may provide complementary mechanistic information for the noninvasive methods by which to understand the neurobiology of dementia [17, 18]
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