sup 18^F-FNDP for PET Imaging of Soluble Epoxide Hydrolase

• Published in: The Journal of nuclear medicine (1978) Vol. 57; no. 11; p. 1817
• Main Authors: Horti, Andrew G, Wang, Yuchuan, Minn, Il, Lan, Xi, Wang, Jian, Koehler, Raymond C, Alkayed, Nabil J, Dannals, Robert F, Pomper, Martin G
• Format: Journal Article
• Language: English
• Published: New York Society of Nuclear Medicine 01.11.2016
• Subjects: Binding sites; Enzymes; Neuropathology; Nuclear medicine; Radioactivity; Stroke; Tomography
• ISSN: 0161-5505; 1535-5667

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme located within cytosol and peroxisomes that converts epoxides to the corresponding diols and hydrolyzes phosphate monoesters. It serves to inactivate epoxyeicosatrienoic acids (EETs), which are generated in the brain to couple neuronal activity and cerebral blood flow in normal and pathologic states. Altered regulation of sEH was observed previously in various neuropathologic disorders including vascular dementia and stroke. Inhibitors of sEH are pursued as agents to mitigate neuronal damage after stroke. We developed N-(3,3-diphenylpropyl)-6-^sup 18^F-fluoronicotinamide (^sup 18^F-FNDP), which proved highly specific for imaging of sEH in the mouse and nonhuman primate brain with PET. Methods: ^sup 18^F-FNDP was synthesized from the corresponding bromo precursor. sEH inhibitory activity of ^sup 18^F-FNDP was measured using an sEH inhibitor screening assay kit. Biodistribution was undertaken in CD-1 mice. Binding specificity was assayed in CD-1 and sEH knock-out mice and Papio anubis (baboon) through pretreatment with an sEH inhibitor to block sEH binding. Dynamic PET imaging with arterial blood sampling was performed in 3 baboons, with regional tracer binding quantified using distribution volume. The metabolism of ^sup 18^F-FNDP in baboons was assessed using high-performance liquid chromatography. Results: ^sup 18^F-FNDP (inhibition binding affinity constant, 1.73 nM) was prepared in 1 step in a radiochemical yield of 14% ± 7%, specific radioactivity in the range of 888-3,774 GBq/μmol, and a radiochemical purity greater than 99% using an automatic radiosynthesis module. The time of preparation was about 75 min. In CD-1 mice, regional uptake followed the pattern of striatum > cortex > hippocampus > cerebellum, consistent with the known brain distribution of sEH, with 5.2% injected dose per gram of tissue at peak uptake. Blockade of 80%-90% was demonstrated in all brain regions. Minimal radiotracer uptake was present in sEH knock-out mice. PET baboon brain distribution paralleled that seen in mouse, with a marked blockade (95%) noted in all regions indicating sEH-mediated uptake of ^sup 18^F-FNDP. Two hydrophilic metabolites were identified, with 20% parent compound present at 90 min after injection in baboon plasma. Conclusion: ^sup 18^F-FNDP can be synthesized in suitable radiochemical yield and high specific radioactivity and purity. In vivo imaging experiments demonstrated that ^sup 18^F-FNDP targeted sEH in murine and nonhuman primate brain specifically. ^sup 18^F-FNDP is a promising PET radiotracer likely to be useful for understanding the role of sEH in a variety of conditions affecting the central nervous system.