18F-FNDP for PET Imaging of Soluble Epoxide Hydrolase

Andrew G. Horti, Yuchuan Wang, Il Minn, Xi Lan, Jian Wang, Raymond C. Koehler, Nabil Alkayed, Robert F. Dannals, Martin G. Pomper

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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 tomitigate neuronal damage after stroke. We developed N-(3,3-diphenylpropyl)- 6-18F-fluoronicotinamide (18F-FNDP), which proved highly specific for imaging of sEH in the mouse and nonhuman primate brain with PET. Methods: 18F-FNDP was synthesized from the corresponding bromo precursor. sEH inhibitory activity of 18F-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 18F-FNDP in baboons was assessed using high-performance liquid chromatography. Results: 18F-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 18F-FNDP. Two hydrophilic metabolites were identified, with 20% parent compound present at 90 min after injection in baboon plasma. Conclusion: 18F-FNDP can be synthesized in suitable radiochemical yield and high specific radioactivity and purity. In vivo imaging experiments demonstrated that 18F-FNDP targeted sEH in murine and nonhuman primate brain specifically. 18F-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.

Original languageEnglish (US)
Pages (from-to)1817-1822
Number of pages6
JournalJournal of Nuclear Medicine
Volume57
Issue number11
DOIs
StatePublished - Nov 1 2016

Fingerprint

Epoxide Hydrolases
Papio
Brain
Knockout Mice
Radioactivity
Primates
Cerebrovascular Circulation
Papio anubis
Stroke
Vascular Dementia
Peroxisomes
Epoxy Compounds
Cytosol
Cerebellum

Keywords

  • Baboon
  • Epoxyeicosatrienoic acid
  • Molecular neuroimaging
  • Positron emission tomography
  • Soluble epoxide hydrolase
  • Stroke
  • Vascular cognitive impairment

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

Horti, A. G., Wang, Y., Minn, I., Lan, X., Wang, J., Koehler, R. C., ... Pomper, M. G. (2016). 18F-FNDP for PET Imaging of Soluble Epoxide Hydrolase. Journal of Nuclear Medicine, 57(11), 1817-1822. https://doi.org/10.2967/jnumed.116.173245

18F-FNDP for PET Imaging of Soluble Epoxide Hydrolase. / Horti, Andrew G.; Wang, Yuchuan; Minn, Il; Lan, Xi; Wang, Jian; Koehler, Raymond C.; Alkayed, Nabil; Dannals, Robert F.; Pomper, Martin G.

In: Journal of Nuclear Medicine, Vol. 57, No. 11, 01.11.2016, p. 1817-1822.

Research output: Contribution to journalArticle

Horti, AG, Wang, Y, Minn, I, Lan, X, Wang, J, Koehler, RC, Alkayed, N, Dannals, RF & Pomper, MG 2016, '18F-FNDP for PET Imaging of Soluble Epoxide Hydrolase', Journal of Nuclear Medicine, vol. 57, no. 11, pp. 1817-1822. https://doi.org/10.2967/jnumed.116.173245
Horti AG, Wang Y, Minn I, Lan X, Wang J, Koehler RC et al. 18F-FNDP for PET Imaging of Soluble Epoxide Hydrolase. Journal of Nuclear Medicine. 2016 Nov 1;57(11):1817-1822. https://doi.org/10.2967/jnumed.116.173245
Horti, Andrew G. ; Wang, Yuchuan ; Minn, Il ; Lan, Xi ; Wang, Jian ; Koehler, Raymond C. ; Alkayed, Nabil ; Dannals, Robert F. ; Pomper, Martin G. / 18F-FNDP for PET Imaging of Soluble Epoxide Hydrolase. In: Journal of Nuclear Medicine. 2016 ; Vol. 57, No. 11. pp. 1817-1822.
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abstract = "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 tomitigate neuronal damage after stroke. We developed N-(3,3-diphenylpropyl)- 6-18F-fluoronicotinamide (18F-FNDP), which proved highly specific for imaging of sEH in the mouse and nonhuman primate brain with PET. Methods: 18F-FNDP was synthesized from the corresponding bromo precursor. sEH inhibitory activity of 18F-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 18F-FNDP in baboons was assessed using high-performance liquid chromatography. Results: 18F-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 18F-FNDP. Two hydrophilic metabolites were identified, with 20{\%} parent compound present at 90 min after injection in baboon plasma. Conclusion: 18F-FNDP can be synthesized in suitable radiochemical yield and high specific radioactivity and purity. In vivo imaging experiments demonstrated that 18F-FNDP targeted sEH in murine and nonhuman primate brain specifically. 18F-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.",
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AU - Horti, Andrew G.

AU - Wang, Yuchuan

AU - Minn, Il

AU - Lan, Xi

AU - Wang, Jian

AU - Koehler, Raymond C.

AU - Alkayed, Nabil

AU - Dannals, Robert F.

AU - Pomper, Martin G.

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N2 - 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 tomitigate neuronal damage after stroke. We developed N-(3,3-diphenylpropyl)- 6-18F-fluoronicotinamide (18F-FNDP), which proved highly specific for imaging of sEH in the mouse and nonhuman primate brain with PET. Methods: 18F-FNDP was synthesized from the corresponding bromo precursor. sEH inhibitory activity of 18F-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 18F-FNDP in baboons was assessed using high-performance liquid chromatography. Results: 18F-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 18F-FNDP. Two hydrophilic metabolites were identified, with 20% parent compound present at 90 min after injection in baboon plasma. Conclusion: 18F-FNDP can be synthesized in suitable radiochemical yield and high specific radioactivity and purity. In vivo imaging experiments demonstrated that 18F-FNDP targeted sEH in murine and nonhuman primate brain specifically. 18F-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.

AB - 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 tomitigate neuronal damage after stroke. We developed N-(3,3-diphenylpropyl)- 6-18F-fluoronicotinamide (18F-FNDP), which proved highly specific for imaging of sEH in the mouse and nonhuman primate brain with PET. Methods: 18F-FNDP was synthesized from the corresponding bromo precursor. sEH inhibitory activity of 18F-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 18F-FNDP in baboons was assessed using high-performance liquid chromatography. Results: 18F-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 18F-FNDP. Two hydrophilic metabolites were identified, with 20% parent compound present at 90 min after injection in baboon plasma. Conclusion: 18F-FNDP can be synthesized in suitable radiochemical yield and high specific radioactivity and purity. In vivo imaging experiments demonstrated that 18F-FNDP targeted sEH in murine and nonhuman primate brain specifically. 18F-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.

KW - Baboon

KW - Epoxyeicosatrienoic acid

KW - Molecular neuroimaging

KW - Positron emission tomography

KW - Soluble epoxide hydrolase

KW - Stroke

KW - Vascular cognitive impairment

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