First-in-human neuroimaging of soluble epoxide hydrolase using [¹⁸F]FNDP PET

Soluble epoxide hydrolase (sEH) is an enzyme with putative effect on neuroinflammation through its influence on the homeostasis of polyunsaturated fatty acids and related byproducts. sEH is an enzyme that metabolizes anti-inflammatory epoxy fatty acids to the corresponding, relatively inert 1,2-diols. A high availability or activity of sEH promotes vasoconstriction and inflammation in local tissues that may be linked to neuropsychiatric diseases. We developed [¹⁸F]FNDP to study sEH in vivo with positron emission tomography (PET).

Brain PET using bolus injection of [¹⁸F]FNDP followed by emission imaging lasting 90 or 180 min was completed in healthy adults (5 males, 2 females, ages 40-53 years). The kinetic behavior of [¹⁸F]FNDP was evaluated using a radiometabolite-corrected arterial plasma input function with compartmental or graphical modeling approaches.

[¹⁸F]FNDP PET was without adverse effects. Akaike information criterion favored the two-tissue compartment model (2TCM) in all ten regions of interest. Regional total distribution volume (V_T) values from each compartmental model and Logan analysis were generally well identified except for corpus callosum V_T using the 2TCM. Logan analysis was assessed as the choice model due to stability of regional V_T values from 90-min data and due to high correlation of Logan-derived regional V_T values with those from the 2TCM. [¹⁸F]FNDP binding was higher in human cerebellar cortex and thalamus relative to supratentorial cortical regions, which aligns with reported expression patterns of the epoxide hydrolase 2 gene in human brain.

These data support further use of [¹⁸F]FNDP PET to study sEH in human brain.