Soluble epoxide hydrolase (sEH) is a cytosolic bi-functional enzyme that hydrolyzes largely beneficial epoxy fatty acids (EpFAs) into their less bioactive form dihydroxy-fatty acids (DHFAs) and is widely expressed in the liver, kidney, and brain. An increased level of sEH have been implicated in many neurological diseases including Alzheimer’s disease (AD). Inhibition of sEH increases the endogenous ratio of EpFAs/DHFAs and is beneficial to neurodegenerative diseases. Therefore, the sEH level could be a biomarker for monitoring disease progression. PET imaging can be used as a non-invasive tool to evaluate the levels of sEH in the brain, which could be a suitable way of performing real-time evaluation of the interaction of drug moeities with receptor targets. Here we report our utilization of the urea scaffold in the synthesis of fluorinated compounds as potential PET radiotracers. The molecules are designed to comply with Lipinski's rule of 5 to ensure it's future clinical application. Nucleophilic aliphatic fluorination will be utilized to strategically induce regiospecific fluorination without altering the physiological properties of the compounds. In this report, we demonstrate the design, synthesis, and subsequent fluorination of the urea compounds for activity testing (determination of IC<sub>50</sub>) which provides the idea of the precursors to synthesize for radiolabeling. iA total of 20 compounds have been synthesized and the activity assay done for 9 of them indicates 4 having IC<sub>50</sub> below 1 nM which is ideal to be radiolabeled for the PET imaging and quantification of sEH.

Design and synthesis of fluorinated 1,3-disubstituted urea as potential radiotracers for PET imaging of soluble epoxide hydrolase

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ACS Fall 2022

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