In vivo imaging of the tumor‐associated enzyme NCEH1 with a covalent PET probe

Chang, J., Bhuiyan, M., Tsai, H., Zhang, H., Li, G., Fathi, S., McCutcheon, D., Leoni, L., Freifelder, R., Chen, C. and Moellering, R.
Angew. Chem. Int. Ed. 2020
doi:10.1002/anie.202004762

Here we report the development of an 18F‐labeled, activity‐based small molecule probe targeting the cancer‐associated serine hydrolase NCEH1. We undertook a focused medicinal chemistry campaign to simultaneously preserve potent and specific NCEH1 labeling in live cells and animals, while permitting facile 18F radionuclide incorporation required for PET imaging. The resulting molecule, [18F]JW199, labels active NCEH1 in live cells at nM concentrations and greater than 1,000‐fold selectivity relative to other serine hydrolases. [18F]JW199 displays rapid, NCEH1‐dependent accumulation in mouse tissues. Finally, we demonstrate that [18F]JW199 labels aggressive cancer tumor cells in vivo, which uncovered localized NCEH1 activity at the leading edge of triple‐negative breast cancer tumors, suggesting roles for NCEH1 in tumor aggressiveness and metastasis. More generally, these data support the broader development of potent and specific covalent PET probes to visualize localized, active enzymes in live animals.