In Vivo Imaging of the Tumor-Associated Enzyme NCEH1 with a Covalent PET Probe

• Type of Material: Article
• Authors: Jae Won Chang, Emory University; Mohammed Bhuiyan, University of Chicago; Hsiu-Ming Tsai, University of Chicago; Hannah J Zhang, University of Chicago; Gang Li, University of Chicago; Shaghayegh Fathi, University of Chicago; David C McCutcheon, University of Chicago; Lara Leoni, University of Chicago; Richard Freifelder, University of Chicago; Chin-Tu Chen, University of Chicago; Raymond E Moellering, University of Chicago
• Language: English
• Date: 2020-08-24
• Publisher: WILEY-V C H VERLAG GMBH
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim
• Final Published Version (URL): http://dx.doi.org/10.1002/anie.202004762
• Title of Journal or Parent Work: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• Volume: 59
• Issue: 35
• Start Page: 15161
• End Page: 15165
• Grant/Funding Information: We are grateful for financial support of this work by the Mary Kay Foundation (to R.E.M.); this work was funded in part by the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust (to R.E.M.); NIH 2T32DK007074-45 (supporting D.C.M.) and Shared Instrumentation Grant S10OD025265; and the University of Chicago Cancer Center Support Grant P30CA014599.
• Keywords: positron emission tomography; PROTEOME; Physical Sciences; Chemistry; imaging; radiotracers; activity-based probes; Chemistry, Multidisciplinary; DISCOVERY; NCEH1; Science & Technology; HYDROLASE

Abstract

© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Herein, 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 nanomolar concentrations and greater than 1000-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.