Caspase-3 Substrates for Noninvasive Pharmacodynamic Imaging of Apoptosis by PET/CT

Brian J. Engel, Seth T. Gammon, Rajan Chaudhari, Zhen Lu, Federica Pisaneschi, Hailing Yang, Argentina Ornelas, Victoria Yan, Lindsay Kelderhouse, Amer M. Najjar, William P. Tong, Shuxing Zhang, David Piwnica-Worms, Robert C. Bast, Steven W. Millward

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Quantitative imaging of apoptosis in vivo could enable real-time monitoring of acute cell death pathologies such as traumatic brain injury, as well as the efficacy and safety of cancer therapy. Here, we describe the development and validation of F-18-labeled caspase-3 substrates for PET/CT imaging of apoptosis. Preliminary studies identified the O-benzylthreonine-containing substrate 2MP-TbD-AFC as a highly caspase 3-selective and cell-permeable fluorescent reporter. This lead compound was converted into the radiotracer [18F]-TBD, which was obtained at 10% decay-corrected yields with molar activities up to 149 GBq/μmol on an automated radiosynthesis platform. [18F]-TBD accumulated in ovarian cancer cells in a caspase- and cisplatin-dependent fashion. PET imaging of a Jo2-induced hepatotoxicity model showed a significant increase in [18F]-TBD signal in the livers of Jo2-treated mice compared to controls, driven through a reduction in hepatobiliary clearance. A chemical control tracer that could not be cleaved by caspase 3 showed no change in liver accumulation after induction of hepatocyte apoptosis. Our data demonstrate that [18F]-TBD provides an immediate pharmacodynamic readout of liver apoptosis in mice by dynamic PET/CT and suggest that [18F]-TBD could be used to interrogate apoptosis in other disease states.

Original languageEnglish (US)
Pages (from-to)3180-3195
Number of pages16
JournalBioconjugate Chemistry
Volume29
Issue number9
DOIs
StatePublished - Sep 19 2018

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

MD Anderson CCSG core facilities

  • Small Animal Imaging Facility

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