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 journalArticle

3 Citations (Scopus)

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 [ 18 F]-TBD, which was obtained at 10% decay-corrected yields with molar activities up to 149 GBq/μmol on an automated radiosynthesis platform. [ 18 F]-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 [ 18 F]-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 [ 18 F]-TBD provides an immediate pharmacodynamic readout of liver apoptosis in mice by dynamic PET/CT and suggest that [ 18 F]-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

Fingerprint

Pharmacodynamics
Cell death
Caspase 3
Apoptosis
Imaging techniques
Liver
Substrates
Lead compounds
Pathology
Caspases
Ovarian Neoplasms
Cisplatin
Hepatocytes
Brain
Cell Death
Cells
Safety
Monitoring
Neoplasms

ASJC Scopus subject areas

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

Cite this

Caspase-3 Substrates for Noninvasive Pharmacodynamic Imaging of Apoptosis by PET/CT. / Engel, Brian J.; Gammon, Seth T.; Chaudhari, Rajan; Lu, Zhen; Pisaneschi, Federica; Yang, Hailing; Ornelas, Argentina; Yan, Victoria; Kelderhouse, Lindsay; Najjar, Amer M.; Tong, William P.; Zhang, Shuxing; Piwnica-Worms, David; Bast, Robert C.; Millward, Steven W.

In: Bioconjugate Chemistry, Vol. 29, No. 9, 19.09.2018, p. 3180-3195.

Research output: Contribution to journalArticle

Engel, Brian J. ; Gammon, Seth T. ; Chaudhari, Rajan ; Lu, Zhen ; Pisaneschi, Federica ; Yang, Hailing ; Ornelas, Argentina ; Yan, Victoria ; Kelderhouse, Lindsay ; Najjar, Amer M. ; Tong, William P. ; Zhang, Shuxing ; Piwnica-Worms, David ; Bast, Robert C. ; Millward, Steven W. / Caspase-3 Substrates for Noninvasive Pharmacodynamic Imaging of Apoptosis by PET/CT. In: Bioconjugate Chemistry. 2018 ; Vol. 29, No. 9. pp. 3180-3195.
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