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

Bioconjugate Chemistry
Brian J EngelSteven W Millward

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...Continue Reading

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Citations

Apr 30, 2019·Organic & Biomolecular Chemistry·Filipe ElvasLeonie Wyffels
Jun 11, 2020·Molecular Imaging and Biology : MIB : the Official Publication of the Academy of Molecular Imaging·Seth T GammonSteven W Millward
Aug 13, 2020·Cancers·Segundo Francisco García-ArgüelloGraham Smith
Mar 10, 2020·Bioconjugate Chemistry·Dongjian ZhangJian Zhang
Apr 4, 2021·International Journal of Molecular Sciences·Christophe Van de WieleMaes Alex
May 1, 2021·International Journal of Molecular Sciences·Lucas BeroskeFilipe Elvas
Jun 14, 2020·Current Medicinal Chemistry·Mona MosayebniaSoraya Shahhosseini
Sep 21, 2021·Molecular Imaging and Biology : MIB : the Official Publication of the Academy of Molecular Imaging·Federica Pisaneschi, Nerissa T Viola

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