TY - JOUR
T1 - Caspase-3 Substrates for Noninvasive Pharmacodynamic Imaging of Apoptosis by PET/CT
AU - Engel, Brian J.
AU - Gammon, Seth T.
AU - Chaudhari, Rajan
AU - Lu, Zhen
AU - Pisaneschi, Federica
AU - Yang, Hailing
AU - Ornelas, Argentina
AU - Yan, Victoria
AU - Kelderhouse, Lindsay
AU - Najjar, Amer M.
AU - Tong, William P.
AU - Zhang, Shuxing
AU - Piwnica-Worms, David
AU - Bast, Robert C.
AU - Millward, Steven W.
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/9/19
Y1 - 2018/9/19
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.bioconjchem.8b00514
DO - 10.1021/acs.bioconjchem.8b00514
M3 - Article
C2 - 30168713
AN - SCOPUS:85053001654
SN - 1043-1802
VL - 29
SP - 3180
EP - 3195
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
IS - 9
ER -