Caspase-3 Substrates for Noninvasive Pharmacodynamic Imaging of Apoptosis by PET/CT
| Autor: | Steven W. Millward, Lindsay E. Kelderhouse, Shuxing Zhang, Rajan Chaudhari, Brian J. Engel, Seth T. Gammon, Hailing Yang, David Piwnica-Worms, Zhen Lu, Argentina Ornelas, Federica Pisaneschi, Victoria C. Yan, Robert C. Bast, William P. Tong, Amer Najjar |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Programmed cell death Traumatic brain injury Biomedical Engineering Mice Nude Pharmaceutical Science Apoptosis Bioengineering Caspase 3 Article Substrate Specificity Mice 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor Positron Emission Tomography Computed Tomography medicine Animals Caspase Pharmacology PET-CT biology Chemistry Organic Chemistry medicine.disease 030104 developmental biology Cell culture 030220 oncology & carcinogenesis Cancer research biology.protein Female Biotechnology |
| Zdroj: | Bioconjugate Chemistry. 29:3180-3195 |
| ISSN: | 1520-4812 1043-1802 |
| DOI: | 10.1021/acs.bioconjchem.8b00514 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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