Radiolabeled isatin binding to caspase-3 activation induced by anti-Fas antibody

Delphine L. Chen, Dong Zhou, Wenhua Chu, Phillip Herrbrich, Jacquelyn T. Engle, Elizabeth Griffin, Lynne A. Jones, Justin M. Rothfuss, Marco Geraci, Richard S. Hotchkiss, Robert H. Mach

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17 Scopus citations


Introduction: Noninvasive imaging methods that can distinguish apoptosis from necrosis may be useful in furthering our understanding of diseases characterized by apoptotic dysregulation as well as aiding drug development targeting apoptotic pathways. We evaluated the ability of radiolabeled isatins to quantify caspase-3 activity induced by the activation of the extrinsic apoptotic pathway by the anti-Fas antibody in mice. Methods: The behavior of three different radiolabeled isatins ([ 18F]WC-II-89, [ 18F]WC-IV-3 and [ 11C]WC-98) was characterized in mice with and without anti-Fas antibody treatment by microPET imaging and biodistribution studies. The activity of [ 18F]WC-II-89 was also compared with [ 99mTc]mebrofenin. The effect of pan-caspase inhibition with quinolyl-valyl-O-methylaspartyl-[2,6-difluorophenoxy]-methyl ketone (Q-VD-OPh) on [ 18F]WC-II-89 uptake was studied. Caspase-3 activity was confirmed by a fluorometric enzyme assay. Results: All three tracers behaved similarly in microPET and biodistribution studies. Increased retention of all tracers was observed in the livers of treated animals and several other organs, all of which demonstrated increased caspase-3 enzyme activity; however, impaired hepatobiliary excretion made attribution of these findings to caspase-3 activity difficult. The isatin [ 18F]WC-II-89 was retained at statistically significantly higher levels in the organs after anti-Fas antibody treatment while [ 99mTc]mebrofenin activity cleared, suggesting specific binding to activated caspase-3, but the magnitude of increased binding was still relatively low. Caspase inhibition with Q-VD-OPh partially blocked [ 18F]WC-II-89 retention but completely blocked caspase-3 enzyme activity in the liver. Conclusions: The radiolabeled isatins appear to bind specifically to caspase-3 in vivo, but their sensitivity is limited. Further optimization is required for these tracers to be useful for clinical applications.

Original languageEnglish
Pages (from-to)137-144
Number of pages8
JournalNuclear Medicine and Biology
Issue number1
StatePublished - Jan 1 2012

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    Chen, D. L., Zhou, D., Chu, W., Herrbrich, P., Engle, J. T., Griffin, E., Jones, L. A., Rothfuss, J. M., Geraci, M., Hotchkiss, R. S., & Mach, R. H. (2012). Radiolabeled isatin binding to caspase-3 activation induced by anti-Fas antibody. Nuclear Medicine and Biology, 39(1), 137-144.