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¹³¹I-Labeled Peptides as Caspase Substrates for Apoptosis Imaging

¹ Department of Radiopharmaceutical Chemistry, German Cancer Research Center, Heidelberg, Germany
² Department of Nuclear Medicine, University of Heidelberg, Heidelberg, Germany

Nonivasive assessment of programmed cell death is currently an attractive research topic for the follow-up of tumor therapy and myocardial infarction. Apoptosis imaging with ^99mTc-HYNIC-annexin V (HYNIC is hydrazinonicotinamide) is based on the binding of the tracer to externalized phosphatidylserine residues. Concurrently with the externalization of phosphatidylserine, a series of caspases are activated after the onset of apoptosis. These enzymes were chosen as an alternative target for apoptosis imaging. Methods: Ten radiolabeled peptides containing the DEVDG sequence, selective for downstream caspases such as caspase-3, were synthesized and evaluated for their uptake kinetics using an apoptosis test system. The molecular requirement of the peptides for being accepted as caspase substrate was studied using a competitive enzyme assay and matrix-assisted laser desorption/ionization mass spectrometry. Results: Within this series of peptides, radioiodinated Tat_49–57-yDEVDG-NH₂ (7) and Tat_57–49-yDEVDG-NH₂ (8) were favorably taken up by apoptotic cells (12.54% ± 1.18% and 12.63% ± 1.17% after 10-min incubation, respectively) as compared with the controls (7.50% ± 0.92% and 8.04% ± 0.28%). The enhanced uptake is interpreted as the interaction of the labeled peptide or fragment with activated caspases. Proof of caspase substrate specificity of peptide 7 and YDEVDG-NH₂ (2) was substantiated. The former peptide was shown to have a stronger competition with the fluorescent Z-DEVD-R110 for caspase-3 than peptide 2. In addition, mass spectrometry revealed only fragmentation for peptide 7. Conclusion: It could be demonstrated that peptides consisting of DEVDG and Tat sequence are caspase substrates with enhanced uptake and retention in apoptotic cells. Current efforts are focused on alternative radioisotopes that include radiometal complexes to further improve these characteristics.

Key Words: apoptosis • caspase substrates • Jurkat cells • Tat • radioiodine

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