Design, Synthesis, and Biological Characterization of a Caspase 3/7 Selective Isatin Labeled with 2-[18F]fluoroethylazide

Imaging of programmed cell death (apoptosis) is important in the assessment of therapeutic response in oncology and for diagnosis in cardiac and neurodegenerative disorders. The executioner caspases 3 and 7 ultimately effect cellular death, thus providing selective molecular targets for in vivo quantification of apoptosis. To realize this potential, we aimed to develop F-18-labeled isatin sulfonamides with high metabolic,stability and moderate lipophilicity while retaining selectivity and affinity for caspase 3/7. A small library of isatins modified with fluorinated aromatic groups and heterocycles was synthesized. A lead compound incorporating 2'-fluoroethyl-1,2,3-triazole was identified with subnanomolar affinity for caspase 3. Click labeling provided the F-18-labeled tracer in 65 +/- 6% decay-corrected radiochemical yield from 2-[F-18]fluoroethylazide. The compound showed high stability in vivo with rapid uptake and elimination in healthy tissues and tumor. The novel F-18-labeled isatin is a candidate radiotracer for further preclinical evaluation for imaging of apoptosis.