Design, synthesis, and biological characterization of a caspase 3/7 selective isatin labeled with 2-[18F]fluoroethylazide

J Med Chem. 2008 Dec 25;51(24):8057-67. doi: 10.1021/jm801107u.

Abstract

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 18F-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 18F-labeled tracer in 65 +/- 6% decay-corrected radiochemical yield from 2-[18F]fluoroethylazide. The compound showed high stability in vivo with rapid uptake and elimination in healthy tissues and tumor. The novel 18F-labeled isatin is a candidate radiotracer for further preclinical evaluation for imaging of apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azides / chemistry*
  • Caspase 3 / chemistry
  • Caspase Inhibitors*
  • Chemistry, Pharmaceutical / methods*
  • Drug Design
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology*
  • Fluorine Radioisotopes / chemistry*
  • Fluorine Radioisotopes / pharmacology
  • Humans
  • Isatin / chemical synthesis*
  • Isatin / pharmacology
  • Male
  • Mice
  • Neoplasm Transplantation
  • Neoplasms / diagnosis*
  • Neoplasms / pathology*
  • Radiopharmaceuticals / pharmacology*

Substances

  • 2-fluoroethylazide
  • Azides
  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Fluorine Radioisotopes
  • Radiopharmaceuticals
  • Isatin
  • Caspase 3