title: Design, synthesis, and biological characterization of a caspase 3/7 selective isatin labeled with 2-[18F]fluoroethylazide.
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.
authors.affiliation: Molecular Therapy Group, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Smith
authors.forename: Matthias
authors.initials: M
authors.lastname: Glaser
authors.forename: Meg
authors.initials: M
authors.lastname: Perumal
authors.forename: Quang-De
authors.initials: QD
authors.lastname: Nguyen
authors.forename: Bo
authors.initials: B
authors.lastname: Shan
authors.forename: Erik
authors.initials: E
authors.lastname: Arstad
authors.forename: Eric O
authors.initials: EO
authors.lastname: Aboagye
mesh_terms: D000818:Animals; D001386:Azides / Q000737:chemistry*; D053148:Caspase 3 / Q000737:chemistry; D061945:Caspase Inhibitors; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005462:Fluorine Radioisotopes / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007510:Isatin / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000175:diagnosis* / Q000473:pathology*; D019275:Radiopharmaceuticals / Q000494:pharmacology*
chemical_list: C522266:2-fluoroethylazide; D001386:Azides; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D007510:Isatin; D053148:Caspase 3