title: Synthesis, radiolabeling, and in vivo evaluation of an 18F-labeled isatin analog for imaging caspase-3 activation in apoptosis.
abstract: A non-peptide-based isatin sulfonamide analog, WC-II-89, was synthesized and its inhibition toward recombinant human caspase-3 and other caspases was determined. This compound showed high potency for inhibiting caspase-3 and -7, and high selectivity against caspases-1, -6, and -8. [(18)F]WC-II-89 was synthesized via a nucleophilic substitution of the corresponding mesylate precursor in high yield and radiochemical purity. Biodistribution studies using [(18)F]WC-II-89 revealed higher uptake in liver and spleen of cycloheximide-treated rats, an animal model of apoptosis, relative to control animals. Western blot analysis confirmed the presence of activated caspase-3 in the liver and spleen of cycloheximide-treated animals. MicroPET imaging studies revealed a high uptake of the radiotracer in the liver of a cycloheximide-treated rat relative to the untreated control. These data suggest that [(18)F]WC-II-89 is a potential radiotracer for imaging caspase-3 activation in tissues undergoing apoptosis.
authors.affiliation: Division of Radiological Sciences, Washington University School of Medicine, 510 South Kingshighway Boulevard, St. Louis, MO 63110, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhou
authors.forename: Wenhua
authors.initials: W
authors.lastname: Chu
authors.forename: Justin
authors.initials: J
authors.lastname: Rothfuss
authors.forename: Chenbo
authors.initials: C
authors.lastname: Zeng
authors.forename: Jinbin
authors.initials: J
authors.lastname: Xu
authors.forename: Lynne
authors.initials: L
authors.lastname: Jones
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welch
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D053179:Caspase 7; D061945:Caspase Inhibitors; D020169:Caspases / Q000032:analysis / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D007510:Isatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D049268:Positron-Emission Tomography; D011877:Radionuclide Imaging / Q000379:methods; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D011994:Recombinant Proteins; D013154:Spleen / Q000378:metabolism; D013449:Sulfonamides; D014018:Tissue Distribution
chemical_list: D061945:Caspase Inhibitors; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D011994:Recombinant Proteins; D013449:Sulfonamides; D007510:Isatin; C505407:CASP3 protein, human; C505520:CASP7 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases