Of the molecular biochemical alterations that occur during apoptosis, activation of caspases, notably caspase-3, is probably the most attractive for developing specific in vivo molecular imaging probes. We recently designed a library of isatin-5 sulfonamides and selected [ 18 F]ICMT-11 for further evaluation on the basis of subnanomolar affinity for activated capsase-3, high metabolic stability, and facile radiolabeling. In this present study, we have demonstrated that [ 18 F]ICMT-11 binds to a range of drug-induced apoptotic cancer cells in vitro and to 38C13 murine lymphoma xenografts in vivo by up to 2-fold at 24 h posttreatment compared to vehicle treatment. We further demonstrated that the increased signal intensity in tumors after drug treatment, detected by whole body in vivo microPET imaging, was associated with increased apoptosis. In summary, we have characterized [ 18 F]ICMT-11 as a caspase-3/7 specific PET imaging radiotracer for the assessment of tumor apoptosis that could find utility in anticancer drug development and the monitoring of early responses to therapy.cell death ͉ response to treatment ͉ small animal imaging
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.
We have assessed the potential of [18 F]fluorothymidine positron emission tomography ([ 18 F]FLT-PET) to measure early cytostasis and cytotoxicity induced by cisplatin treatment of radiation-induced fibrosarcoma 1 (RIF-1) tumorbearing mice. Cisplatin-mediated arrest of tumor cell growth and induction of tumor shrinkage at 24 and 48 hours, respectively, were detectable by [18 F]FLT-PET. At 24 and 48 hours, the normalized uptake at 60 minutes (tumor/liver radioactivity ratio at 60 minutes after radiotracer injection; NUV 60 ) for [18 F]FLT was 0.76 F 0.08 (P = 0.03) and 0.51 F 0.08 (P = 0.03), respectively, compared with controls (1.02 F 0.12). The decrease in [18 F]FLT uptake at 24 hours was associated with a decrease in cell proliferation assessed immunohistochemically (a decrease in proliferating cell nuclear antigen labeling index, LI PCNA , from 14.0 F 2.0% to 6.2 F 1.0%; P = 0.001), despite the lack of a change in tumor size. There were G 1 -S and G 2 -M phase arrests after cisplatin treatment, as determined by cell cycle analysis. For the quantitative measurement of tumor cell proliferation, [18 F]FLT-PET was found to be superior to [18 F]fluorodeoxglucose-PET (NUV 60 versus LI PCNA : r = 0.89, P = 0.001 and r = 0.55, P = 0.06, respectively
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