Comparison of radiolabeled isatin analogs for imaging apoptosis with positron emission tomography.
BACKGROUND
Caspase-3 is one of the executioner caspases activated as a result of apoptosis. Radiolabeled isatins bind to caspase-3 with high affinity and are potential tracers for use with positron emission tomography to image apoptosis. We compared the ability of two novel radiolabeled isatins, [18F]WC-IV-3 and [11C]WC-98, to detect caspase-3 activation in a rat model of cycloheximide-induced liver injury.


METHODS
Male Sprague-Dawley rats were treated with cycloheximide and then imaged with microPET 3 h later with [18F]WC-IV-3 and [11C]WC-98. Biodistribution studies were also performed simultaneously, with caspase-3 activation verified by fluorometric enzyme assay and Western blots.


RESULTS
MicroPET imaging studies demonstrated similar behavior of both tracers but with a lower maximum peak with [11C]WC-98 than with [18F]WC-IV-3. Biodistribution studies demonstrated increased uptake of both tracers in the liver and spleen, but this was statistically significant only in the liver with both compounds. The level of [18F]WC-IV-3 uptake appeared to correlate roughly with rates of caspase-3 activation by the enzyme assay, but the magnitude of difference between treated and control groups was lower than that observed in previously published data with [18F]WC-II-89, another radiolabeled isatin analog. Activation was also confirmed in the liver and spleen but not in fat by Western blot.


CONCLUSIONS
[18F]WC-IV-3 uptake appears to correlate with increased caspase-3 enzyme activity, but the dynamic range of uptake of these two tracers appears to be less than that seen with [18F]WC-II-89. Studies are ongoing to verify these results in other animal models of apoptosis.
Chen
Delphine L
DL
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Zhou
Dong
D
Chu
Wenhua
W
Herrbrich
Phillip E
PE
Jones
Lynne A
LA
Rothfuss
Justin M
JM
Engle
Jacquelyn T
JT
Geraci
Marco
M
Welch
Michael J
MJ
Mach
Robert H
RH
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D003513:Cycloheximide / Q000494:pharmacology; D004789:Enzyme Activation; D007510:Isatin / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D007553:Isotope Labeling; D008099:Liver / Q000000981:diagnostic imaging / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D008297:Male; D049268:Positron-Emission Tomography; D011759:Pyrrolidines / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014018:Tissue Distribution
D061945:Caspase Inhibitors; D011759:Pyrrolidines; D007510:Isatin; D003513:Cycloheximide; D053148:Caspase 3; C032519:pyrrolidine