64Cu-azabicyclo[3.2.2]nonane thiosemicarbazone complexes: Radiopharmaceuticals for PET of topoisomerase II expression in tumors

Lihui Wei, Johnny Easmon, Ravneet K. Nagi, Brian D. Muegge, Laura A. Meyer, Jason S. Lewis

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29 Scopus citations


Topoisomerase II (Topo-II) is an essential enzyme in the DNA replication process and is the primary cellular target for many of the most widely used and effective anticancer agents. It has been reported that thiosemicarbazones (TSCs) are potent antitumor agents that inhibit Topo-II. The aim of this study was to investigate the relationship between the in vitro and in vivo behavior of novel 64Cu-TSC complexes and the expression of Topo-II activity. Methods: Four 4N-azabicyclo[3.2.2]nonane TSC derivatives (EPH142, EPH143, EPH144, and EPH270) were successfully radiolabeled with 64Cu, to form lipophilic cations of the general formula [64Cu(L)]Cl, and the partition coefficient (logP) values were determined. One agent [ 64Cu-EPH270]+ was observed in vitro in cultured cell studies. The kinetics of 2 compounds, [64Cu-EPH144]+ and [64Cu-EPH270]+, were examined in mice bearing L1210 tumors and small-animal PET was conducted in mice bearing L1210 and PC-3 tumors, which expressed high and low levels of Topo-II, respectively. All data were compared with the activity and levels of Topo-II, as determined by a commercially available assay kit and western blot analysis. Results: The 4 complexes were radiolabeled by incubation of 64CuCl2 with the ligand in ethanolic solution. The complexes were isolated in high radiochemical purity, as determined by radio-thin-layer chromatography and radio-high-performance liquid chromatography. The compounds were shown to be lipophilic with logP values ranging from 1.34 to 1.92. In biodistribution studies, good L1210 tumor uptake was noted ([64Cu-EPH144]+ at 1 h, 4.70 %ID/g [percentage injected dose per gram]; 4 h, 8.80 %ID/g; 24 h, 6.64 %ID/g; and [ 64Cu-EPH270]+ at 1 h, 2.58 %ID/g; 4 h, 6.00 %ID/g; 24 h, 4.80 %ID/g). Small-animal PET of animals with L1210 tumors (high Topo-II expressing) showed excellent tumor accumulation compared with that of animals with PC-3 tumors (low Topo-II expressing), and the L1210 tumor uptake was significantly reduced by coadministration of a Topo-II poison. Conclusion: Here we describe the characterization of a new class of copper-radiolabeled TSC analogs. We demonstrate that the accumulation of the 64Cu-compounds is related to the expression levels of Topo-II in tumor tissue.

Original languageEnglish
Pages (from-to)2034-2041
Number of pages8
JournalJournal of Nuclear Medicine
Issue number12
StatePublished - Dec 1 2006


  • Cu
  • Small-animal PET
  • Thiosemicarbazones
  • Topoisomerase-II


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