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⁶⁴Cu-Azabicyclo[3.2.2]Nonane Thiosemicarbazone Complexes: Radiopharmaceuticals for PET of Topoisomerase II Expression in Tumors

¹ Division of Radiological Sciences, Mallinckrodt Institute of Radiology, and Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri; and ² Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria

Correspondence: For correspondence or reprints contact: Jason S. Lewis, PhD, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd., Campus Box 8225, St. Louis, MO 63110. E-mail: j.s.lewis{at}wustl.edu

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.

Key Words: small-animal PET • ⁶⁴Cu • topoisomerase-II • thiosemicarbazones

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