Complexes: Radiopharmaceuticals for PET of Topoisomerase II Expression in Tumors

TopoisomeraseII(Topo-II)isanessentialenzymeintheDNAreplication 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 64 Cu-TSC complexes and the expression of Topo-II activity.Methods:Four 4 N-azabicyclo[3.2.2]nonane TSCderivatives (EPH142, EPH143, EPH144, and EPH270) were successfully radiolabeled with 64 Cu, to form lipophilic cations of the general formula [ 64 Cu(L)]Cl, and the partition coefficient (logP) values were determined. One agent [64Cu-EPH270]1 was observed in vitro in cultured cell studies. The kinetics of 2 compounds, [64Cu-EPH144]1 and [64Cu-EPH270]1, 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 64 CuCl2 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 ([ 64 Cu-EPH144] 1