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

64Cu-azabicyclo[3.2.2]nonane thiosemicarbazone complexes: radiopharmaceuticals for PET of topoisomerase II expression in tumors. Research Abstract Details 

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64Cu-azabicyclo[3.2.2]nonane thiosemicarbazone complexes: radiopharmaceuticals for PET of topoisomerase II expression in tumors. Abstract Text:

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

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 (64)Cu-TSC complexes and the expression of Topo-II activity. METHODS: Four (4)N-azabicyclo[3.2.2]nonane TSC derivatives (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 [(64)Cu-EPH270](+) was observed in vitro in cultured cell studies. The kinetics of 2 compounds, [(64)Cu-EPH144](+) and [(64)Cu-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 (64)CuCl(2) 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](+) 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 [(64)Cu-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 (64)Cu-compounds is related to the expression levels of Topo-II in tumor tissue.

64Cu-azabicyclo[3.2.2]nonane thiosemicarbazone complexes: radiopharmaceuticals for PET of topoisomerase II expression in tumors. Publishing Authors By Initials

L Wei,J Easmon,RK Nagi,BD Muegge,LA Meyer,JS Lewis,

For similar biochemical phenomena, metabolism, and nutrition: metabolism: pharmacokinetics: tissue distribution research abstracts see: biochemical phenomena, metabolism, and nutrition: metabolism: pharmacokinetics: tissue distribution research

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64Cu-azabicyclo[3.2.2]nonane thiosemicarbazone complexes: radiopharmaceuticals for PET of topoisomerase II expression in tumors. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Journal of nuclear medicine : official publication

VOLUME: 47

Page Numbers: 2034-41

Journal Abbreviation: J. Nucl. Med.

ISSN: 0161-5505

DAY: 3

MONTH: Dec

YEAR: 2006

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

Number of References:

LANGUAGE: eng

NlmUniqueID: 217410

64Cu-azabicyclo[3.2.2]nonane thiosemicarbazone complexes: radiopharmaceuticals for PET of topoisomerase II expression in tumors. Keywords Mesh Terms:

KEYWORDS: Tissue Distribution

MESH TERMS: pharmacokinetics

Chemical & Substance for Abstract: 64Cu-azabicyclo[3.2.2]nonane thiosemicarbazone complexes: radiopharmaceuticals for PET of topoisomerase II expression in tumors. Information

Substance Name: DNA Topoisomerases, Type II

Registry Number: EC 5.99.1.3

Grant and Affiliation Information for 64Cu-azabicyclo[3.2.2]nonane thiosemicarbazone complexes: radiopharmaceuticals for PET of topoisomerase II expression in tumors.

AFFILIATION: Division of Radiological Sciences, Mallinckrodt Institute of Radiology, and Alvin J Siteman Cancer Center, Washington University School of Medicine, St Louis, MO 63110, USA.

Country: United States

AGENCY: United States NCI

GRANT: R24 CA086307

ACRONYM: CA

MEDLINETA: J Nucl Med

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