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The Synthesis and Radiolabeling of 2-Nitroimidazole Derivatives of Cyclam and Their Preclinical Evaluation as Positive Markers of Tumor Hypoxia

¹ Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
² The Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania

The cyclam ligand (1,4,8,11-tetraazacyclotetradecane) was condensed with various azomycin-containing synthons to produce chemical compounds that could chelate radioactive metals. It was expected that these radiolabeled markers would become bound selectively to hypoxic cells on the bioreduction of their azomycin substituent. Methods: The markers were radiolabeled with ^99mTc, ⁶⁷Cu, or ⁶⁴Cu. Their uptake and binding to tumor cells in vitro was characterized as a function of time and oxygen concentration. These data defined the hypoxia-specific factor, the ratio of the initial rate of marker binding to severely hypoxic relative to aerobic cells. In addition, the concentration of oxygen (in the equilibrium gas phase) that inhibited binding to 50% of the maximum rate was determined. The in vivo biodistribution and clearance kinetics of the favorable markers were investigated with severe combined immune deficiency mice bearing EMT-6 tumors whose radiobiologic hypoxic fraction (RHF) was 40%. The specific activity (percentage injected dose per gram [%ID/g]) in normal and tumor tissue and the tumor-to-blood and tumor-to-muscle ratios of the optimal markers were also measured for Dunning prostate carcinomas of anaplastic (RHF = 15%–20%) and well-differentiated (RHF < 1%) histology growing in Fischer X Copenhagen rats. Planar images were acquired with some markers from these tumor-bearing rats. Results: The tumor uptake of these cyclam-based markers is approximately 10 times higher when they are labeled with copper isotopes than when labeled with ^99mTc. FC-327 and FC-334, di-azomycin-substituted cyclams, exhibited hypoxia-specific factors 7.0. The oxygen concentration that inhibited their binding to 50% of the maximal rate was 0.5% O₂, similar to that of the radiobiologic oxygen effect. The %ID/g of ⁶⁴Cu-FC-334 retained in EMT-6 tumors in mice and in the anaplastic and well-differentiated prostate tumors in rats 6 h after administration was 6.5, 0.4, and 0.1, respectively. Marker activity in tumor was always less than that in liver and kidney. The tumor-to-blood and tumor-to-muscle ratios of ⁶⁴Cu-FC-327 and ⁶⁴Cu-FC-334 activity in R3327-AT tumor-bearing rats are higher than those observed for ⁶⁴Cu-di-acetyl-bis (N⁴-methylthiosemicarbazone) and approach those of ß-D-¹²⁵I-iodinated azomycin galactopyranoside, the optimal hypoxia marker of the azomycin-nucleoside class. Conclusion: These data suggest that some azomycin-cyclams exhibit good hypoxia-marking potential to tumor cells in vitro and to animal tumors of known RHF. Both PET and SPECT could be used to image tumor hypoxia with markers labeled with ⁶⁴Cu and ⁶⁷Cu, respectively.

Key Words: bioreducible marker • cyclam • 2-nitroimidazole • hypoxia • radioresistance