Synthesis and bioevaluation of the cyclopentadienyl tricarbonyl technetium-99m 2-nitroimidazole derivatives for tumor hypoxia imaging

Hypoxia imaging agents can play an important role in the tumor treatment by avoiding the worse effect of radiotherapy and chemotherapy due to the tumor hypoxia. Due to the small size and easy coordination, tricarbonyl technetium-99m can be used to label a wide range of imaging agents. In this work, the tricarbonyl Tc-99m labeled small-sized hypoxia imaging agents containing 2-nitroimidazoles were prepared, which have different carbon chain lengths between cyclopentadienyl and 2-nitroimidazole, and which have one or two 2-nitroimidazole groups. The results of S180 cell experiment and biodistribution indicated that these molecules have different hypoxic selectivity. When contains one 2-nitroimidazole, as the carbon chain lengthens, which means the molecular volume becomes larger, hypoxia cellular uptake and selectivity decrease in S180 cell uptake experiment. In biodistribution study in mice bearing S180 tumor, Tc-2 (1-cyclopentadienyl-5-(2-nitro-1H-imidazol-1-yl)-pentan-1-one tricarbonyl Tc-99m complex), which has intermediate carbon chain, is better due to the more complex factors. Its tumor/blood (T/B) ratio is 3.56 & PLUSMN; 0.25, tumor/muscle(T/M) ratio is 1.73 & PLUSMN; 0.29 and tumor uptake is 2.23 & PLUSMN; 0.24%ID/g at 2 h. Comparing to other tricarbonyl technetium complexes containing one 2-nitroimidazole, the complexes in this work have an advantage in tumor/blood ratio and tumor uptake. This suggests that the small-volume cyclopentadienyl may have an advantage when used as a ligand. When contains two 2nitroimidazole groups, the complex, 1-cyclopentadienyl-5-di(2-(2-nitro-1H-imidazol-1-yl)ethyl)amino-pentan1-one tricarbonyl Tc-99m complex (Tc-4), has the better results in the cell experiment than those which contain one 2-nitroimidazole group. Thus the hypoxia imaging agent contains two 2-nitroimidazole groups is more advantageous, but further modifications of Tc-4 are needed to improve its clearance rate in the blood, because the increased lipophilicity leads to a decrease in the T/B ratio of Tc-4. In conclusion, small volume hypoxia imaging agents with two 2-nitroimidazole groups may be the trend of development.

Automated summary

Hypoxia imaging agents labeled with tricarbonyl technetium-99m were prepared and evaluated for their hypoxic selectivity. The results showed that the agents with different carbon chain lengths and 2-nitroimidazole groups exhibited varying hypoxic selectivity. Compounds with one 2-nitroimidazole group showed decreased hypoxic selectivity as the carbon chain lengthened. However, compounds with two 2-nitroimidazole groups demonstrated better hypoxic selectivity in cell experiments. Further modifications are needed to improve the clearance rate in the blood for these agents.