SYNTHESIS AND EVALUATION OF TWO TECHNETIUM-99M-LABELED PEPTIDIC 2-NITROIMIDAZOLES FOR IMAGING HYPOXIA

摘要

The presence of hypoxic cells in solid tumors is a marker for therapy resistant, aggressive disease. The non-invasive detection of hypoxic cells in tumors by radiolabeled 2-nitroimidazoles is a diagnostic technique under current evaluation. Two peptidic chelating agents, dimethylglycyl-L-seryl-L-cysteinyl-lysyl{N E-¢1-(2-nitro-1H-imidazolyl)acetamido!}-glycine (RP435) and dimethylglycyl-tert-butylglycyl-L-cysteinylglycine-¢2-(2-nitro-1H-imidazolyl)ethyl!amide (RP535) have been synthesized. Both chelating agents contain an N3S class chelator for 99m Tc and Re, and a 2-nitroimidazole group which can be enzymatically reduced and trapped in cells under hypoxic conditions. Two isomers of 99m TcO-RP435, which are assumed to be syn and anti conformations, have been observed on HPLC analysis. The interconversion of the two isomers in aqueous solution was investigated. In contrast, RP535 chelates 99m Tc to form a single isomer and no conversion to its counterpart has been observed on HPLC analysis. The tert-butyl group on the chelator may inhibit the formation and interconversion of the syn and anti isomers of 99m TcO-RP535. Both tracers showed a significant degree of hypoxia-specific accumulation in an in vitro assay, with 99m TcO-RP535 showing higher selectivity for hypoxic cells than 99m TcO-RP435. These results suggest that 99m TcO-RP535 represents a lead compound worthy of further investigation as an agent for imaging hypoxia in tumors.