Synthesis and Biological Evaluation of a New Nitroimidazole-(99m)Tc-Complex for Imaging of Hypoxia in Mice Model

BACKGROUND: This study was specifically designed to develop a new (99m)Tc compound with 3-amino-4-[2-(2-methyl-5-nitro-1H-imidazol)-ethylamino]-4-oxo-butyrate (5-ntm-asp) and to verify whether this compound is feasible to be a radiopharmaceutical for hypoxic tumors. MATERIAL/METHODS: Metronidazole derivative 5-ntm-asp was synthesized and then radio-labeled by Na [(99m)TcO(4)], forming (99m)Tc-5-ntm-asp. Another two complexes of (99m)Tc-2- and (99m)Tc-5-nitroimidazole-iminodiacetic acid ((99m)Tc-2-ntm-IDA and (99m)Tc-5-ntm-IDA) were also synthesized based on previous studies. Physicochemical properties (stability, lipophilicity, protein binding) of the compounds were compared, and we also assessed the accumulation status of the compounds within A549 cells under both hypoxic and aerobic conditions. Distribution of the complex was also studied in vivo using BALB/c nude mice that were injected with A549 cells. RESULTS: Compared with (99m)Tc-2-ntm-IDA and (99m)Tc-5-ntm-IDA, (99m)Tc-5-ntm-asp was more stable in both phosphate-buffered saline (PBS) buffer and human plasma (P<0.05). Besides that, (99m)Tc-5-ntm-asp offered lower lipophilicity and protein-binding rate than the two complexes (P<0.05). During assessment of hypoxic uptake status and high hypoxic/aerobic ratio in mice injected with A549 cells, (99m)Tc-5-ntm-asp exhibited a more favorable profile than (9m)Tc-2-ntm-IDA and (99m)Tc-5-ntm-IDA, including uptake ratio of tumor/blood and uptake ratio of tumor/muscle. CONCLUSIONS: With overall consideration of physicochemical properties and biological uptake behavior, it is feasible to use (99m)Tc-5-ntm-asp as an imaging agent for tumor hypoxia.