BRU59-21, a second-generation 99mTc-labeled 2-nitroimidazole for imaging hypoxia in tumors

Hypoxia in tumors is believed to be an important cause of local failure of radiotherapy in certain types of cancer. BRU59-21 (BMS194796) is a second-generation Tc-99m-labeled 2-nitroimidazole that has been shown to offer improved characteristics for imaging myocardial ischemia. It has now been evaluated in models of tumor hypoxia. Methods: Accumulation of BRU59-21 was compared with that of BMS181321 in Chinese hamster ovary cells incubated under aerobic or hypoxic conditions. The effects of competition with unlabeled nitroimidazoles and oxygen were studied. Biodistribution studies were performed in mice bearing transplanted KHT-C tumors in the leg. Results: Within 5 min, BRU59-21 partitioned into aerobic cells in vitro at a level 10 times higher than external medium with no further increase over time. In hypoxic cells this initial partitioning was followed by selective accumulation to levels 5 times higher than in aerobic cells by 4 h. Low levels of oxygen (similar to 40 ppm) inhibited the maximal accumulation rate by 50%. Unlabeled misonidazole, a e-nitroimidazole, inhibited accumulation of radioactivity, whereas tinidazole, a 5-nitroimidazole, enhanced accumulation; similar effects had been reported with BMS181321. Biodistribution studies in mice showed rapid clearance of radioactivity from the blood, resulting in enhanced tumor-to-blood ratios compared with BMS181321. Increasing the hypoxic fraction in the tumor by injection of nitro-L-arginine resulted in increased retention of tracer in the tumor without affecting other tissues. Conclusion: These results suggest that BRU59-21 warrants further investigation as an agent for imaging tumor hypoxia in the clinic.