Modifying the in vitro accumulation of BMS181321, a Technetium-99m-nitroimidazole, with unlabelled nitroaromatics

Abstract

BMS181321, [ 99mTc]oxo[[3,3,9,9-tetramethyl-1-(2-nitro-1 H-imidazol-1-yl)-4,8-diazaundecane-2, 10-dione dioximato]-(3)- N, N′, N″, N′″]technetium, is a 99mTc-nitroimidazole that is being investigated as a hypoxic marker in tumors. Due to the high specific activity of 99mTc, the concentration of BMS181321 used in its applications is very low. Metabolic depletion and non-specific binding of the drug may limit its ability to fully map out hypoxic regions. An attempt has been made to modify the in vitro accumulation of BMS181321 in hypoxic Chinese hamster ovary (CHO) cells with unlabelled nitroaromatics. The 2-nitroimidazole etanidazole (0.08 to 8 mM) caused a concentration-dependent decrease in BMS181321 accumulation to 70-28% and metabolism to 70-40% of the control level in hypoxic cells at 4 hr. In contrast, the 5-nitroimidazole tinidazole (0.09 to 9 mM) caused a concentration-dependent increase in BMS181321 accumulation to 110–170% and metabolism to 100–150% of the control level in hypoxic cells at 4 hr. Nitroaromatics with an electron affinity similar to or greater than that of BMS181321 inhibited its accumulation and metabolism, and 5-nitroimidazoles, which have an electron affinity lower than that of BMS181321, enhanced its accumulation and metabolism. The enhanced accumulation with the addition of metronidazole was not observed in the presence of low oxygen levels or of a nitrofuran of higher electron affinity than BMS181321. These results suggest that a competition for reducing equivalents and/or for the BMS181321 radical anion itself can occur in cells, leading to the inhibition of BMS181321 reduction in the presence of nitroaromatics of similar or greater electron affinity. A transfer of electrons from the radical anion form of the reduced 5-nitroimidazole to the more electron affinic BMS181321 compound may occur, causing increased hypoxic accumulation of BMS181321.