Synthesis, Radiolabeling and Biological Evaluation of Propylene Amine Oxime Complexes Containing Nitrotriazoles as Hypoxia Markers

Abstract: Two propylene amine oxime (PnAO) complexes, 1, containing a 3-nitro-1,2,4-triazole and 2, containing two 3-nitro-1,2,4-triazoles, were synthesized and radiolabeled with ^99mTc in high labeling yields. Cellular uptakes of ^99mTc-1 and ^99mTc-2 were tested using a S180 cells line. Under anoxic conditions, the cellular uptakes of ^99mTc-1 and ^99mTc-2 were 33.7 ± 0.2% and 35.0 ± 0.7% at 4 h, whereas the normoxic uptakes of the two complexes were 6.0 ± 1.6% and 4.6 ± 0.9%, respectively. Both ^99mTc-1 and ^99mTc-2 displayed significant anoxic/normoxic differentials. The cellular uptakes were highly dependent on oxygen and temperature. Biodistribution studies revealed that both ^99mTc-1 and ^99mTc-2 showed a selective localization in tumor and slow clearance from it. At 4 h, the tumor-to-muscle ratios (T/M) were 3.79 for ^99mTc-1 and 4.58 for ^99mTc-2. These results suggested that ^99mTc-labeled PnAO complexes ^99mTc-1 and ^99mTc-2 might serve as novel hypoxia markers. By introducing a second nitrotriazole redox center, the hypoxic accumulation of the marker was slightly enhanced.