Development of 99mTc-N4-NIM for molecular imaging of tumor hypoxia

Abstract

The nitro group of 2-nitroimidazole (NIM) enters the tumor cells and is bioreductively activated and fixed in the hypoxia cells. 1,4,8,11- tetraazacyclotetradecane (N4) has shown to be a stable chelator for 99mTc. The present study was aimed to develop 99mTc -cyclam-2-nitroimidazole (99mTc -N4-NIM) for tumor hypoxia imaging. N4-NIM precursor was synthesized by reacting N4-oxalate and 1,3-dibromopropane- NIM, yielded 14 (total synthesis). Cell uptake of 99mTc -N4-NIM and 99mTc -N4 was obtained in 13762 rat mammary tumor cells and mesothelioma cells in 6-well plates. Tissue distribution of 99mTc -N4-NIM was evaluated in breast-tumor-bearing rats at 0.5-4hrs. Tumor oxygen tension was measured using an oxygen probe. Planar imaging was performed in the tumor-bearing rat and rabbit models. Radiochemical purity of 99mTc -N4-NIM was 96 by HPLC. Cell uptake of 99mTc -N4-NIM was higher than 99mTc -N4 in both cell lines. Biodistribution of 99mTc -N4-NIM showed increased tumor-to-blood and tumor-to-muscle count density ratios as a function of time. Oxygen tension in tumor tissue was 6-10mmHg compared to 40-50mmHg in normal muscle tissue. Planar imaging studies confirmed that the tumors could be visualized clearly with 99mTc -N4-NIM in animal models. Efficient synthesis of N4-NIM was achieved. 99mTc -N4-NIM is a novel hypoxic probe and may be useful in evaluating cancer therapy. © 2012 Mohammad S. Ali et al.