Development of Tc99m-N4-NIM for Molecular Imaging of Tumor Hypoxia

Abstract EN

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 Tc99m.

The present study was aimed to develop Tc99m-cyclam-2-nitroimidazole (Tc99m-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 Tc99m-N4-NIM and Tc99m-N4 was obtained in 13762 rat mammary tumor cells and mesothelioma cells in 6-well plates.

Tissue distribution of Tc99m-N4-NIM was evaluated in breast-tumor-bearing rats at 0.5–4 hrs.

Tumor oxygen tension was measured using an oxygen probe.

Planar imaging was performed in the tumor-bearing rat and rabbit models.

Radiochemical purity of Tc99m-N4-NIM was >96% by HPLC.

Cell uptake of Tc99m-N4-NIM was higher than Tc99m-N4 in both cell lines.

Biodistribution of Tc99m-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 6–10 mmHg compared to 40–50 mmHg in normal muscle tissue.

Planar imaging studies confirmed that the tumors could be visualized clearly with Tc99m-N4-NIM in animal models.

Efficient synthesis of N4-NIM was achieved.

Tc99m-N4-NIM is a novel hypoxic probe and may be useful in evaluating cancer therapy.