Development of (99m)Tc-N4-NIM for molecular imaging of tumor hypoxia

J Biomed Biotechnol. 2012:2012:828139. doi: 10.1155/2012/828139. Epub 2012 Jun 10.

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 (99m)Tc. The present study was aimed to develop (99m)Tc-cyclam-2-nitroimidazole ((99m)Tc-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 (99m)Tc-N4-NIM and (99m)Tc-N4 was obtained in 13762 rat mammary tumor cells and mesothelioma cells in 6-well plates. Tissue distribution of (99m)Tc-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 (99m)Tc-N4-NIM was >96% by HPLC. Cell uptake of (99m)Tc-N4-NIM was higher than (99m)Tc-N4 in both cell lines. Biodistribution of (99m)Tc-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 (99m)Tc-N4-NIM in animal models. Efficient synthesis of N4-NIM was achieved. (99m)Tc-N4-NIM is a novel hypoxic probe and may be useful in evaluating cancer therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Hypoxia / physiology
  • Female
  • Heterocyclic Compounds, 1-Ring / chemistry
  • Heterocyclic Compounds, 1-Ring / pharmacokinetics
  • Humans
  • Male
  • Molecular Imaging / methods
  • Neoplasms / diagnostic imaging*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Nitroimidazoles / chemistry
  • Nitroimidazoles / pharmacokinetics
  • Organotechnetium Compounds / chemistry
  • Organotechnetium Compounds / pharmacokinetics*
  • Oxygen / metabolism
  • Rabbits
  • Radioactive Tracers
  • Radionuclide Imaging
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacokinetics*
  • Rats
  • Rats, Inbred F344
  • Tissue Distribution
  • Tumor Microenvironment

Substances

  • Heterocyclic Compounds, 1-Ring
  • Nitroimidazoles
  • Organotechnetium Compounds
  • Radioactive Tracers
  • Radiopharmaceuticals
  • technetium Tc 99m cyclam
  • Oxygen