Noninvasive assessment of tumor hypoxia with 99mTc labeled metronidazole

Pharm Res. 1999 May;16(5):743-50. doi: 10.1023/a:1018836911013.

Abstract

Purpose: The assessment of tumor hypoxia by imaging modality prior to radiation therapy would provide a rational means of selecting patients for treatment with radiosensitizers or bioreductive drugs. This study aimed to develop a 99mTc-labeled metronidazole (MN) using ethylene-dicysteine (EC) as a chelator and evaluate its potential use to image tumor hypoxia.

Methods: EC was conjugated to amino analogue of MN using Sulfo-N-hydroxysuccinimide and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide-HCl as coupling agents, the yield was 55%. Tissue distribution of 99mTc-EC-MN was determined in breast tumor-bearing rats at 0.5, 2, and 4 hrs. Planar imaging and whole-body autoradiograms were performed. The data was compared to that using 99mTc-EC (control), [18F]fluoromisonidazole (FMISO) and [(131)I] iodomisonidazole (IMISO).

Results: In vivo biodistribution of 9mTc-EC-MN in breast tumor-bearing rats showed increased tumor-to-blood and tumor-to-muscle ratios as a function of time. Conversely, tumor-to-blood values showed time-dependent decrease with 9mTc-EC in the same time period. Planar images and autoradiograms confirmed that the tumors could be visualized clearly with 99mTc-EC-MN from 0.5 to 4 hrs. There was no significant difference of tumor-to-blood count ratios between 99mTc-EC-MN and [(131)I]IMISO at 2 and 4 hrs postinjection. From 0.5 to 4 hrs, both 9mTc-EC-MN and [(131)I]MISO have higher tumor-to-muscle ratios compared to [18]FMISO.

Conclusions: It is feasible to use 9mTc-EC-MN to image tumor hypoxia.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Autoradiography
  • Cell Hypoxia
  • Cysteine / analogs & derivatives*
  • Cysteine / chemical synthesis
  • Cysteine / pharmacokinetics
  • Female
  • Fluorine Radioisotopes / pharmacokinetics
  • Iodine Radioisotopes / pharmacokinetics
  • Mammary Neoplasms, Experimental / blood supply*
  • Mammary Neoplasms, Experimental / diagnostic imaging*
  • Mammary Neoplasms, Experimental / metabolism
  • Metronidazole* / chemical synthesis
  • Metronidazole* / pharmacokinetics
  • Microelectrodes
  • Misonidazole / analogs & derivatives
  • Misonidazole / chemical synthesis
  • Misonidazole / pharmacokinetics
  • Neovascularization, Pathologic
  • Organotechnetium Compounds* / chemical synthesis
  • Organotechnetium Compounds* / pharmacokinetics
  • Oxygen / analysis
  • Radiation-Sensitizing Agents* / chemical synthesis
  • Radiation-Sensitizing Agents* / pharmacokinetics
  • Radionuclide Imaging
  • Rats
  • Rats, Inbred F344
  • Tissue Distribution

Substances

  • Fluorine Radioisotopes
  • Iodine Radioisotopes
  • Organotechnetium Compounds
  • Radiation-Sensitizing Agents
  • fluoromisonidazole
  • technetium Tc 99m-ethylenedicysteine
  • Metronidazole
  • Misonidazole
  • Cysteine
  • Oxygen