title: Noninvasive assessment of tumor hypoxia with 99mTc labeled metronidazole.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Nuclear Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Yang
authors.forename: S
authors.initials: S
authors.lastname: Ilgan
authors.forename: T
authors.initials: T
authors.lastname: Higuchi
authors.forename: F
authors.initials: F
authors.lastname: Zareneyrizi
authors.forename: C S
authors.initials: CS
authors.lastname: Oh
authors.forename: C W
authors.initials: CW
authors.lastname: Liu
authors.forename: E E
authors.initials: EE
authors.lastname: Kim
authors.forename: D A
authors.initials: DA
authors.lastname: Podoloff
mesh_terms: D000818:Animals; D001345:Autoradiography; D015687:Cell Hypoxia; D003545:Cysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000000981:diagnostic imaging* / Q000378:metabolism; D008795:Metronidazole / Q000138:chemical synthesis / Q000493:pharmacokinetics; D008839:Microelectrodes; D008920:Misonidazole / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics; D009389:Neovascularization, Pathologic; D015609:Organotechnetium Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics; D010100:Oxygen / Q000032:analysis; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D007457:Iodine Radioisotopes; D015609:Organotechnetium Compounds; D011838:Radiation-Sensitizing Agents; C031843:fluoromisonidazole; C073806:technetium Tc 99m-ethylenedicysteine; D008795:Metronidazole; D008920:Misonidazole; D003545:Cysteine; D010100:Oxygen