title: A study on nitroimidazole-99mTc(CO)3 complexes as hypoxia marker: some observations towards possible improvement in in vivo efficacy.
abstract: BACKGROUND
  Hypoxia plays a negative role in the clinical management of cancer. Detection of hypoxic status of a cancer is important for selecting patients for hypoxia directed therapy. Though [(18)F]fluoromisonidazole ([(18)F]FMISO), a PET radiopharmaceutical, is presently being used in the clinic for the detection of hypoxia, considering the logistical advantages of (99m)Tc and wider availability of SPECT scanners, a radiopharmaceutical based on this isotope may find wider applicability.
  
  
  METHODS
  Nine nitroimidazole (2-, 4- and 5-nitroimidazole) ligands were synthesized and radiolabeled using [(99m)Tc(CO)3(H2O)3](+) precursor to obtain a group of complexes possessing different single electron reduction potential (SERP), overall charge and lipophilicity, the three attributes which decide the efficacy of the complex to detect hypoxic cells in vivo. The nitroimidazole-(99m)Tc(CO)3 complexes as well as [(18)F]FMISO were evaluated in fibrosarcoma tumor bearing mice.
  
  
  RESULTS
  The (99m)Tc(CO)3 complexes of nitroimidazole iminodiacetic acid (IDA) showed better tumor uptake and retention than nitroimidazole diethylenetriamine (DETA) and nitroimidazole aminoethylglycine (AEG) complexes. Tumor uptake observed with [(18)F]FMISO was higher than any of the nitroimidazole-IDA- (99m)Tc(CO)3 complexes. However, [(18)F]FMISO clearance from tumor was found to be faster compared to 2-nitroimidazole-IDA-(99m)Tc(CO)3 complex. Observed tumor uptake and retention of the radiotracers evaluated could be correlated to its blood clearance pattern and SERP.
  
  
  CONCLUSIONS
  Results of the present study indicated that uptake of the radiotracer in tumor is closely associated with its rate of clearance from blood. The study also indicated that along with SERP, clearance of radiotracer from blood (net effect of charge and lipophilicity) is a critical factor which decides the in vivo efficacy of the hypoxia detecting radiopharmaceutical.
authors.affiliation: Isotope Applications and Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai, 400085, India.
authors.forename: Madhava B
authors.initials: MB
authors.lastname: Mallia
authors.affiliation: Isotope Applications and Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai, 400085, India.
authors.forename: Suresh
authors.initials: S
authors.lastname: Subramanian
authors.affiliation: Medical and Biological Products Program, Board of Radiation and Isotope Technology, Mumbai, 400705, India.
authors.forename: Anupam
authors.initials: A
authors.lastname: Mathur
authors.affiliation: Radiation Biology and Health Science Division, Bhabha Atomic Research Centre, Mumbai, 400085, India.
authors.forename: H D
authors.initials: HD
authors.lastname: Sarma
authors.affiliation: Isotope Applications and Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai, 400085, India. Electronic address: sharmila@barc.gov.in.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Banerjee
mesh_terms: D000818:Animals; D001692:Biological Transport; D014408:Biomarkers, Tumor / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D015687:Cell Hypoxia; D005354:Fibrosarcoma / Q000473:pathology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D009593:Nitroimidazoles / Q000737:chemistry*; D015609:Organotechnetium Compounds / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D011854:Radiochemistry; D014018:Tissue Distribution
chemical_list: D014408:Biomarkers, Tumor; D009593:Nitroimidazoles; D015609:Organotechnetium Compounds; C052587:4-nitroimidazole
keywords: Fibrosarcoma; Hypoxia; Lipophilicity; Nitroimidazole; Single electron reduction potential; Technetium tricarbony complexes