title: Radiosynthesis of [(131)I]IAZGP via nucleophilic substitution and its biological evaluation as a hypoxia marker - is specific activity a factor influencing hypoxia-mapping ability of a hypoxia marker?
abstract: BACKGROUND
  The hypoxia marker IAZGP, 1-(6-deoxy-6-iodo-beta-d-galactopyranosyl)-2-nitroimidazole, has been labeled with (123)I/(124)I/(125)I/(131)I via iodine-radioiodine exchange, which gives the radiotracer in a specific activity of 10-90 MBq/micromol. We synthesized the same radiotracer possessing several hundred to thousand times higher specific activity (high-SA IAZGP) via nucleophilic substitution and compared its biological behavior with that of conventionally produced IAZGP (low-SA IAZGP) to determine if specific activity is a factor influencing cell uptake kinetics, biodistribution and intratumor microregional localization of the radiotracer.
  
  
  METHODS
  High-SA [(131)I]IAZGP was prepared by substitution of the tosyl functionality with [(131)I]iodide. In vitro uptake of high- and low-SA [(131)I]IAZGP by HCT8 and HT29 cells was assessed in normoxic and hypoxic conditions. Biodistribution and intratumor localization of high- and low-SA [(131)I]IAZGP were determined by injection into HT29 tumor-bearing mice.
  
  
  RESULTS
  The nucleophilic substitution reaction proceeded efficiently in acetonitrile at 150 degrees C, giving the final product in an average yield of 42% and an average specific activity of 30 GBq/micromol. In vitro, high-SA [(131)I]IAZGP was incorporated into the tumor cells with similar kinetics and oxygen dependence to low-SA [(131)I]IAZGP. In HT29 tumor-bearing mice, biodistributions of high- and low-SA [(131)I]IAZGP were equivalent. Ex vivo autoradiography revealed heterogeneous intratumor localization of high-SA [(131)I]IAZGP corresponding closely to distributions of other exogenous and endogenous hypoxia markers. Comparable microregional distribution patterns were observed with low-SA [(131)I]IAZGP.
  
  
  CONCLUSIONS
  Radiolabeled IAZGP produced via nucleophilic substitution is validated as an exogenous hypoxia marker. Specific activity does not appear to influence the in vivo hypoxia-mapping ability of the radiotracer.
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. suehirom@mskcc.org
authors.forename: Makiko
authors.initials: M
authors.lastname: Suehiro
authors.forename: Paul
authors.initials: P
authors.lastname: Burgman
authors.forename: Sean
authors.initials: S
authors.lastname: Carlin
authors.forename: Sean
authors.initials: S
authors.lastname: Burke
authors.forename: Guangbin
authors.initials: G
authors.lastname: Yang
authors.forename: Ouathek
authors.initials: O
authors.lastname: Ouerfelli
authors.forename: Christoph
authors.initials: C
authors.lastname: Oehler-Janne
authors.forename: Joseph
authors.initials: J
authors.lastname: O'Donoghue
authors.forename: Clifton
authors.initials: C
authors.lastname: Ling
authors.forename: John
authors.initials: J
authors.lastname: Humm
mesh_terms: D000818:Animals; D001345:Autoradiography; D001692:Biological Transport / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005697:Galactosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D010100:Oxygen / Q000494:pharmacology; D013379:Substrate Specificity; D014018:Tissue Distribution
chemical_list: C543418:1-(6-deoxy-6-iodogalactopyranosyl)-2-nitroimidazole; D015415:Biomarkers; D005697:Galactosides; D009593:Nitroimidazoles; D010100:Oxygen