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

INTRODUCTION:

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: Makiko Suehiro, Paul Burgman, Sean Carlin, Sean Burke, Guangbin Yang, Ouathek Ouerfelli, Christoph Oehler-Janne, Joseph O'Donoghue, Clifton Ling, John Humm
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 36 Issue 5 Pg. 477-87 (Jul 2009) ISSN: 1872-9614 [Electronic] United States
• PMID: 19520288 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 1-(6-deoxy-6-iodogalactopyranosyl)-2-nitroimidazole
• Biomarkers
• Galactosides
• Nitroimidazoles
• Oxygen

Topics

• Animals
• Autoradiography
• Biological Transport (drug effects)
• Biomarkers (metabolism)
• Cell Hypoxia
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Galactosides (chemical synthesis, chemistry, metabolism, pharmacokinetics)
• Humans
• Mice
• Nitroimidazoles (chemical synthesis, chemistry, metabolism, pharmacokinetics)
• Oxygen (pharmacology)
• Substrate Specificity
• Tissue Distribution