Radiosynthesis of [131I]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?

Suehiro, Makiko; Burgman, Paul; Carlin, Sean; Burke, Sean; Yang, Guangbin; Ouerfelli, Ouathek; Oehler-Janne, Christoph; O'Donoghue, Joseph; Ling, Clifton; Humm, John

doi:10.1016/j.nucmedbio.2009.03.002

« Previous Next »Nuclear Medicine and Biology
Volume 36, Issue 5 , Pages 477-487, July 2009

Radiosynthesis of [¹³¹I]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?

Makiko Suehiro
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Corresponding author. Tel.: +1 646 888 2153; fax: +1 212 639 2611.
Paul Burgman
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Sean Carlin
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Sean Burke
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Guangbin Yang
- Organic Synthesis Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Ouathek Ouerfelli
- Organic Synthesis Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Christoph Oehler-Janne
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Joseph O'Donoghue
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Clifton Ling
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
John Humm
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

Received 30 September 2008; received in revised form 24 February 2009; accepted 6 March 2009. published online 08 May 2009.

Abstract

Introduction

The hypoxia marker IAZGP, 1-(6-deoxy-6-iodo-β-d-galactopyranosyl)-2-nitroimidazole, has been labeled with ¹²³I/¹²⁴I/¹²⁵I/¹³¹I via iodine–radioiodine exchange, which gives the radiotracer in a specific activity of 10–90 MBq/μmol. 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 [¹³¹I]IAZGP was prepared by substitution of the tosyl functionality with [¹³¹I]iodide. In vitro uptake of high- and low-SA [¹³¹I]IAZGP by HCT8 and HT29 cells was assessed in normoxic and hypoxic conditions. Biodistribution and intratumor localization of high- and low-SA [¹³¹I]IAZGP were determined by injection into HT29 tumor-bearing mice.

Results

The nucleophilic substitution reaction proceeded efficiently in acetonitrile at 150°C, giving the final product in an average yield of 42% and an average specific activity of 30 GBq/μmol. In vitro, high-SA [¹³¹I]IAZGP was incorporated into the tumor cells with similar kinetics and oxygen dependence to low-SA [¹³¹I]IAZGP. In HT29 tumor-bearing mice, biodistributions of high- and low-SA [¹³¹I]IAZGP were equivalent. Ex vivo autoradiography revealed heterogeneous intratumor localization of high-SA [¹³¹I]IAZGP corresponding closely to distributions of other exogenous and endogenous hypoxia markers. Comparable microregional distribution patterns were observed with low-SA [¹³¹I]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.

Keywords: Specific activity, IAZGP, Hypoxia, Nucleophilic substitution