[ 131 I]Iodoazomycin arabinoside for low-dose-rate isotope radiotherapy: radiolabeling, stability, long-term whole-body clearance and radiation dosimetry estimates in mice Piyush Kumar a , Steven A. McQuarrie a,b , Aihya Zhou b , Alexander J.B. McEwan a , Leonard I. Wiebe a,b, T a Department of Oncologic Imaging, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada T6G 2N8 b Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8 Received 15 February 2005; received in revised form 17 April 2005; accepted 27 April 2005 Abstract Background: The preliminary characterization of [ 131 I]iodoazomycin arabinoside ([ 131 I]IAZA) as a potential radiotherapeutic radiopharmaceutical is described. Methods: High-specific-activity [ 131 I]IAZA was prepared in therapeutic doses (up to 3 GBq per batch) by isotope exchange in pivalic acid melt and was purified on Sep-Pak cartridges. Stability in 15% ethanol in saline at 48C was determined by high-performance liquid chromatography. IAZA cytotoxicity (IC 50 , ~0.1 mM) against both murine (EMT-6) and human (143B, 143B-LTK) tumor cells determined by MTT test was in the range previously reported for EMT-6 cells using a clonogenic assay. Tissue radioactivity levels were measured in a murine tumor model for the 24- to 168-h postinjection period. Radiation dose estimates obtained from the tissue activity levels for this period were calculated from pharmacokinetic (WinNonlin) and dosimetry (MIRD and RAdiation Dose Assessment Resource) parameters. Results: The radioiodination efficiency was N 90%, but with systematic losses during Sep-Pak purification, the recovered yields of [ 131 I]IAZA were ~75%. The product (specific activity, 4.6– 6.4 GBq/Amol) was stable for at least 2 weeks, with only ~6% degradation over this storage period. Extended biodistribution studies in Balb/c mice bearing implanted EMT-6 tumors showed that the highest tumor/blood radioactivity ratio (T/B; 4.8) occurred 24 h after dosing; the T/B ratio was ~1.5 at the end of the 7-day study. The 24- to 168-h tissue radioactivity data fit a one-compartment model except for liver data, which best fit a two-compartment model. Dosimetry estimates showed a tumor self-dose of 7.4 mGy/MBq, which is several-fold higher than for the liver or the kidney. Conclusions: [ 131 I]IAZA can be efficiently radiolabeled at high specific activity, purified by a simple Sep-Pak technique and stored with little radiolysis or chemical decomposition at these specific activities. Based on measured radioactivity burdens during the week following injection and on published animal ([ 125 I]IAZA) and clinical ([ 123 I]IAZA) dosimetry data, the current dose estimates point to selective tumor irradiation at low dose rates. D 2005 Elsevier Inc. All rights reserved. Keywords: [ 131 I]IAZA; Hypoxia; Radioiodination; Biodistribution; Isotope dosimetry; Isotope radiotherapy 1. Introduction Azomycins (2-nitroimidazoles) are bioreductively acti- vated by single-electron transfer. The resulting chemically reactive intermediates can selectively bind with cellular components to form molecular adducts within viable hypoxic cells. The reversibility of this single-electron reduction in the presence of oxygen limits adducts formation primarily to cells that are pathologically hypoxic [1–3]. This oxygen- dependent selectivity forms the basis for selective accumu- lation of these substances within the hypoxic region and creates an opportunity for selective imaging of hypoxic regions with radiolabeled nitroimidazoles [4]. Azomycin nucleosides are relatively hydrophilic, highly diffusible radiosensitizers that readily permeate hypoxic tissues. Sev- eral radioiodinated azomycin nucleosides have been synthe- sized and evaluated as radioimaging agents for the detection 0969-8051/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.nucmedbio.2005.04.019 T Corresponding author. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8. Tel.: +1 780 492 5783; fax: +1 780 435 0636. E-mail address: leonard.wiebe@ualberta.ca (L.I. Wiebe). Nuclear Medicine and Biology 32 (2005) 647 – 653 www.elsevier.com/locate/nucmedbio