Process development and robustness of producing high specific activity I-131-MIBG for radiotherapy using the solid state Ultratrace™ technology

Abstract

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Objectives: Meta-iodobenzylguanidine (MIBG), like norepinephrine, is concentrated in sympathomedullary tissues by an active uptake mechanism and stored within the intracellular catecholamine storage vesicles. It has been used clinically for the diagnosis and radiotherapy of various neuroendocrine tumors. A commercial process to rapidly and efficiently produce multi-curie quantities of ultra-high specific activity I-131-MIBG will enable nano-dosing and enhanced therapeutic potential for radiotherapy. Multiple batches of a solid phase supported precursor were produced that contain polystyrene bound (dibutyltin)-benzylguanidine to evaluate the performance and impurity profile characteristics of the resin. Radiolabeling was performed by incubating [131I]-NaI with an oxidizing agent and purifying the labeled MIBG from any starting material in the reaction. This Ultratrace™ radiolabeling process affords the production of true “carrier free” radiopharmaceuticals to avoid the presence of substrate competition for a receptor target or pharmacological effects of the drug.

Methods: Process development experiments evaluated the performance of the radiolabeling procedure with I-131, iodine loss onto resin, impurity profiles and radiochemical purity of MIBG as a function of resin type and quantity and carrier isotope concentration, oxidizing agents, reaction time and temperature. A purification technique was also developed to remove any incompletely reacted radioiodine species and reagents without leaching other chemical impurities into solution. The reaction mixtures were analyzed by radiometric and UV detection HPLC, ICP-MS, and analysis for volatile organic carbon.

Results: Radio-labeling with commercial [I-131] sodium iodide (at 6-8 Ci/mg) resulted in reproducible lots of drug product solution for injection at 3 Ci/mg of MIBG. ICP-MS tin analysis of the reaction solution following incubation with the resin showed 3 ppm or less per entire iodination batch run. Residual solvent analyses by GC-FID on reaction mixtures showed concentrations less than 0.005 ppm for residual solvents including methanol, dichloromethane, THF, toluene, DMF, acetone, 2-propanol, 2-butanone, and ethyl acetate.

Conclusions: The Ultratrace™ labeling technique gave optimal performance with radioactive iodine to yield large quantities of high specific activity meta-iodobenzylguanidine (MIBG). The ultra-high specific activity formulations successfully obtained by this approach will lead to improved diagnostic sensitivity and more effective therapeutics without pharmacological induced side effects.

Research Support (if any): NIH Small Business Innovation Reward 1R43CA115120-01