Radiopharmaceutical Chemistry of Targeted Radiotherapeutics, Part 1: Effects of Solvent on the Degradation of Radiohalogenation Precursors by 211At Alpha-particles

Unlabelled: The high energy and short range of alpha-particles make them attractive for targeted radiotherapy. However, these properties can be problematic when the production of high activity levels of alpha-particle-emitting radiotherapeutics is required. For example, difficulties were encountered in the production of N-succinimidyl 3-[211At]-astatobenzoate (SAB), when 370-MBq doses of 211At-labeled antibody were required. The purpose of this study was to investigate a potential cause of this behavior--radiolytic degradation of the radiohalogenation precursor.

Methods: Both N-succinimidyl 3-(tri-n-butylstannyl)benzoate (BuSTB) and N-succinimidyl 3-trimethylstannylbenzoate (MeSTB) were incubated with various 211At time-activity combinations such that the radiation dose received by the reaction medium ranged from about 0 to 20,000 Gy. Studies were performed using chloroform, methanol, and benzene as the solvent, and both at neutral pH and at a pH of approximately 5.5, as used in SAB synthesis. The fraction of tin precursor remaining and the generation of unlabeled byproducts were determined from high-performance liquid chromatograms and then plotted against radiation dose.

Results: Extensive radiolytic decomposition of BuSTB and MeSTB was observed in chloroform, with 50% degradation taking place even at doses below 500 Gy. Formation of a byproduct, most likely N-succinimidyl 3-chlorobenzoate, increased with radiation dose. A greater degree of stability was seen in both methanol and benzene, with more than 85% of the precursor remaining at 3,500 Gy. No cold byproducts were observed with either solvent.

Conclusion: The nature of the solvent profoundly influences the ability to synthesize high activity levels of SAB and possibly other 211At-labeled radiopharmaceuticals.