A variety of promising targeted radiotherapeutics labeled with alpha-emitters have been developed. Clinical investigation of these radiopharmaceuticals requires the production of high activity levels, which can be hindered by alpha-particle-mediated radiolytic effects on labeling chemistry. The purpose of this study was to investigate the effects of radiation dose on the synthesis of N-succinimidyl 3-(211)At-astatobenzoate (SAB), a compound used in our clinical trials for labeling antibodies with alpha-particle-emitting (211)At.

Methods: Yields for the synthesis of SAB as a function of the radiation dose received by the reaction medium were determined. The variables studied included the radiohalogenation precursors N-succinimidyl 3-(tri-n-butylstannyl)benzoate (BuSTB) and N-succinimidyl 3-(trimethylstannyl)benzoate (MeSTB); the solvents chloroform, benzene, and methanol; and the addition of acetic acid and the oxidant N-chlorosuccinimide. The (211)At product spectra were determined from high-performance liquid chromatograms and then plotted against radiation dose.

Results: SAB production declined rapidly with increasing dose, consistent with the documented radiolytic decomposition of BuSTB and MeSTB in chloroform. Even though these tin precursors were not appreciably degraded in benzene, SAB could not be produced in this solvent; instead, highly lipophilic (211)At-labeled species were generated in nearly quantitative yields. Although a dose-dependent decline in SAB yield also was observed in methanol, both in the presence and in the absence of an oxidant, the results were better than those obtained with the other solvents. An unexpected observation was that SAB could be obtained at a yield of greater than 30% when the reaction was run in methanol without the addition of acetic acid or an oxidant; these 2 components previously were considered essential for astatodestannylation.

Conclusion: Radiolytic factors can play an important role in the synthesis of clinical-level activities of (211)At-labeled radiopharmaceuticals, necessitating the development of reaction conditions different from those that are used successfully at lower activity levels.