Production of 211At and automated radiosynthesis of [211At]MABG via electrophilic astatodesilylation

Abstract

Background

[²¹¹At]m-Astatobenzylguanidine ([²¹¹At]MABG) has demonstrated potent antitumor efficacy in preclinical models of malignant neuroendocrine tumours including neuroblastoma and pheochromocytoma/paraganglioma. The high linear energy transfer and short tissue penetration range of alpha particles enable highly localized cytotoxic effects, potentially overcoming therapeutic limitations associated with conventional beta-emitting radiopharmaceuticals. However, under clinical-scale (i.e., high radioactivity) conditions, the efficient and stable production of [²¹¹At]MABG has been hindered by radiolytic degradation during the manufacturing process limiting the availability of reliable methods offering high radiochemical yield and purity. In this study, we aimed to develop a scalable production methodology for [²¹¹At]MABG suitable for clinical translation.

Results

²¹¹At was produced via the ²⁰⁹Bi(α,2n)²¹¹At nuclear reaction using a cyclotron, with ²¹⁰At formation minimised by precise control of the alpha particle energy. The resulting product was purified using an automated dry distillation system. [²¹¹At]MABG was synthesised using the COSMiC-Mini automated synthesiser in 28.2 ± 2.8 min from initial ²¹¹At activities of up to 586.1 MBq. The radiochemical yield and purity were 80.3 ± 4.4% (decay-corrected RCY: 84.0 ± 4.5%) and 99.0 ± 0.7%, respectively (n = 6). The addition of sodium ascorbate as a radical scavenger contributed to maintaining a high radiochemical yield and purity during large-scale production. The final product was obtained as a sterile solution.

Conclusions

In this study, we established a reliable and scalable production methodology for [²¹¹At]MABG, consistently achieving high radiochemical yield and purity across a wide range of radioactivity levels through optimization of the automated radiosynthesis process and the use of radiolytic stabilizers. This approach provides a solid technical foundation for the clinical application of [²¹¹At]MABG in targeted alpha therapy.