Kondo Yuto, Joho Taiki, Sasaki Shigenori, Mochizuki Kazumasa, Hasegawa Naoko, Ukon Naoyuki, Nishijima Ken-Ichi, Washiyama Kohshin, Tanaka Hiroshi, Higashi Tatsuya, Ishioka Noriko S, Takahashi Kazuhiro
Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan.
SHI Accelerator Service Ltd., 7-1-1 Nishigotanda, Shinagawa, Tokyo, 141-0031, Japan.
EJNMMI Radiopharm Chem. 2025 Aug 5;10(1):52. doi: 10.1186/s41181-025-00376-1.
[At]m-Astatobenzylguanidine ([At]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 [At]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 [At]MABG suitable for clinical translation.
At was produced via the Bi(α,2n)At nuclear reaction using a cyclotron, with At formation minimised by precise control of the alpha particle energy. The resulting product was purified using an automated dry distillation system. [At]MABG was synthesised using the COSMiC-Mini automated synthesiser in 28.2 ± 2.8 min from initial At 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.
In this study, we established a reliable and scalable production methodology for [At]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 [At]MABG in targeted alpha therapy.
[砹]间位碘苄胍（[At]MABG）在恶性神经内分泌肿瘤的临床前模型（包括神经母细胞瘤和嗜铬细胞瘤/副神经节瘤）中已显示出强大的抗肿瘤功效。α粒子的高线性能量传递和短组织穿透范围能够实现高度局部化的细胞毒性作用，有可能克服与传统β发射放射性药物相关的治疗局限性。然而，在临床规模（即高放射性）条件下，[At]MABG的高效稳定生产受到制造过程中辐射降解的阻碍，限制了提供高放射化学产率和纯度的可靠方法的可用性。在本研究中，我们旨在开发一种适用于临床转化的[At]MABG可扩展生产方法。
通过使用回旋加速器的Bi(α,2n)At核反应生产砹，通过精确控制α粒子能量将砹的形成降至最低。所得产物使用自动干馏系统进行纯化。使用COSMiC-Mini自动合成仪在28.2±2.8分钟内从初始砹活度高达586.1 MBq合成[At]MABG。放射化学产率和纯度分别为80.3±4.4%（衰变校正RCY：84.0±4.5%）和99.0±0.7%（n = 6）。添加抗坏血酸钠作为自由基清除剂有助于在大规模生产过程中保持高放射化学产率和纯度。最终产物以无菌溶液形式获得。
在本研究中，我们建立了一种可靠且可扩展的[At]MABG生产方法，通过优化自动放射合成过程和使用辐射稳定剂，在广泛的放射性水平范围内始终实现高放射化学产率和纯度。该方法为[At]MABG在靶向α治疗中的临床应用提供了坚实的技术基础。
