Extended single-dose toxicity study of [211At]meta-astatobenzylguanidine in normal mice in preparation for the first-in-human clinical trial of targeted alpha therapy for pheochromocytoma and paraganglioma.

Objective: Targeted alpha-particle therapy (TAT) is promising with a greater therapeutic effect than conventional beta radionuclide therapy. To develop human clinical trials of [²¹¹At]meta-astatobenzylguanidine ([²¹¹At]MABG), we have conducted an extended single-dose toxicity study of [²¹¹At]MABG in normal mice in consultation with the Pharmaceuticals and Medical Devices Agency (PMDA). We are currently working for human clinical trials of [²¹¹At]MABG. After consultation with the Pharmaceuticals and Medical Devices Agency, we conducted a single-dose toxicity study of [²¹¹At]MABG in normal mice in preparation for a human clinical trial of [²¹¹At]MABG.

Methods: [²¹¹At]MABG was manufactured at Fukushima Medical University, where doses of 16, 48, and 80 MBq/kg were administered to BALB/cCrSlc mice (90 males and 90 females, 9 weeks old). The mice were observed and weighed every day for 14 days after [²¹¹At]MABG administration, as well as at any time between 14 and 35 days after [²¹¹At]MABG administration. At the end of the observation period, necropsy, blood examination, organ weighing, and histopathological examinations were performed. Statistical analyses of body weight, blood test results, and organ weights were performed to compare the data between the control and treatment groups.

Results: In the 80-MBq/kg-administered group of females, two mice were emergently euthanized on day 8 because of the deterioration of their general condition. One mouse died spontaneously on day 9. Except for the two emergently euthanized mice and one mouse that died, both males and females showed volume-dependent deterioration in body weight, general condition, necropsy findings, blood test results, organ weights, and histopathological findings, but all except for genital organ weights showed a recovery trend after 35 days.

Conclusions: The extended single-dose toxicity study of [²¹¹At]MABG conducted under the reliability criteria showed the toxicity of [²¹¹At]MABG to hematopoietic cells, gastrointestinal mucosa, adrenal glands, and genital organs, especially at the dose of 80 MBq/kg. Under the conditions of this study, the approximate lethal dose of [²¹¹At]MABG exceeds 80 MBq/kg, so the severely toxic dose in 10% of the animals was estimated to be 80 MBq/kg or greater.