Ac‑225 radiochemistry through the lens of [ 225Ac]Ac‑DOTA‑TATE

Background: Targeted alpha therapy with Ac-225 showed to be efective in treating metastatic cancers. However, the complex decay chain requires optimized radiolabeling and quality control. This study aims to determine critical parameters and establish optimal labeling and accurate measuring techniques for radiochemical yield and purity with DOTA-TATE as a model molecule. Ac-225 sources were analyzed for metals (ΣFe, Zn, Cu) and quantifed by UPLC. Optimization of radiolabeling kinetics for clinical conditions was performed in regards to temperature (20–90 °C), heating time (5–60 min), pH (2.5–10, with/without excess of metal ions), bufers, quenchers, volume (0.1–10 mL) and molar activity (90–540 kBq/nmol). The quality control was investigated using radio-TLC/HPLC by changing gradient to evaluate peak separation, radiolysed peptide and impurity separation. Results: Metal ingrowth was observed in Ac-225 stocks (n=3), (time of arrival: 17.9, 36.8 and 101.4 nmol per 10 MBq). Optimal radiochemical yields were achieved with>80 °C (20 min) at pH 8.5 (15 mM TRIS) up to 270 kBq. Labeling at a high pH showed a higher RCY, even in presence of an excess of metals. High stability (RCP>90%) was achieved after addition of quenchers (cysteine, methionine, ascorbate, histidine, or gentisic acid (35 mM)) up to 24 h. For optimal determination of the radiochemical purity (indirect HPLC) ffty fractions are required. Conclusion: The quality of Ac-225 labeled DOTA-radiopharmaceuticals is highly dependent on the pH and stabilization (bufer/quencher). Within this research it is demonstrated that optimized quality control methods and accurate measurement of the radiolabeling kinetics are crucial to ensure safe implementation for patient treatment.

HOOIJMAN Eline;  DE JONG Jan R.;  NTIHABOSE Caroline;  BRUCHERTSEIFER Frank;  MORGENSTERN Alfred;  SEIMBILLE Yann;  BRABANDER Tessa;  KOOLEN Stijn;  DE BLOIS Erik; 

2025-03-19

SPRINGER SCIENCE AND BUSINESS MEDIA DEUTSCHLAND GMBH

JRC141705

2365-421X (online),   

https://ejnmmipharmchem.springeropen.com/articles/10.1186/s41181-025-00332-z,    https://publications.jrc.ec.europa.eu/repository/handle/JRC141705,   

10.1186/s41181-025-00332-z (online),