Towards DFO*¹²-Preliminary Results of a New Chelator for the Complexation of Actinium-225

Background: Actinium-225 (²²⁵Ac) has gained interest in nuclear medicine for use in targeted alpha therapy (TAT) for the treatment of cancer. However, the number of suitable chelators for the stable complexation of ²²⁵Ac³⁺ is limited. The promising physical properties of ²²⁵Ac result in an increased demand for the radioisotope that is not matched by its current supply. To expand the possibilities for the development of ²²⁵Ac-based TAT therapeutics, a new hydroxamate-based chelator, DFO*¹², is described. We report the DFT-guided design of dodecadentate DFO*¹² and an efficient and convenient automated solid-phase synthesis for its preparation. To address the limited availability of ²²⁵Ac, a small-scale ²²⁹Th/²²⁵Ac generator was constructed in-house to provide [²²⁵Ac]AcCl₃ for research. Methods: DFT calculations were performed in ORCA 5.0.1 using the BP86 functional with empirical dispersion correction D3 and Becke-Johnson damping (D3BJ). The monomer synthesis over three steps enabled the solid-phase synthesis of DFO*¹². The small-scale ²²⁹Th/²²⁵Ac generator was realized by extracting ²²⁹Th from aged ²³³U material. Radiolabeling of DFO*¹² with ²²⁵Ac was performed in 1 M TRIS pH 8.5 or 1.5 M NaOAc pH 4.5 for 30 min at 37 °C. Results: DFT calculations directed the design of a dodecadentate chelator. The automated synthesis of the chelator DFO*¹² and the development of a small-scale ²²⁹Th/²²⁵Ac generator allowed for the radiolabeling of DFO*¹² with ²²⁵Ac quantitatively at 37 °C within 30 min. The complex [²²⁵Ac]Ac-DFO*¹² indicated good stability in different media for 20 h. Conclusions: The novel hydroxamate-based dodecadentate chelator DFO*¹², together with the developed ²²⁹Th/²²⁵Ac generator, provide new opportunities for ²²⁵Ac research for future radiopharmaceutical development and applications in TAT.