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

Background: Actinium-225 ((225)Ac) 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 (225)Ac(3+) is limited. The promising physical properties of (225)Ac result in an increased demand for the radioisotope that is not matched by its current supply. To expand the possibilities for the development of (225)Ac-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 (225)Ac, a small-scale (229)Th/(225)Ac generator was constructed in-house to provide [(225)Ac]AcCl(3) 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 (229)Th/(225)Ac generator was realized by extracting (229)Th from aged (233)U material. Radiolabeling of DFO*(12) with (225)Ac 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 (229)Th/(225)Ac generator allowed for the radiolabeling of DFO*(12) with (225)Ac quantitatively at 37 °C within 30 min. The complex [(225)Ac]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 (229)Th/(225)Ac generator, provide new opportunities for (225)Ac research for future radiopharmaceutical development and applications in TAT.