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

## TL;DR

Researchers designed a new chelator called DFO*12 for Actinium-225, which could improve targeted alpha therapy for cancer treatment.

## Contribution

The novel dodecadentate hydroxamate-based chelator DFO*12 was developed for stable complexation of Actinium-225.

## Key findings

- DFO*12 was successfully radiolabeled with 225Ac quantitatively within 30 minutes at 37°C.
- The [225Ac]Ac-DFO*12 complex showed good stability in various media for 20 hours.
- A small-scale 229Th/225Ac generator was developed to address the limited availability of 225Ac.

## Abstract

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.