Towards DFO*<sup>12</sup>—Preliminary Results of a New Chelator for the Complexation of Actinium-225

Author(s): Irene V.J. Feiner, Dennis Svatunek, Martin Pressler, Tori Demuth, Xabier Guarrochena, Johannes H. Sterba, Susanne Dorudi, Clemens Pichler, Christoph Denk, Thomas L. Mindt
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.
Organisation(s): Department of Inorganic Chemistry
External organisation(s): Medizinische Universität Wien, Ludwig Boltzmann Intitute Applied Diagnostics, Technische Universität Wien, DSD Pharma GmbH
Journal: Pharmaceutics
Volume: 17
ISSN: 1999-4923
DOI: https://doi.org/10.3390/pharmaceutics17030320
Publication date: 03-2025
Peer reviewed: Yes
Austrian Fields of Science 2012: 303039 Radiological technology, 301207 Pharmaceutical chemistry, 104020 Radiochemistry
Keywords
ASJC Scopus subject areas: Pharmaceutical Science
Sustainable Development Goals: SDG 3 - Good Health and Well-being
Portal url: https://ucrisportal.univie.ac.at/en/publications/22b2fd4a-8f1c-4f36-a396-8af0f35ef298