Feiner Irene V J, Svatunek Dennis, Pressler Martin, Demuth Tori, Guarrochena Xabier, Sterba Johannes H, Dorudi Susanne, Pichler Clemens, Denk Christoph, Mindt Thomas L
Bioinorganic Radiochemistry, Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Straße 42, 1090 Vienna, Austria.
Ludwig Boltzmann Institute Applied Diagnostics, AKH Wien c/o Sekretariat Nuklearmedizin, Währinger Gürtel 18-20, 1090 Vienna, Austria.
Pharmaceutics. 2025 Mar 1;17(3):320. doi: 10.3390/pharmaceutics17030320.
: Actinium-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 Ac is limited. The promising physical properties of 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 Ac-based TAT therapeutics, a new hydroxamate-based chelator, DFO*, is described. We report the DFT-guided design of dodecadentate DFO* and an efficient and convenient automated solid-phase synthesis for its preparation. To address the limited availability of Ac, a small-scale Th/Ac generator was constructed in-house to provide [Ac]AcCl for research. : 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*. The small-scale Th/Ac generator was realized by extracting Th from aged U material. Radiolabeling of DFO* with Ac was performed in 1 M TRIS pH 8.5 or 1.5 M NaOAc pH 4.5 for 30 min at 37 °C. : DFT calculations directed the design of a dodecadentate chelator. The automated synthesis of the chelator DFO* and the development of a small-scale Th/Ac generator allowed for the radiolabeling of DFO* with Ac quantitatively at 37 °C within 30 min. The complex [Ac]Ac-DFO* indicated good stability in different media for 20 h. : The novel hydroxamate-based dodecadentate chelator DFO*, together with the developed Th/Ac generator, provide new opportunities for Ac research for future radiopharmaceutical development and applications in TAT.
锕-225（Ac）在核医学中已引起关注，可用于靶向α治疗（TAT）来治疗癌症。然而，用于稳定络合Ac的合适螯合剂数量有限。Ac具有良好的物理性质，导致对这种放射性同位素的需求增加，而目前的供应却无法满足。为了扩大基于Ac的TAT治疗药物的开发可能性，本文描述了一种新型的基于异羟肟酸的螯合剂DFO*。我们报告了十二齿DFO的密度泛函理论（DFT）指导设计以及一种高效便捷的自动化固相合成方法来制备它。为了解决Ac可用性有限的问题，我们在内部构建了一个小型钍/锕发生器，以提供用于研究的[Ac]AcCl。：使用带有经验色散校正D3和Becke-Johnson阻尼（D3BJ）的BP86泛函在ORCA 5.0.1中进行DFT计算。通过三步单体合成实现了DFO的固相合成。小型钍/锕发生器是通过从老化的铀材料中提取钍来实现的。在1 M Tris pH 8.5或1.5 M NaOAc pH 4.5中于37°C下对DFO进行Ac放射性标记30分钟。：DFT计算指导了一种十二齿螯合剂的设计。螯合剂DFO的自动化合成以及小型钍/锕发生器的开发使得在37°C下30分钟内能够对DFO进行Ac的定量放射性标记。络合物[Ac]Ac-DFO在不同介质中20小时内显示出良好的稳定性。：新型的基于异羟肟酸的十二齿螯合剂DFO*，连同所开发的钍/锕发生器，为未来放射性药物开发和TAT应用中的Ac研究提供了新的机会。
