Irene V J Feiner, Dennis Svatunek, Martin Pressler, Tori Demuth, Xabier Guarrochena, Johannes H Sterba, Susanne Dorudi, Clemens Pichler, Christoph Denk, Thomas L Mindt
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引用次数: 0
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.
背景:锕-225 (225Ac)已引起核医学的兴趣,用于靶向α治疗(TAT)治疗癌症。然而,适合于稳定络合225Ac3+的螯合剂数量有限。225Ac有希望的物理性质导致对放射性同位素的需求增加,而目前的供应与之不匹配。为了扩大开发基于225ac的TAT治疗方法的可能性,描述了一种新的基于羟酸盐的螯合剂DFO*12。我们报道了dft引导下十二烷基DFO*12的设计和高效方便的自动化固相合成制备。为了解决225Ac可用性有限的问题,我们在内部建造了一台小型229 /225Ac发电机,为研究提供[225Ac]AcCl3。方法:在ORCA 5.0.1中使用BP86泛函进行DFT计算,并结合经验色散校正D3和Becke-Johnson阻尼(D3BJ)。通过三步合成单体,实现了DFO*12的固相合成。从老化的233U材料中提取229,实现了小型229 /225Ac发电机。用225Ac对DFO*12进行放射性标记,在1 M TRIS pH 8.5或1.5 M NaOAc pH 4.5中,在37°C下放置30分钟。结果:DFT计算指导了十二烷螯合剂的设计。螯合剂DFO*12的自动合成和小型229 /225Ac发生器的开发,使DFO*12在37°C下30分钟内定量地与225Ac进行放射性标记。配合物[225Ac]Ac-DFO*12在不同介质中表现出良好的稳定性,持续时间为20小时。新型羟酸盐基十二烷酸螯合剂DFO*12与已开发的229 /225Ac发生器一起,为未来放射性药物的开发和在TAT中的应用提供了新的225Ac研究机会。
PharmaceuticsPharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
7.90
自引率
11.10%
发文量
2379
审稿时长
16.41 days
期刊介绍:
Pharmaceutics (ISSN 1999-4923) is an open access journal which provides an advanced forum for the science and technology of pharmaceutics and biopharmaceutics. It publishes reviews, regular research papers, communications, and short notes. Covered topics include pharmacokinetics, toxicokinetics, pharmacodynamics, pharmacogenetics and pharmacogenomics, and pharmaceutical formulation. Our aim is to encourage scientists to publish their experimental and theoretical details in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.