Irene V J Feiner, Dennis Svatunek, Martin Pressler, Tori Demuth, Xabier Guarrochena, Johannes H Sterba, Susanne Dorudi, Clemens Pichler, Christoph Denk, Thomas L Mindt
{"title":"Towards DFO*<sup>12</sup>-Preliminary Results of a New Chelator for the Complexation of Actinium-225.","authors":"Irene V J Feiner, Dennis Svatunek, Martin Pressler, Tori Demuth, Xabier Guarrochena, Johannes H Sterba, Susanne Dorudi, Clemens Pichler, Christoph Denk, Thomas L Mindt","doi":"10.3390/pharmaceutics17030320","DOIUrl":null,"url":null,"abstract":"<p><p><b>Background</b>: Actinium-225 (<sup>225</sup>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 <sup>225</sup>Ac<sup>3+</sup> is limited. The promising physical properties of <sup>225</sup>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 <sup>225</sup>Ac-based TAT therapeutics, a new hydroxamate-based chelator, DFO*<sup>12</sup>, is described. We report the DFT-guided design of dodecadentate DFO*<sup>12</sup> and an efficient and convenient automated solid-phase synthesis for its preparation. To address the limited availability of <sup>225</sup>Ac, a small-scale <sup>229</sup>Th/<sup>225</sup>Ac generator was constructed in-house to provide [<sup>225</sup>Ac]AcCl<sub>3</sub> for research. <b>Methods</b>: 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*<sup>12</sup>. The small-scale <sup>229</sup>Th/<sup>225</sup>Ac generator was realized by extracting <sup>229</sup>Th from aged <sup>233</sup>U material. Radiolabeling of DFO*<sup>12</sup> with <sup>225</sup>Ac was performed in 1 M TRIS pH 8.5 or 1.5 M NaOAc pH 4.5 for 30 min at 37 °C. <b>Results</b>: DFT calculations directed the design of a dodecadentate chelator. The automated synthesis of the chelator DFO*<sup>12</sup> and the development of a small-scale <sup>229</sup>Th/<sup>225</sup>Ac generator allowed for the radiolabeling of DFO*<sup>12</sup> with <sup>225</sup>Ac quantitatively at 37 °C within 30 min. The complex [<sup>225</sup>Ac]Ac-DFO*<sup>12</sup> indicated good stability in different media for 20 h. <b>Conclusions</b>: The novel hydroxamate-based dodecadentate chelator DFO*<sup>12</sup>, together with the developed <sup>229</sup>Th/<sup>225</sup>Ac generator, provide new opportunities for <sup>225</sup>Ac research for future radiopharmaceutical development and applications in TAT.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 3","pages":""},"PeriodicalIF":4.9000,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11946154/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmaceutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3390/pharmaceutics17030320","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
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.
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.