Isopeptidic Desferrioxamine Analogues: The Role of Hydroxamate Spacing for Chelation of Zr4.

IF 3.6 4区 医学 Q2 CHEMISTRY, MEDICINAL ChemMedChem Pub Date : 2024-12-10 DOI:10.1002/cmdc.202400890
Lasse Outzen, Darius Ludolfs, Maximilian Irl, Susanne Kossatz, Wolfgang Maison
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Abstract

[89Zr]Zr4+ is a radionuclide of increasing clinical relevance for PET (positron emission tomography). However, an ideal chelator for stable Zr-chelation remains to be discovered. This study describes the solid-phase synthesis of octadentate Zr-chelators based on an isopeptidic (ip) scaffold derived from the natural siderophore desferrioxamine (DFOB). Several analogues with different spacers separating the chelating hydroxamates have been prepared and converted to [89Zr]Zr-complexes. The stability of these complexes was evaluated in human serum and in competition to excess of competing chelators. The assays revealed a beneficial effect of long hydroxamate spacing (9 atoms). Shorter spacing led to a decrease in complex stability. The most stable [89Zr]Zr-ipDFO complex had a high stability in challenging competition experiments with a large excess of EDTA for 72 h as determined by radio TLC and LC/MS. The straightforward synthesis, high complex stability and a modular character make ipDFO derivatives promising chelators for applications in targeted PET.

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[89Zr]Zr4+是一种与PET(正电子发射断层扫描)临床相关性越来越大的放射性核素。然而,用于稳定螯合 Zr 的理想螯合剂仍有待发现。本研究介绍了基于从天然苷元去铁胺(DFOB)中提取的异肽(ip)支架的八齿锆螯合剂的固相合成。我们制备了几种具有不同间隔的类似物,将螯合羟肟酸酯分隔开来,并将其转化为[89Zr]Zr-络合物。对这些复合物在人体血清中的稳定性以及与过量竞争螯合剂的竞争性进行了评估。检测结果表明,羟基氨基甲酸酯间距长(9 个原子)会产生有利影响。较短的间距会导致复合物稳定性下降。通过无线电 TLC 和 LC/MS 测定,最稳定的[89Zr]Zr-ipDFO 复合物在大量过量 EDTA 的竞争实验中 72 小时内具有很高的稳定性。简单的合成、高络合物稳定性和模块化特性使 ipDFO 衍生物成为有望应用于靶向 PET 的螯合剂。
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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
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