Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH) Zurich , Wolfgang-Pauli Strasse 10, CH-8093, Zurich, Switzerland.
J Med Chem. 2013 Oct 10;56(19):7552-63. doi: 10.1021/jm400857f. Epub 2013 Sep 18.
Silicon-containing prosthetic groups have been conjugated to peptides to allow for a single-step labeling with (18)F radioisotope. The fairly lipophilic di-tert-butylphenylsilane building block contributes unfavorably to the pharmacokinetic profile of bombesin conjugates. In this article, theoretical and experimental studies toward the development of more hydrophilic silicon-based building blocks are presented. Density functional theory calculations were used to predict the hydrolytic stability of di-tert-butylfluorosilanes 2-23 with the aim to improve the in vivo properties of (18)F-labeled silicon-containing biomolecules. As a further step toward improving the pharmacokinetic profile, hydrophilic linkers were introduced between the lipophilic di-tert-butylphenylsilane building block and the bombesin congeners. Increased tumor uptake was shown with two of these peptides in xenograft-bearing mice using positron emission tomography and biodistribution studies. The introduction of a hydrophilic linker is thus a viable approach to improve the tumor uptake of (18)F-labeled silicon-bombesin conjugates.
已将含硅的拟肽与肽连接起来，以允许与（18）F 放射性同位素进行单步标记。相当亲脂的二叔丁基苯基硅烷砌块不利于蛙皮素缀合物的药代动力学特性。本文介绍了开发更亲水的基于硅的砌块的理论和实验研究。使用密度泛函理论计算预测了二叔丁基氟硅烷 2-23 的水解稳定性，旨在改善（18）F 标记的含硅生物分子的体内性质。作为进一步改善药代动力学特性的步骤，在亲脂性二叔丁基苯基硅烷砌块和蛙皮素同系物之间引入了亲水性接头。使用正电子发射断层扫描和生物分布研究在荷瘤小鼠中显示出两种这些肽的肿瘤摄取增加。因此，引入亲水性接头是提高（18）F 标记的硅-蛙皮素缀合物肿瘤摄取的可行方法。
