Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 19, Pages 7552-7563Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm400857f
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Silicon-containing prosthetic groups have been conjugated to peptides to allow for a single-step labeling with F-18 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 F-18-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 F-18-labeled silicon bombesin conjugates.
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