ABSTRACT
BACKGROUND: Analogues of exendin-4 have been radiolabeled for imaging the glucagon-like peptide type 1 receptors (GLP-1R) which are overexpressed in insulinoma. The aim of this research was to synthesize an 18F-labeled silicon containing exendin-4 peptide (18F-2) and to evaluate its in vitro and in vivo behavior in CHL-GLP-1 receptor positive tumor-bearing mice. 18F-labeled silicon containing exendin-4 peptide (18F-2) was prepared via one-step nucleophilic substitution of a silane precursor with 18F-fluoride in the presence of acetic acid and K222. 18F-2 was then administered to tumor-bearing mice for PET imaging and ex vivo biodistribution experiments. RESULTS: 18F-2 was produced in a radiochemical yield (decay corrected) of 1.5% and a molar activity of max. 16 GBq/µmol. The GLP-1R positive tumors were clearly visualized by PET imaging. Biodistribution studies showed reduced uptake of 18F-2 in the kidneys compared to radiometal labeled exendin-4 derivatives. The radiotracer showed specific tumour uptake which remained steady over 2 h. CONCLUSIONS: This exendin-4 analogue, 18F-2, is a potential probe for imaging GLP-1R positive tumors.
ABSTRACT
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.
