Synthesis, 18F-labeling, and in vitro and in vivo studies of bombesin peptides modified with silicon-based building blocks.

Abstract

The gastrin-releasing peptide receptor (GRPr) is overexpressed on various human tumors. The goal of our study was the synthesis of new 18F-labeled bombesin analogues for the PET imaging of GRPr expression in prostate tumor using a silicon-based one-step n. c. a. radiolabeling method. The silicon-containing building blocks were efficiently coupled to the N-terminus of the peptides via solid-phase synthesis. Radiolabeling of the obtained peptide precursors proceeded smoothly under acidic conditions (34-85% conversion). Using the di-tert-butyl silyl building block as labeling moiety, products containing a hydrolytically stable 18F-label were obtained. In in vitro receptor binding experiments 2-(4-(di-tert-butylfluorosilyl)phenyl)acetyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH 2 ( 4b, IC50 = 22.9 nM) displayed a 12-fold higher binding affinity than 2-(4-(di-tert-butylfluorosilyl)phenyl)acetyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 ( 3b, IC50 = 276.6 nM), and 4b was therefore chosen for further evaluation. In vitro and ex vivo metabolite studies of [18F]4b showed no significant degradation. In biodistribution experiments, tumor uptake of [18F]4b was low and unspecific, whereas the GRPr-rich pancreas revealed a high and specific accumulation of the radiotracer. This study demonstrates the applicability of our silicon-based one-step n. c. a. radiolabeling method for the synthesis of new 18F-labeled bombesin derivatives. This innovative approach represents a general, straightforward access to radiolabeled peptides as PET imaging probes.

• Authors: Aileen Höhne, Linjing Mu, Michael Honer, P August Schubiger, Simon M Ametamey, Keith Graham, Timo Stellfeld, Sandra Borkowski, Dietmar Berndorff, Ulrich Klar, Ulrike Voigtmann, John E Cyr, Matthias Friebe, Ludger Dinkelborg, Ananth Srinivasan
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 19 Issue 9 Pg. 1871-9 (Sep 2008) ISSN: 1520-4812 [Electronic] United States
• PMID: 18754574 (Publication Type: Journal Article)

Chemical References

• Fluorine Radioisotopes
• Neurotransmitter Agents
• Receptors, Bombesin
• Bombesin
• Silicon

Topics

• Amino Acid Sequence
• Binding Sites
• Bombesin (analogs & derivatives, chemical synthesis)
• Fluorine Radioisotopes (chemistry)
• Humans
• Isotope Labeling
• Male
• Molecular Sequence Data
• Neurotransmitter Agents (chemical synthesis)
• Positron-Emission Tomography (methods)
• Prostatic Neoplasms (metabolism, pathology)
• Receptors, Bombesin (metabolism)
• Silicon (chemistry, metabolism)
• Substrate Specificity