title: 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.affiliation: Center for Radiopharmaceutical Science of ETH, PSI and USZ, Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093 Zurich, Switzerland.
authors.forename: Aileen
authors.initials: A
authors.lastname: Höhne
authors.forename: Linjing
authors.initials: L
authors.lastname: Mu
authors.forename: Michael
authors.initials: M
authors.lastname: Honer
authors.forename: P August
authors.initials: PA
authors.lastname: Schubiger
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
authors.forename: Keith
authors.initials: K
authors.lastname: Graham
authors.forename: Timo
authors.initials: T
authors.lastname: Stellfeld
authors.forename: Sandra
authors.initials: S
authors.lastname: Borkowski
authors.forename: Dietmar
authors.initials: D
authors.lastname: Berndorff
authors.forename: Ulrich
authors.initials: U
authors.lastname: Klar
authors.forename: Ulrike
authors.initials: U
authors.lastname: Voigtmann
authors.forename: John E
authors.initials: JE
authors.lastname: Cyr
authors.forename: Matthias
authors.initials: M
authors.lastname: Friebe
authors.forename: Ludger
authors.initials: L
authors.lastname: Dinkelborg
authors.forename: Ananth
authors.initials: A
authors.lastname: Srinivasan