title: Studies toward the development of new silicon-containing building blocks for the direct (18)F-labeling of peptides.
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.
authors.affiliation: 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.
authors.forename: Lukas O
authors.initials: LO
authors.lastname: Dialer
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Selivanova
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Müller
authors.forename: Adrienne
authors.initials: A
authors.lastname: Müller
authors.forename: Timo
authors.initials: T
authors.lastname: Stellfeld
authors.forename: Keith
authors.initials: K
authors.lastname: Graham
authors.forename: Ludger M
authors.initials: LM
authors.lastname: Dinkelborg
authors.forename: Stefanie D
authors.initials: SD
authors.lastname: Krämer
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.forename: Markus
authors.initials: M
authors.lastname: Reiher
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
mesh_terms: D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics; D004355:Drug Stability; D005462:Fluorine Radioisotopes; D064593:Heterografts; D006801:Humans; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism; D010455:Peptides / Q000737:chemistry*; D049268:Positron-Emission Tomography; D011789:Quantum Theory; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000493:pharmacokinetics; D018004:Receptors, Bombesin / Q000378:metabolism; D012821:Silanes / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D010455:Peptides; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D012821:Silanes; D001839:Bombesin