title: 3,4,6-Tri-O-acetyl-2-deoxy-2-[18F]fluoroglucopyranosyl phenylthiosulfonate: a thiol-reactive agent for the chemoselective 18F-glycosylation of peptides.
abstract: 3,4,5-Tri-O-acetyl-2-[18F]fluoro-2-deoxy-d-glucopyranosyl 1-phenylthiosulfonate (Ac3-[18F]FGlc-PTS) was developed as a thiol-reactive labeling reagent for the site-specific 18F-glycosylation of peptides. Taking advantage of highly accessible 1,3,4,6-tetra-O-acetyl-2-deoxy-2-[18F]fluoroglucopyranose, a three-step radiochemical pathway was investigated and optimized, providing Ac3-[18F]FGlc-PTS in a radiochemical yield of about 33% in 90 min (decay-corrected and based on starting [18F]fluoride). Ac3-[18F]FGlc-PTS was reacted with the model pentapeptide CAKAY, confirming chemoselectivity and excellent conjugation yields of >90% under mild reaction conditions. The optimized method was adopted to the 18F-glycosylation of the alphavbeta3-affine peptide c(RGDfC), achieving high conjugation yields (95%, decay-corrected). The alphavbeta3 binding affinity of the glycosylated c(RGDfC) remained uninfluenced as determined by competition binding studies versus 125I-echistatin using both isolated alphavbeta3 and human umbilical vein endothelial cells (Ki = 68 +/- 10 nM (alphavbeta3) versus Ki = 77 +/- 4 nM (HUVEC)). The whole radiosynthetic procedure, including the preparation of the 18F-glycosylating reagent Ac3-[18F]FGlc-PTS, peptide ligation, and final HPLC purification, provided a decay-uncorrected radiochemical yield of 13% after a total synthesis time of 130 min. Ac3-[18F]FGlc-PTS represents a novel 18F-labeling reagent for the mild chemoselective 18F-glycosylation of peptides indicating its potential for the design and development of 18F-labeled bioactive S-glycopeptides suitable to study their pharmacokinetics in vivo by positron emission tomography (PET).
authors.affiliation: Laboratory of Molecular Imaging, Clinic of Nuclear Medicine, Friedrich-Alexander University, 91054 Erlangen, Germany. olaf.prante@nuklear.imed.uni-erlangen.de
authors.forename: Olaf
authors.initials: O
authors.lastname: Prante
authors.forename: Jürgen
authors.initials: J
authors.lastname: Einsiedel
authors.forename: Roland
authors.initials: R
authors.lastname: Haubner
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
authors.forename: Torsten
authors.initials: T
authors.lastname: Kuwert
authors.forename: Simone
authors.initials: S
authors.lastname: Maschauer
mesh_terms: D000107:Acetylation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D019788:Fluorodeoxyglucose F18 / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013450:Sulfones / Q000737:chemistry*
chemical_list: D010455:Peptides; D013438:Sulfhydryl Compounds; D013450:Sulfones; D019788:Fluorodeoxyglucose F18