title: Direct one-step 18F-labeling of peptides via nucleophilic aromatic substitution.
abstract: Methods for the radiolabeling molecules of interest with [18F]-fluoride need to be rapid, convenient, and efficient. Numerous [18F]-labeled prosthetic groups, e.g., N-succinimidyl 4 [18F]-fluorobenzoate ([18F]-SFB), 4-azidophenacyl-[18F]-fluoride ([18F]-APF), and 1-(3-(2-[18F]fluoropyridin-3-yloxy)propyl)pyrrole-2,5-dione ([18F]-FpyMe), for conjugating to biomolecules have been developed. As the synthesis of these prosthetic groups usually requires multistep procedures, there is still a need for direct methods for the nucleophilic [18F]-fluorination of biomolecules. We report here on the development of a procedure based on the trimethylammonium (TMA) leaving group attached to an aromatic ring and activated with different electron-withdrawing groups (EWGs). A series of model compounds containing different electron-withdrawing substituents, a trimethylammonium leaving group, and carboxylic functionality for subsequent coupling to peptides were designed and synthesized. The optimal model compound, 2-cyano-4-(methoxycarbonyl)-N,N,N-trimethylbenzenaminium trifluoromethanesulfonate, was converted to carboxylic acid and coupled to peptides. The results of the one-step [18F]-fluorination of tetrapeptides and bombesin peptides show that the direct 18F-labeling of peptides is feasible under mild conditions and in good radiochemical yields.
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: Jessica
authors.initials: J
authors.lastname: Becaud
authors.forename: Linjing
authors.initials: L
authors.lastname: Mu
authors.forename: Mylène
authors.initials: M
authors.lastname: Karramkam
authors.forename: Pius A
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: Lutz
authors.initials: L
authors.lastname: Lehmann
authors.forename: Sandra
authors.initials: S
authors.lastname: Borkowski
authors.forename: Dietmar
authors.initials: D
authors.lastname: Berndorff
authors.forename: Ludger
authors.initials: L
authors.lastname: Dinkelborg
authors.forename: Ananth
authors.initials: A
authors.lastname: Srinivasan
authors.forename: René
authors.initials: R
authors.lastname: Smits
authors.forename: Beate
authors.initials: B
authors.lastname: Koksch
mesh_terms: D001555:Benzene Derivatives / Q000737:chemistry*; D005462:Fluorine Radioisotopes / Q000737:chemistry; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D013237:Stereoisomerism; D050337:Trimethyl Ammonium Compounds / Q000737:chemistry*
chemical_list: D001555:Benzene Derivatives; D005462:Fluorine Radioisotopes; D010455:Peptides; D050337:Trimethyl Ammonium Compounds