Direct One-Step18F-Labeling of Peptides via Nucleophilic Aromatic Substitution

Methods for the radiolabeling molecules of interest with [(18)]-fluoride need to be rapid, convenient, and efficient. Numerous [F-18]-labeled prosthetic groups, e.g., N-succinimidyl 4 [F-18]-fluorobenzoate ([F-18]-SFB), 4-azidophenacyl-[F-18]-fluoride ([F-18]-APF), and 1-(3-(2-[F-18]fluoropyridin-3-yloxy)propyl)pyrrole-2,5-dione ([F-18]-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 [F-18]-fluorination of biomolecules. We report here on the development of a procedure based on the trimethylammonium (TMA) leaving group attached to in 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 [F-18]-fluorination of tetrapeptides and bombesin peptides show that the direct F-18-labeling of peptides is feasible under mild conditions and in good radiochemical yields.