Direct one-step 18F-labeling of peptides via nucleophilic aromatic substitution.
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.
Becaud
Jessica
J
Center for Radiopharmaceutical Science of ETH, PSI and USZ, Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093 Zurich, Switzerland.
Mu
Linjing
L
Karramkam
Mylène
M
Schubiger
Pius A
PA
Ametamey
Simon M
SM
Graham
Keith
K
Stellfeld
Timo
T
Lehmann
Lutz
L
Borkowski
Sandra
S
Berndorff
Dietmar
D
Dinkelborg
Ludger
L
Srinivasan
Ananth
A
Smits
René
R
Koksch
Beate
B
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*
D001555:Benzene Derivatives; D005462:Fluorine Radioisotopes; D010455:Peptides; D050337:Trimethyl Ammonium Compounds