Synthesis of [18F]4-(4-fluorophenyl)-1,2,4-triazole-3,5-dione: an agent for specific radiolabelling of tyrosine.

Objectives: Metal-free and mild tyrosine modification reactions are an attractive alternative to the commonly used lysine and cysteine modification protocols for peptide and proteins labelling. Recently, Ban and co-workers have reported a tyrosine bioconjugation through ene-type reactions. Cyclic diazodicarboxamides, which are electrophilic compounds, react selectively in o-position on the phenol side chain of tyrosine in mild aqueous conditions and the 1,2,4-triazolidine-3,5-dione linkage is hydrolytically and thermally stable.
We herein present the synthesis of [18F]4-(4-fluorophenyl)-1,2,4-triazole-3,5-dione and the coupling with N-acyl tyrosine methylamide.
Methods: The N,N,N-trimethyl-4-nitrobenzeneammonium trifluoromethanesulfonate 1 was prepared following a procedure previously reported [2]. The [18F]prosthetic group 6, [18F]4-(4-fluorophenyl)-1,2,4-triazole-3,5-dione, was synthesized in five steps.
Results: The synthesis of the [18F]prosthetic group has been realized with a decay-corrected radiochemical yield of 20% in 90 minutes. The radiochemical yield of the coupling with N-acyl tyrosine methylamide is 40% (DC). This presented synthetic pathway should be easily automated: particulary because the purifications between the different steps are exclusively done on SPE cartridges.
Conclusions: We successfully developed an efficient bioconjugation method for fluorine-18 labelling of tyrosine without prior modifications of the peptide in very mild conditions.