Cu(II)-Mediated direct 18F-dehydrofluorination of phosphine oxides in high molar activity

Abstract

Abstract Background The 18F/19F-isotope exchange method employing P(V)-centered prosthetic groups demonstrates advantages in addressing mild one-step aqueous 18F-labeling of peptides and proteins. However, the molar activity (Am) achieved through isotope exchange remains relatively low, unless employing a high initial activity of [18F]F−. To overcome this drawback, our work introduces a novel approach through a Cu-mediated direct 18F-dehydrofluorination of phosphine oxides. This method leverages the straightforward separation of the 18F-labeled product from the phosphine oxide precursors, aiming to primarily increase Am. Results Through a 19F-dehydrofluorination efficiency test, Cu(OAc)2 was identified as the optimal oxidative metal salt, exhibiting a remarkable 100% conversion within one hour. Leveraging the straightforward separation of phosphine oxide precursors and phosphinic fluoride products, the Am of an activated ester, [18F]4, sees an impressive nearly 15-fold increase compared to the 18F/19F-isotope exchange, with the same initial activity of [18F]F−. Furthermore, this Cu(II)-mediated 18F-dehydrofluorination approach demonstrates tolerance up to 20% solvent water content, which enables the practical radiosynthesis of 18F-labeled water-soluble molecules under non-drying conditions. Conclusions The direct 18F-dehydrofluorination of phosphine oxide prosthetic groups has been successfully accomplished, achieving a high Am via Cu(II)-mediated oxidative addition and reductive elimination.