Abstract
BACKGROUND: The (18)F/(19)F-isotope exchange method employing P(V)-centered prosthetic groups demonstrates advantages in addressing mild one-step aqueous (18)F-labeling of peptides and proteins. However, the molar activity (A(m)) achieved through isotope exchange remains relatively low, unless employing a high initial activity of [(18)F]F(-). To overcome this drawback, our work introduces a novel approach through a Cu-mediated direct (18)F-dehydrofluorination of phosphine oxides. This method leverages the straightforward separation of the (18)F-labeled product from the phosphine oxide precursors, aiming to primarily increase A(m). RESULTS: Through a (19)F-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 A(m) of an activated ester, [(18)F]4, sees an impressive nearly 15-fold increase compared to the (18)F/(19)F-isotope exchange, with the same initial activity of [(18)F]F(-). Furthermore, this Cu(II)-mediated (18)F-dehydrofluorination approach demonstrates tolerance up to 20% solvent water content, which enables the practical radiosynthesis of (18)F-labeled water-soluble molecules under non-drying conditions. CONCLUSIONS: The direct (18)F-dehydrofluorination of phosphine oxide prosthetic groups has been successfully accomplished, achieving a high A(m) via Cu(II)-mediated oxidative addition and reductive elimination.