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

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.

“AquaF” Building Blocks for Water-Compatible SN2 18F-Fluorination of Small-Molecule Radiotracers

“…Despite advancements in bulky alkyl-substituted P(O)− 18 F building blocks, achieving high A m values has proven challenging, whether through water-compatible 18 F/ 19 Fexchange 21,32 or Cu(II)-mediated 18 F-dehydrofluorination. 33 The construction of charged P(O/S)− 18 F building blocks, from lipophilic precursors with limited water solubility, tolerated less than 10% solvent water fraction to achieve a satisfactory radiochemical yield (RCY). 34,35 Furthermore, notable uptake in the abdomen has been observed for both bare bulky alkyl-substituted P(O)− 18 F and charged P(S)− 18 F building blocks.…”

“…The high predicted bond dissociation energy of 602 kJ/mol, high stability in the presence of nucleophiles (amines, anilines, and alkoxides) or reductants, , and capacity to enhance hydrophilicity and modulate drug metabolic pathways through the PO moiety underscore the significant potential of P­(O)–F motifs as hydrophilic building blocks. Despite advancements in bulky alkyl-substituted P­(O)– 18 F building blocks, achieving high A m values has proven challenging, whether through water-compatible 18 F/ 19 F-exchange , or Cu­(II)-mediated 18 F-dehydrofluorination . The construction of charged P­(O/S)– 18 F building blocks, from lipophilic precursors with limited water solubility, tolerated less than 10% solvent water fraction to achieve a satisfactory radiochemical yield (RCY). , Furthermore, notable uptake in the abdomen has been observed for both bare bulky alkyl-substituted P­(O)– 18 F and charged P­(S)– 18 F building blocks.…”