Copper-Mediated Radiofluorination of Arylstannanes with [¹⁸F]KF

Abstract

A copper-mediated nucleophilic radiofluorination of aryl- and vinylstannanes with [18F]KF is described. This method is fast, uses commercially available reagents, and is compatible with both electron-rich and electron-deficient arene substrates. This method has been applied to the manual synthesis of a variety of clinically relevant radiotracers including protected [18F]F-phenylalanine and [18F]F-DOPA. In addition, an automated synthesis of [18F]MPPF is demonstrated that delivers a clinically validated dose of 200 ± 20 mCi with a high specific activity of 2400 ± 900 Ci/mmol.

Synthesis of [18F]Fluoroarenes by Nucleophilic Radiofluorination of N‐Arylsydnones

“…[5] Fluorination with the radioisotope fluorine-18 has in turn significantly expanded the scope and diversity of 18 F-labeled small molecules. [4, 6] These metal-mediated methods offer approaches to previously inaccessible 18 F-labeled aromatics, thus increasing the potential radiochemical space for pre-clinical or clinical PET. [7] However, many methods rely on stoichiometric quantities of transition metals to forge the carbon-fluorine bond, require complex starting materials, or suffer from competing protonation side-reactions.…”

Radiosynthesis of the norepinephrine transporter tracer [18F]NS12137 via copper‐mediated 18F‐labelling

“…Several methods have recently been introduced to improve nucleophilic 18 F‐labelling reactions; for example, the use of iodonium or sulfonium salts enables 18 F‐labelling of nonactivated aromatic compounds. Recently, a new pathway, termed transition metal–mediated 18 F‐fluorination, was introduced to produce 18 F‐labelled arenes with high A m s . This transition metal–mediated synthesis pathway is based on the use of cyclotron‐produced [ 18 F]F − .…”

“…This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. was introduced to produce 18 F-labelled arenes with high A m s. [11][12][13][14][15][16][17][18][19][20] This transition metal-mediated synthesis pathway is based on the use of cyclotron-produced [ 18 F]F − . In 2011, Lee et al 11 reported the use of palladium complexes in 18 F-labelling reactions, but due to the moisture-sensitive nature of these complexes, a more convenient labelling method was still needed.…”

“…[13][14][15][16][17] In 2013, Ye and Sanford 21 reported the mild copper-mediated fluorination of aryl stannanes and aryl trifluoroborates. Soon thereafter, Tredwell et al 18 used this method for radiofluorination with [ 18 F] KF starting from aryl boronic esters, and Mossine et al 19 used it starting from boronic acids and Makaravage et al 20 starting from aryl stannanes. Copper-mediated radiofluorination shows great promise as a suitable method for producing clinical tracers.…”

Effect of Pyridine Addition on the Efficiency of Copper‐Mediated Radiofluorination of Aryl Pinacol Boronates

“…Using a different approach, the Cu(OTf) 2 (py) 4 catalyst can be generated in situ from copper triflate in the presence of an excess of pyridine. The utility of Cu(OTf) 2 as a copper source has been recently demonstrated by high‐yield radiofluorinations of a series of organoboron compounds, including aryl‐ and vinyl‐boronic acids and pinacol esters of arylboronic acids, as well as application of the methodology to arylstannanes (Scheme , B) . The radiofluorination reaction was optimized by using K[ 18 F]F − /KOTf/K 2 CO 3 as a source of nucleophilic 18 F‐fluoride ,.…”