Broad-scope Syntheses of [11C/18F]Trifluoromethylarenes from Aryl(mesityl)iodonium Salts

Efficient methods for labeling aryl trifluoromethyl groups to provide novel radiotracers for use in biomedical research with positron emission tomography (PET) are keenly sought. We report a broad-scope method for labeling trifluoromethylarenes with either carbon-11 (t(1/2)=20.4 min) or fluorine-18 (t(1/2)=109.8 min) from readily accessible aryl(mesityl)iodonium salts. In this method, the aryl(mesityl)iodonium salt is treated rapidly with no-carrier-added [C-11]CuCF3 or [F-18]CuCF3. The mesityl group acts as a spectator allowing radiolabeled trifluoromethylarenes to be obtained with very high chemoselectivity. Radiochemical yields from aryl(mesityl)iodonium salts bearing either electron-donating or electron-withdrawing groups at meta- or para- position are good to excellent (67-96 %). Ortho-substituted and otherwise sterically hindered trifluoromethylarenes still give good yields (15-34 %). Substituted heteroaryl(mesityl)iodonium salts are also viable substrates. The broad scope of this method was further exemplified by labeling a previously inaccessible target, [C-11]p-trifluoromethylphenyl boronic acid, as a potentially useful labeling synthon. In addition, fluoxetine, leflunomide, and 3-trifluoromethyl-4-aminopyridine, as examples of small drug-like molecules and candidate PET radioligands, were successfully labeled in high yields (69-81 %).

Automated summary

Efficient methods for labeling aryl trifluoromethyl groups using readily accessible aryl(mesityl)iodonium salts have been developed. The labeling can be achieved with either carbon-11 or fluorine-18, resulting in high chemoselectivity and good to excellent radiochemical yields. The method is applicable to a wide range of substrates, including substituted heteroaryl(mesityl)iodonium salts, and has been successfully demonstrated on several drug-like molecules.