Pd0-Mediated Rapid C-[18F]Fluoromethylation by the Cross-Coupling Reaction of a [18F]Fluoromethyl Halide with an Arylboronic Acid Ester: Novel Method for the Synthesis of a 18F-Labeled Molecular Probe for Positron Emission Tomography

Pd-0-Mediated C-[F-18]fluoromethylation of pinacolborane-substituted benzoate 1 and [F-18]FCH2X (X = Br or I) has been carried out with a focus on the rapid incorporation of a [F-18]fluoromethyl group into an aryl carbon framework. The reaction of 1 and [F-18]FCH2I under the conditions of [Pd-2(dba)(3)]/P(o-CH3C6H5)(3) (1:6) and K2CO3 in DMF at 65 degrees C for 5 min afforded the [F-18]fluoromethylated benzoate [F-18]-2 in 23% HPLC analytical yield. The coupling efficiency was significantly enhanced by the reaction of 1 and [F-18]FCH2Br under the conditions of [Pd-2(dba)(3)]/P(o-tolyl)(3) (1:6) and K2CO3 in DMPU:H2O (9:1) at 120 degrees C within 15 min to afford [F-18]-2 in 64% HPLC analytical yield (up to 86% HPLC analytical yield when strictly controlling the reaction temperature with +/- 3 degrees C accuracy) and 66% decay-corrected isolated yield based on [F-18]FCH2Br. The total synthesis time starting from the production of F-18(-) in the cyclotron was 88 min. The reaction was extended to various aryl compounds.