Pd0-Mediated Rapid Cross-Coupling Reactions, the Rapid C-[11C]Methylations, Revolutionarily Advancing the Syntheses of Short-Lived PET Molecular Probes

Positron emission tomography is a noninvasive method for monitoring drug (or diagnostic) behavior and its localization on the target molecules in the living systems, including the human body, using a short‐lived positron‐emitting radionuclide. New methodologies for introducing representative short‐lived radionuclides, 11C and 18F, into the carbon frameworks of biologically active organic compounds have been established by developing rapid C‐[11C]methylations and C‐[18F]fluoromethylations using rapid Pd0‐mediated cross‐coupling reactions between [11C]methyl iodide (sp3‐hybridized carbon) and an excess amount of organotributylstannane or organoboronic acid ester having sp2(phenyl, heteroaromatic, or alkenyl), sp(alkynyl), or sp3(benzyl and cinnamyl)‐hybridized carbons; and [18F]fluoromethyl halide (iodide or bromide) and an organoboronic acid ester, respectively. These rapid reactions provide a firm foundation for an efficient and general synthesis of short‐lived 11C‐ or 18F‐labeled PET molecular probes to promote in vivo molecular imaging studies. New synthetic methodologies for introducing short‐lived positron‐emitting radionuclides, 11C and 18F, into the carbon frameworks of biologically active organic compounds have been established by newly developed rapid C‐[11C]methylations and their extension to C‐[18F]fluoromethylations using Pd0‐mediated rapid cross‐coupling reactions of [11C]methyl iodide or [18F]fluoromethyl halides with an excess of organotributylstannanes or organoboronic acid esters. These rapid reactions provide a firm foundation for the efficient and general synthesis of 11C‐ or 18F‐labeled molecular probes to promote PET molecular imaging studies in in vivo systems including humans.