Recent Progress in Nucleophilic Fluoride Mediated Fluorine-18 Labeling of Arenes and Heteroarenes

Fluorine-18 is the most frequently used radioisotope in positron emission tomography radiopharmaceuticals for both clinical and preclinical researches. A variety of labeling methodologies have also been developed in recent years. For most purposes, nucleophilic F-18-fluoride is preferentially used for F-18-labeling because this reagent is easy to handle and made available with high specific activity. Meanwhile, fluorine substitution has also served the purpose of modulating conformational and stereoelectronic properties, and favorably influences pharmacokinetic parameters such as polarity, lipophilicity and pK(a) values. Arenes and heteroarenes are privileged candidates for F-18-incorporation as they are metabolically robust and therefore widely used for F-18-labeling. Nucleophilic fluoride mediated fluorine-18 labeling reaction has emerged as a promising green and efficient synthetic tool and provides a novel approach for F-18-labeling. The recent developments in nucleophilic fluoride mediated fluorine-18 labeling of arenes and heteroarenes are summarized on the basis of different labeling precursor, including phenols, aryl iodoniums, aryl sulfoniums, aromatic metallic compounds and C(sp(2))-H bond. The scope of labeling substrate, some application for radiopharmaceuticals and mechanism of several reactions are also discussed.

Automated summary

Fluorine-18 is widely used in positron emission tomography radiopharmaceuticals, with nucleophilic F-18 fluoride being a common labeling reagent. Fluorine substitution can impact pharmacokinetic parameters, and arenes and heteroarenes are commonly used candidates for F-18 labeling.