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 ¹⁸F-fluoride is preferentially used for ¹⁸F-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 ¹⁸F-incorporation as they are metabolically robust and therefore widely used for ¹⁸F-labeling. Nucleophilic fluoride mediated fluorine-18 labeling reaction has emerged as a promising green and efficient synthetic tool and provides a novel approach for ¹⁸F-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(sp²)—H bond. The scope of labeling substrate, some application for radiopharmaceuticals and mechanism of several reactions are also discussed.

Key words: fluorine-18, nucleophilic substitution reaction, labeling reaction, radiopharmaceuticals, positron emission tomography