The Radiopharmaceutical Chemistry of Fluorine-18: Next-Generation Fluorinations

Abstract

This chapter introduces “next-generation” methods for radiofluorination reactions with fluorine-18. We will primarily focus on two topics: (1) methods for the 18F-fluorination of heteroatoms and (2) methods for the transition metal-mediated 18F-fluorination of aromatic and allylic carbons. Fluorine forms bonds with several group 13-15 elements, including carbon (obviously), boron, nitrogen, aluminum, silicon, and phosphorous. For example, [18F]fluoride and aluminum form a stable [18F][AlF]2+ complex which can be incorporated into biomolecular targeting vectors using bifunctional chelators such as NOTA and NODA. With boron, [18F]fluoride readily forms organotrifluoroborate salts which can be synthesized using boronic esters in finely controlled carrier-added conditions or via 18F-19F isotopic exchange from trifluoroborate salts of the stable isotope. Both methods can be utilized for the synthesis of 18F-labeled radiopharmaceuticals with high radiochemical yields (RCYs) and high molar activities (GBq/µmol). Shifting gears a bit, transition metals can be used to catalyze the 18F-fluorination of sp2 carbons at aromatic and allylic positions using nucleophilic [18F]fluoride. Selective fluorinations of these positions have been notoriously challenging using conventional radiosynthetic methods, especially when products with high molar activity are needed (see the chapters on “The Radiopharmaceutical Chemistry of Fluorine-18: Nucleophilic Fluorinations” and “The Radiopharmaceutical Chemistry of Fluorine-18: Electrophilic Fluorinations”). Yet novel methods based on palladium- and nickel-aryl complexes as well as copper(II) salts have revolutionized this area, providing access to a wide variety of 18F-fluorinated aromatic and allylic substrates in moderate to high yields and formerly unattainable molar activities (GBq/µmol).