Exploring Metal-Fluoride Bonding and Fluorine-18 Radiolabeling of Zr(IV)-Based Complexes Targeting the Prostate-Specific Membrane Antigen.

The formation of discrete metal-fluoride bonds represents a promising strategy for the late-stage introduction of 18F-radioactivity to create targeted positron-emitting cancer imaging agents. This approach typically involves the coordination of [18F]fluoride to metal ion complexes that retain a vacant and accessible coordination site. While trivalent metal ions such as Al3+, Ga3+, and Sc3+ have shown promise due to their high fluoride affinity, experimental exploration of metal-fluoride bonding remains limited in scope with respect to metal ions used. According to standard tables of thermodynamic data on bond enthalpies, zirconium(IV) ions exhibit one of the highest reported affinities for fluoride, making Zr(IV) complexes promising candidates for developing new 18F-labeled radiotracers featuring [18F]ZrF bonds. Here, we investigated both the macroscopic (nonradioactive) and radiochemical behavior of the Zr(EDTA) complex with fluoride (or [18F]fluoride) ions. A combination of experimental and computational methods including electronic absorption spectroscopy, 19F NMR studies, isothermal titration calorimetry, density functional theory calculations, and 18F-radiochemical experiments confirmed that the Zr-F bond does form with the Zr(EDTA) complex in aqueous conditions. However, the [ZrF(EDTA)(OH2)]- complex is unstable with respect to fluoride exchange with the solvent. 18F-radiolabeling control reactions using metal-ion-free EDTA or RESCA derivatives revealed highly unusual behavior in which fluoride ions formed a tight ion pair with the chelating unit.