Mechanistic insights for the preparation of improved metal-fluoride based radioimaging agents

Metal-fluoride complexes incorporating fluorine-18 are advancing PET imaging, and creating new opportunities for Total Body PET and theranostics, but the factors governing metal-chelator selection, radiofluorination mechanisms, and hydroxide competition remain unclear. Although several Al-¹⁸F tracers based on NOTA and NODA chelators have reached clinical use, mechanistic understanding is limited and has hindered both extension to other metals and chelators and understanding of the relative merits of "one-pot" (radio)fluorination protocols vs. late-stage (radio)fluorination of pre-formed complexes and the design criteria to optimise (radio)metal/¹⁸F tracers for theranostics. Here, density functional theory (DFT) calculations are used to investigate F^-/Cl^- and OH^-/Cl^- substitution in the archetypal [MCl(Bn-NODA)] (M = Al, Ga). These reactions proceed through a concerted one-step pathway involving temporary dissociation of a carboxylate arm and formation of a transient ionic intermediate, as well as a two-step pathway. Hydroxide substitution is exothermic, favouring formation of [M(OH)(Bn-NODA)], and provides insight into hydroxide competition during radiolabelling. Parallel DFT studies reveal how OH^- influences [MF(Bn-NODA)] and radiolabelling efficiency. The computational results align with experimental observations of rapid, late-stage ¹⁸F radiolabelling of pre-formed gallium complexes under mild conditions and provide design principles for developing new metal-fluoride radiotracers for imaging and therapy. More broadly, the study highlights the value of computational screening in guiding the development of a wider range of metal-fluoride-based agents for imaging and therapy.