Charting the coordinative landscape of the 18 F-Sc/ 44 Sc/ 177 Lu triad with the tri-aza-cyclononane (tacn) scaffold

The widely established PET isotope F does not have a therapeutic partner. We have recently established that the Sc-F bond can be formed under aqueous, high yielding conditions, paving the way to providing F as diagnostic partners to Sc and Lu radiotherapeutics. Here, we synthesized a library of tacn-based chelators comprised of 10 structurally unique permutations incorporating acetate, methyl-benzylamide and picolinate donor arms. The chelator library encompasses chelators ranging from 6- to 9-dentate, and produces complex changes ranging from +3 to -1. The corresponding Sc-F/Sc and Lu chelate complexes were characterized using computational, spectroscopic and potentiometric methods, followed by optimization of radiolabeling with F, Sc and Lu and concluded by validation. We identify characterization benchmarks that chart the coordinative landscape of radiochelation approaches for this unusual triad. Our screening identifies two ligand systems, H L and H L as ideal, readily functionalizable constructs for prospective, targeted theranostic applications with F/ Sc/ Lu.