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

Abstract

The widely established PET isotope ¹⁸F 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 ¹⁸F as diagnostic partners to ⁴⁷Sc and ¹⁷⁷Lu 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 ¹⁸F, ⁴⁴Sc and ¹⁷⁷Lu and concluded by in vivo validation. We identify characterization benchmarks that chart the coordinative landscape of radiochelation approaches for this unusual triad. Our screening identifies two ligand systems, H₂L¹¹¹ and H₃L²⁰¹ as ideal, readily functionalizable constructs for prospective, targeted theranostic applications with ¹⁸F/⁴⁴Sc/¹⁷⁷Lu.