Highly stable acyclic bifunctional chelator for ⁶⁴Cu PET imaging

Abstract

Ligand L¹, based on a pyridine scaffold, functionalized by two bis(methane phosphonate)aminomethyl groups, was shown to display a very high affinity towards Cu(II) (log K_CuL=22.7) and selectivity over Ni(II), Co(II), Zn(II) and Ga(III) (Δ log K_ML>4) as shown by the values of the stability constants obtained from potentiometric measurements. Insights into the coordination mode of the ligand around Cu(II) cation were obtained by UV-Vis absorption and EPR spectroscopies as well as density functional theory (DFT) calculations (B3LYP model) performed in aqueous solution. The results point to a pentacoordination pattern of the metal ion in the fully deprotonated [CuL¹]⁶⁻ species. Considering the beneficial thermodynamic parameters of this ligand, kinetic experiments were run to follow the formation of the copper(II) complexes, indicating a very rapid formation of the complex, appropriat e for ⁶⁴Cu complexation. As L¹ represents a particularly interesting target within the frame of ⁶⁴Cu PET imaging, a synthetic protocol was developed to introduce a labeling function on the pyridyl moiety of L¹, thereby affording L², a potential bifunctional chelator (BFC) for PET imaging.