Highly stable acyclic bifunctional chelator for 64Cu PET imaging

Ligand L-1, 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) (Delta 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, appropriate for Cu-64 complexation. As L-1 represents a particularly interesting target within the frame of Cu-64 PET imaging, a synthetic protocol was developed to introduce a labeling function on the pyridyl moiety of L-1, thereby affording L-2, a potential bifunctional chelator (BFC) for PET imaging.