NOTA Complexes with Copper(II) and Divalent Metal Ions: Kinetic and Thermodynamic Studies

H₃nota derivatives are among the most studied macrocyclic ligands and are widely used for metal ion binding in biology and medicine. Despite more than 40 years of chemical research on H₃nota, the comprehensive study of its solution chemistry has been overlooked. Thus, the coordination behavior of H₃nota with several divalent metal ions was studied in detail with respect to its application as a chelator for copper radioisotopes in medical imaging and therapy. In the solid-state structure of the free ligand in zwitterionic form, one proton is bound in the macrocyclic cavity through a strong intramolecular hydrogen-bond system supporting the high basicity of the ring amine groups (log K_a = 13.17). The high stability of the [Cu(nota)]^- complex (log K_ML = 23.33) results in quantitative complex formation, even at pH <1.5. The ligand is moderately selective for Cu(II) over other metal ions (e.g., log K_ML(Zn) = 22.32 and log K_ML(Ni) = 19.24). This ligand forms a more stable complex with Mg(II) than with Ca(II) and forms surprisingly stable complexes with alkali-metal ions (stability order Li(I) > Na(I) > K(I)). Thus, H₃nota shows high selectivity for small metal ions. The [Cu(nota)]^- complex is hexacoordinated at neutral pH, and the equatorial N₂O₂ interaction is strengthened by complex protonation. Detailed kinetic studies showed that the Cu(II) complex is formed quickly (millisecond time scale at c_Cu ≈ 0.1 mM) through an out-of-cage intermediate. Conversely, conductivity measurements revealed that the Zn(II) complex is formed much more slowly than the Cu(II) complex. The Cu(II) complex has medium kinetic inertness (τ_1/2 46 s; pH 0, 25 °C) and is less resistant to acid-assisted decomplexation than Cu(II) complexes with H₄dota and H₄teta. Surprisingly, [Cu(nota)]^- decomplexation is decelerated in the presence of Zn(II) ions due to the formation of a stable dinuclear complex. In conclusion, H₃nota is a good carrier of copper radionuclides because the [Cu(nota)]^- complex is predominantly formed over complexes with common impurities in radiochemical formulations, Zn(II) and Ni(II), for thermodynamic and, primarily, for kinetic reasons. Furthermore, the in vivo stability of the [Cu(nota)]^- complex may be increased due to the formation of dinuclear complexes when it interacts with biometals.