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 <i>K</i>_a = 13.17). The high stability of the [Cu­(nota)]⁻ complex (log <i>K</i>_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 <i>K</i>_ML(Zn) = 22.32 and log <i>K</i>_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 <i>c</i>_Cu ≈ 0.1 mM) through an <i>out-of-cage</i> 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

Cyclam Derivatives with a Bis(phosphinate) or a Phosphinato–Phosphonate Pendant Arm: Ligands for Fast and Efficient Copper(II) Complexation for Nuclear Medical Applications

Cyclam derivatives bearing one geminal bis­(phosphinic acid), −CH₂PO₂HCH₂PO₂H₂ (H₂<b>L</b>^<b>1</b>), or phosphinic–phosphonic acid, −CH₂PO₂HCH₂PO₃H₂ (H₃<b>L</b>^<b>2</b>), pendant arm were synthesized and studied as potential copper­(II) chelators for nuclear medical applications. The ligands showed good selectivity for copper­(II) over zinc­(II) and nickel­(II) ions (log <i>K</i>_CuL = 25.8 and 27.7 for H₂<b>L</b>^<b>1</b> and H₃<b>L</b>^<b>2</b>, respectively). Kinetic study revealed an unusual three-step complex formation mechanism. The initial equilibrium step leads to <i>out-of-cage</i> complexes with Cu²⁺ bound by the phosphorus-containing pendant arm. These species quickly rearrange to an <i>in-cage</i> complex with cyclam conformation <b>II</b>, which isomerizes to another <i>in-cage</i> complex with cyclam conformation <b>I</b>. The first <i>in-cage</i> complex is quantitatively formed in seconds (pH ≈5, 25 °C, Cu:L = 1:1, <i>c</i>_M ≈ 1 mM). At pH >12, <b>I</b> isomers undergo nitrogen atom inversion, leading to <b>III</b> isomers; the structure of the <b>III</b>-[Cu­(H<b>L</b>^<b>2</b>)] complex in the solid state was confirmed by X-ray diffraction analysis. In an alkaline solution, interconversion of the <b>I</b> and <b>III</b> isomers is mutual, leading to the same equilibrium isomeric mixture; such behavior has been observed here for the first time for copper­(II) complexes of cyclam derivatives. Quantum-chemical calculations showed small energetic differences between the isomeric complexes of H₃<b>L</b>^<b>2</b> compared with analogous data for isomeric complexes of cyclam derivatives with one or two methylphosphonic acid pendant arm(s). Acid-assisted dissociation proved the kinetic inertness of the complexes. Preliminary radiolabeling of H₂<b>L</b>^<b>1</b> and H₃<b>L</b>^<b>2</b> with ⁶⁴Cu was fast and efficient, even at room temperature, giving specific activities of around 70 GBq of ⁶⁴Cu per 1 μmol of the ligand (pH 6.2, 10 min, ca. 90 equiv of the ligand). These specific activities were much higher than those of H₃<b>nota</b> and H₄<b>dota</b> complexes prepared under identical conditions. The rare combination of simple ligand synthesis, very fast copper­(II) complex formation, high thermodynamic stability, kinetic inertness, efficient radiolabeling, and expected low bone tissue affinity makes such ligands suitably predisposed to serve as chelators of copper radioisotopes in nuclear medicine