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