Cyclam Derivatives with a Bis(phosphinate) or a Phosphinato-Phosphonate Pendant Arm: Ligands for Fast and Efficient Copper(II) Complexation for Nuclear Medical Applications
Abstract
Cyclam derivatives bearing one geminal bis(phosphinic acid), -CH2PO2HCH2PO2H2 (H2L_1), or phosphinic-phosphonic acid, -CH2PO2HCH2PO3H2 (H3L_2), 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 K(CuL) = 25.8 and 27.7 for H2L_1 and H3L_2, respectively).
Kinetic study revealed an unusual threestep complex formation mechanism. Quantum-chemical calculations showed small energetic differences between the isomeric complexes of H3L_2 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 H2L_1 and H3L_2 with (64)Cu was fast and efficient, even at room temperature, giving specific activities of around 70 GBq of (64)Cu per 1 μmol of the ligand (pH 6.2, 10 min, ca. 90 equiv of the ligand).
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.