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 (H2L1), or phosphinic–phosphonic
acid, −CH2PO2HCH2PO3H2 (H3L2), 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 KCuL = 25.8 and 27.7 for H2L1 and H3L2, respectively). Kinetic study revealed an unusual
three-step complex formation mechanism. The initial equilibrium step
leads to out-of-cage complexes with Cu2+ bound by the phosphorus-containing pendant arm. These species quickly
rearrange to an in-cage complex with cyclam conformation II, which isomerizes to another in-cage complex
with cyclam conformation I. The first in-cage complex is quantitatively formed in seconds (pH ≈5, 25 °C,
Cu:L = 1:1, cM ≈ 1 mM). At pH >12, I isomers undergo nitrogen atom inversion, leading to III isomers; the structure of the III-[Cu­(HL2)] complex in the solid state was
confirmed by X-ray diffraction analysis. In an alkaline solution,
interconversion of the I and III 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 H3L2 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 H2L1 and H3L2 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 H3nota and H4dota 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.