Kinetically Inert Bispidol-Based Cu(II) Chelate for Potential Application to 64/67Cu Nuclear Medicine and Diagnosis

A family of 2,4-pyridyl-disubstituted bispidol derivatives bearing methylene carboxylic acid ethyl esters (L1–L3), methylene carboxylic acids (L4 and L5), or methylenethiophene (L6) groups were synthesized. In water, all ligands form rigid 1:1 complexes in the presence of Zn­(II) in which the bicycle adopts a chair–chair conformation (cis isomer), as observed by 1H NMR and, in the case of ligand L1, by an X-ray diffraction crystal structure. Interestingly, addition of Zn­(II) ions on ligand L1 induces a metal-mediated selective hydrolysis of the ethyl esters. This selective hydrolysis was not observed upon addition of other cations such as Na+, Mg+, and Ca2+. Reduction of the central ketone was achieved to prevent ring opening via retro Diels–Alder reactions and to afford highly stable and water-soluble ligands (L4, L5, L6). The complexation properties of L4 and L6 were studied in solution, with a particular interest for ligand L4. Fast complexation occurs in strongly acidic media (pH = 1), with a high affinity toward Cu­(II) (log KCuL4 = 19.2(3), pCu = 17.0 at pH 7.4, pCu = −log­[Cufree], [Cu] = 1 × 10–6 M, [L] = 1 × 10–5 M) and high selectivity versus Co­(II), Ni­(II), and Zn­(II), as shown by the values of the binding constants obtained from potentiometric and spectrophotometric titrations. Reversible redox potential with E1/2 = −430 mV (vs normal hydrogen electrode) was measured. The complex was found to be fairly inert from acid-assisted dissociation experiments in 5 M HClO4 (t1/2 = 110 d at 25 °C).