Chemical, radiochemical and biological studies of new gallium(iii) complexes with hexadentate chelators

Abstract

New N₄O₂-donor acyclic chelators 2-[[2-[2-(3,5-dimethylpyrazol-1-yl)ethyl-[2-[(2-hydroxyphenyl)methylamino]ethyl]amino]ethylamino]methyl]phenol (H₂L^pz*,NH) and 2-[[2-[2-[(2-hydroxyphenyl)methylamino]ethyl-(2-pyridylmethyl)amino]ethylamino]methyl]phenol (H₂L^py,NH) were obtained upon introduction of pyridyl or pyrazolyl coordinating units at the central nitrogen atom of diethylenetriamine (dien) and by functionalization of its terminal amines with phenol groups. The coordination behavior of H₂L^pz*,NH and H₂L^py,NH was evaluated towards ^natGa/⁶⁷Ga, aiming to assess their suitability to obtain Ga(III) chelates relevant for biomedical applications. Single crystal X-ray diffraction analysis of the complexes [GaL^pz*,NH](ClO₄) and [GaL^py,NH](ClO₄) confirmed the presence of N₄O₂-hexadentate chelators with the phenoxide groups coordinated cis relatively to the pyridyl/pyrazolyl arms. Unlike [GaL^pz*,NH](ClO₄), [GaL^py,NH](ClO₄) exists in solution as a mixture of isomers, as confirmed by several NMR techniques. The corresponding radiocomplex [⁶⁷GaL^py,NH]⁺ was obtained smoothly in almost quantitative radiochemical yield, contrary to [⁶⁷GaL^pz*,NH]⁺ that seems to be (hemi)labile under the same conditions. [⁶⁷GaL^py,NH]⁺ presents a high in vivo stability and a favourable biodistribution profile in mice. The imine congeners 2-[(E)-2-[2-(3,5-dimethylpyrazol-1-yl)ethyl-[2-[(E)-(2-hydroxyphenyl)methyleneamino]ethyl]amino]ethyliminomethyl]phenol (H₂L^pz*,CN) and 2-[(E)-2-[2-[(E)-(2-hydroxyphenyl)methyleneamino]ethyl-(2-pyridylmethyl)amino]ethyliminomethyl]phenol (H₂L^py,CN) were also evaluated but they did not form complexes compatible for biomedical applications owing to their high reactivity.