New bis-(3-hydroxy-4-pyridinone)-NTA-derivative: Synthesis, binding ability towards Ca2+, Cu2+, Zn2+, Al3+, Fe3+ and biological assays

A new bis-(3-hydroxy-4-pyridinone) ligand (NTA(PrHP)(2)), derived from nitrilotriacetic acid (NTA), was synthesized and evaluated for its selective solution metal complexation capacity as well as its in vivo sequestering power for hard metal cations. After the study of its acid-base properties and determination of the protonation constants, the binding ability of NTA(PrHP)(2) towards divalent (Ca2+, Cu2+, Zn2+) and trivalent (Al3+, Fe3+) metal cations was investigated by means of UV-Vis spectrophotometric, potentiometric and H-1 NMR measurements. The determined speciation models consist of MpLqHr species with different stoichiometry. The obtained stability constants for the ML species follow the trend: Fe3+ > Al3+ > Cu2+ > Zn2+ > Ca2+. Furthermore, the sequestering ability of the ligand towards these metal cations was investigated by the determination of the pL(0.5) and pM parameters calculated at different pHs and pH = 7.4, respectively. High pL(0.5) values were obtained with significant variation of the sequestering ability with the investigated pH range. Analysis of the pM values at pH = 7.4 showed that the metal-ligand affinity follows the trend: Fe3+ > Al3+ > Cu2+ > Zn2+ > Ca2+. Finally, in vivo assays were performed to verify the efficacy of NTA(PrHP)(2) as sequestering agent towards trivalent metal cations, when administered to mice preloaded with the radiotracer Ga-67-citrate. (C) 2018 Published by Elsevier B.V.