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

Abstract 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 1H NMR measurements. The determined speciation models consist of M p L q H r species with different stoichiometry. The obtained stability constants for the M L 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 67Ga–citrate. Graphical abstract A new bis-(3-hydroxy-4-pyridinone) ligand, NTA(PrHP) 2 , with illustration of the its metal chelation capacity and selectivity based on the pM values calculated vs. pH for the different Mn+/ligand systems (a, Ca2+ = Image 4 , Cu2+ = Image 3 , Zn2+ = Image 2 , Al3+ = Image 1 , Fe3+ = ○) and its in vivo excretion capacity in animal model (mice overload with 67Ga) (b). Unlabelled Image Highlights • A new bis-(3-hydroxy-4-pyridinone) ligand derived from nitrilotriacetic acid was synthesized. • Its acid-base properties and binding ability towards M2+ and M3+ were investigated. • The sequestration of the ligand towards Mn+ was studied by the determination of pL 0.5 values at different pHs. • Analysis of pM values at pH = 7.4 showed that the metal-ligand affinity follows the trend Fe3+ > Al3+ > Cu2+ > Zn2+ > Ca2+. • Bioassays indicated that the ligand has high in vivo chelating ability towards trivalent metal cations. [ABSTRACT FROM AUTHOR]