Seven coordinate Co(ii) and six coordinate Ni(ii) complexes of an aromatic macrocyclic triamide ligand as paraCEST agents for MRI

Abstract

We are reporting Co(ii) and Ni(ii) complexes of a pyridine containing aromatic macrocyclic triamide ligand, 3,6,9,15-tetraazabicyclo(9.3.1)pentadeca-1(15),11,13-triene-3,6,9-triacetamide (TPTA), as paramagnetic chemical exchange saturation transfer (paraCEST) MRI contrast agents. The synthesis and characterization of TPTA and its complexes are reported. The solution chemistry and solid-state structure of Co(ii) and Ni(ii) complexes are studied. Crystallographic data show that the [Co(TPTA)]·Cl₂·2H₂O complex (seven-coordinate, all four N atoms of ring and three amide O atoms) has a distorted pentagonal bipyramidal geometry, however the [Ni(TPTA)Cl]·Cl·0.25H₂O complex (six-coordinate, all four N atoms of the ring, one amide O and one chloride ion) adopts a distorted octahedral geometry. Notably the two pendent amide arms are not coordinated in the [Ni(TPTA)Cl]⁺ complex and one chloride ion fulfils its sixth coordination. The CEST effect of [Co(TPTA)]²⁺ and [Ni(TPTA)Cl]⁺ amide protons is observed at 57 ppm and 78 ppm downfield of the bulk water proton respectively in a buffer solution containing 20 mM N-(2-hydroxyethyl)piperazine-N'-ethanesulfonic acid and 100 mM NaCl at pH 7.4 at 37 °C on a 9.4 T NMR spectrometer. The effects of CEST intensity and exchange rate constant with variation of pH of the solution were studied. The CEST effect and exchange rate constant for the amide protons of the [Co(TPTA)]²⁺ complex have been monitored in HEPES buffer, fetal bovine serum (FBS), rabbit serum and 4% agarose gel (w/w). The stability of the [Co(TPTA)]²⁺ complex in aqueous solution towards oxidation was verified by cyclic voltammetry measurement. The stability of [Co(TPTA)]²⁺ has further been monitored in the presence of biologically relevant ions including HPO₄^2-, CO₃^2-, and Zn²⁺ and under acidic conditions.