Fe(III) T 1 MRI Probes Containing Phenolate or Hydroxypyridine-Appended Triamine Chelates and a Coordination Site for Bound Water

Fe­(III) complexes containing a triamine framework and phenolate or hydroxypyridine donors are characterized and studied as T 1 MRI probes. In contrast to most Fe­(III) MRI probes of linear chelates reported to date, the ligands reported here are pentadentate to give six-coordinate complexes with a coordination site for inner-sphere water. The crystal structure of the complex containing unsubstituted phenolate donors, Fe­(L1)­Cl, shows a six-coordinate iron center and contains a chloride ligand that is displaced in water. Two additional derivatives are sufficiently water-soluble for study as MRI probes, including a complex with a hydroxypyridine group, Fe­(L2), and a hydroxybenzoic acid group, Fe­(L3). The pH potentiometric titrations give protonation constants of 7.2 and 7.5 for Fe­(L2) and Fe­(L3), respectively, which are assigned to deprotonation of the bound water. Changes in the electronic absorbance spectra of the complexes as a function of pH are consistent with the deprotonation of phenol pendants at acidic pH values. However, the inner-sphere water ligand of Fe­(L2) and Fe­(L3) does not exchange rapidly on the NMR timescale at pH 6.0 or 7.4, as shown by variable-temperature 17O NMR spectroscopy. The pH-dependent proton relaxivity profiles show a maximum in relaxivity at a near-neutral pH, suggesting that exchange of the protons of the bound water is an important contribution. Competitive binding studies with ethylenediaminetetraacetic acid (EDTA) show effective stability constants for Fe­(L2) and Fe­(L3) at pH 7.4 with log K values of 21.1 and 20.5, respectively. These two complexes are kinetically inert in carbonate phosphate buffer at 37 °C for several hours but transfer iron to transferrin. Fe­(L2) and Fe­(L3) show enhanced contrast in T 1-weighted imaging analyses in BALB/c mice. These studies show that Fe­(L2) clears through mixed renal and hepatobiliary routes, while Fe­(L3) has a similar pharmacokinetic clearance profile to a macrocyclic Gd­(III) contrast agent.