Defining the conditions for the development of the emerging class of Fe^III-based MRI contrast agents

Abstract

An integrated 1H and 17O NMR relaxometric study on model systems allowed to highlight that the Fe(III) complexes might represent the best alternative to Gd-based MRI contrast agents at the magnetic fields of current and future clinical scanners.

Liposomal Fe(III) Macrocyclic Complexes with Hydroxypropyl Pendants as MRI Probes

“…The decrease in r 1 relaxivity with increasing pH for LipoB1 is consistent with acid-catalyzed proton exchange contributions of the hydroxypropyl groups on the exterior of the liposome. Such proton exchange contributions to relaxivity have been observed for Gd­(III) complexes with hydroxy pendants and for Fe­(III) aquo complex . A liposome-based Gd­(III) system reported previously showed a pronounced increase of the water proton relaxation rates at acidic pH .…”

“…41 Full field strength dependence in the form of nuclear magnetic dispersion (NMRD) studies on iron coordination complexes are scarce, but increasing interest in Fe(III) contrast agents has brought renewed effort in this endeavor. 45,56,57 An explanation for the trend for Fe(III) complexes is that the relatively fast electronic relaxation times of the Fe(III) centers are better suited for the higher field strengths that are studied here. 58 On the other hand, the r 2 relaxivity of LipoA increases substantially at 9.4 T. The increase of r 2 relaxivity with field strength is predicated on the large field strength dependence of the magnetic susceptibility contribution to r 2 .…”

“…Such proton exchange contributions to relaxivity have been observed for Gd(III) complexes with hydroxy pendants 64 and for Fe(III) aquo complex. 45 A liposome-based Gd(III) system reported previously showed a pronounced increase of the water proton relaxation rates at acidic pH. 65 For LipoA, the proton relaxivity also increases with a decrease in pH, but the shape of the pH profile is convex.…”

“…29,44 Such classical Fe(III) complexes have been recently analyzed in detail through nuclear magnetic dispersion studies and theoretical calculations to elucidate contributions to proton relaxivity. 45 Two different types of liposomes are studied here, including LipoA with internally loaded Fe(III) coordination complex and LipoB with internally loaded Fe(III) complex and an amphiphilic Fe(III) complex that incorporates into the bilayer. 17 Two of the Fe(III) complexes lack inner-sphere water 42 but have protons on the hydroxypropyl groups to facilitate second-sphere water interactions or proton exchangebased T 1 relaxation.…”

“…The coordination complexes studied here are members of a new class of high spin Fe­(III) complexes with macrocyclic ligands that are effective T 1 MRI probes. ,, Members of this class of compounds produce r 1 relaxivity values that are comparable to Gd­(III) agents in serum and show enhanced contrast in mice at 4.7 T . These macrocyclic complexes are part of a larger recent effort to develop Fe­(III) coordination complexes as alternatives to the current clinically used Gd­(III) contrast agents. , Some of the new Fe­(III) contrast agents lack an exchangeable water ligand yet still show pronounced r 1 proton relaxivity through second-sphere interactions. , The better-known Fe­(III) coordination complexes that are seven-coordinate and contain linear polyaminocarboxylate ligands and an exchangeable inner-sphere water ligand have been studied for many years; , however, improved derivatives have been recently reported. , Such classical Fe­(III) complexes have been recently analyzed in detail through nuclear magnetic dispersion studies and theoretical calculations to elucidate contributions to proton relaxivity …”