About half of all MRI procedures use agents to better improve contrast between tissues and to increase signal to noise. Nearly all clinically used contrast agents contain gadolinium (as Gd(III)), a paramagnetic lanthanide ion that effectively increases the longitudinal (T1) relaxation rates of water protons to give positive contrast. Yet, currently there is increasing concern over the deposition of Gd(III) ion in skin, bone and brain tissue. This concern has led to interest in alternatives to Gd(III) agents. One alternative is to develop trivalent iron (Fe(III)) coordination complexes as T1 agents. The research proposed here involves the development of the first Fe(III) macrocyclic complexes as MRI contrast agents. The proposed complexes have many advantages over previously reported complexes. For example, the Fe(III) oxidation state is highly stabilized by the macrocyclic ligand in order to prevent reduction to Fe(II) that would produce reactive oxygen species. In addition, ligand donor groups that form extensive hydrogen bonds are chosen to maximize outersphere water relaxivity. Specific goals include: 1) tuning the water exchange rate constant and pKa of Fe(III) water ligands to optimize T1 relaxivity, 2) derivatization of the macrocyclic complexes with benzyloxymethyl and other benzyl groups to produce Fe(III) contrast agents for hepatobiliary uptake and imaging, 3) to increase the rotational correlation time by connecting three Fe(III) complexes to a central linker for the production of even more highly effective contrast agents and 4) to study our lead complexes in mice on a 4.7 T scanner. In vivo MRI studies will monitor the bio-distribution and clearance of the contrast agent over time. Comparison will be made to commercial Gd(III) agents. We anticipate that the development of these Fe(III)T1 MRI contrast agents will open up new applications for contrast agents as well as reach additional patient populations.
Magnetic resonance imaging (MRI) is a non-invasive, non-ionizing imaging procedure that is used extensively in clinical medicine. Nearly half of the procedures use contrast agents that contain gadolinium, yet a substantial proportion of patients in the US population are considered at risk for being given gadolinium contrast agents. Iron complexes that produce contrast by the same mechanism as do the gadolinium MRI contrast agents are proposed as potentially safer alternatives.