Octahedral iron coordination cages as T1 MRI probes

Project summary MRI contrast agents that contain biologically relevant metal ions such as iron are of interest as alternatives for gadolinium-based contrast agents. Self-assembled Fe(III) coordination cages are a promising class of compounds for development as T1 MRI probes. Coordination cages have the advantage of being kinetically robust towards dissociation in aqueous solution and produce high proton relaxivity from the tightly connected Fe(III) centers to increase the molecular orientation time in solution. Specific aims include the preparation of a class of octahedral iron coordination cages containing acylhydrazone linkages and six high-spin Fe(III) centers. Four derivatives will be prepared including one with sulfonate or carboxylate substituents on the phenolate groups to increase the charge and solubility of the complexes. Neutral methoxy-substituents will be prepared to increase aqueous solubility of the parent octahedral cages without the addition of charge. Finally, the conjugation of amino acids to the phenolate groups will be explored as a more advanced and versatile type of derivatization. Longitudinal and transverse proton relaxation of bulk water will be studied for all new iron coordination cages which will also be characterized by magnetic susceptibility, mass spectrometry and x-ray crystallography. Diamagnetic Ga(III) analogs will be prepared to further study the properties of the cages by using NMR spectroscopy. Binding of the Fe(III) cages to serum albumins and determination of the mode of binding by relaxivity studies in the presence of competitive binders will be explored to better understand how to modulate these interactions. The most promising water-soluble cages will be studied by dynamic magnetic resonance contrast imaging in mice containing subcutaneous CT26 tumors. Long-term objectives include the development of this new class of MRI probes that have versatile scaffolds for functionalization towards tissue targeting and drug encapsulation.