In the past two decades, magnetic resonance imaging (MRT) has revolutionized diagnostic medicine. MRI enables the acquisition of high resolution, three-dimensional images in the detection of a wide variety of physical abnormalities and recent advances in dynamic MRJ show the prospect of real-time imaging. About 30 percent of MRI scans are now acquired using a paramagnetic contrast agent, which enhances the image quality. Gadolinium complexes are most widely used and these complexes currently are all based on a poly(aminoearboxylate) ligand scaffold . 'While effective, the water proton relaxivity of these agents are only a few percent of that theoretically possible. Attachment of the agent to macromolecules, either synthetic or in vivo biomolecules, can increase the relaxivity by lowering the rotational correlation time but the rate of water exchange from the gadolinium center then becomes the limiting factor. We have a new family of gadolinium complexes (based on a hexadentate hydroxypyridonate ligand scaffold) that are stable and have substantially higher relaxivity than most poly(amino-carboxylate) complexes due to a water exchange rate about two orders of magnitude higher. The main objective of this project is to synthesize a novel series of Gd(III) MRI contrast agents for different diagnostic needs through selective structural modifications of the hexadentate ligand scaffold. The solution properties, including stability, will be assessed and the fundamental physical chemistry of their relaxivity explored in collaborative studies. Other collaborative studies will investigate initial biodistribution and toxicity screening (with a cell assay) and further studies will be done in a mouse or rat model. Our ultimate goal is to develop second generation MRI contrast agents with greater accuracy and specificity than those currently available or theoretically possible based on amino carboxylate ligands. These second generation agents will be made by introducing a new Gd complex unit that enables relaxivity of one or two orders of magnitude greater than what is routine today.
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