NITROXIDE FREE RADICAL CONTRAST MEDIA FOR NMR IMAGING

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Nuclear magnetic resonance (NMR) imaging is an emerging diagnostic tool capable of tomographic imaging of humans without the use of ionizing radiation. Two NMR imagers, developed in our department, utilize the magnetic behavior of hydrogen nuclei and depict their distribution and magnetic relaxation characteristic within bodily tissues. The aims of this project are to better define by animal experimentation the diagnostic benefits, the toxicity, and the pharamacology of nitroxide stable free radicals (NSFR) used in vivo as NMR contrast agents. The proposed investigations require the combined disciplines of diagnostic imaging, synthetic chemistry, physics and pharmacology. Preliminary studies in animals show that NSFR, a group of organic paramagnetic compounds used as contrast media can enhance the NMR contrast differences between urinary structures and surrounding tissues and permit evaluation of renal function. Tested NSFR are rapidly excreted by glomerular filtration and appear within urinary structures to produce a dramatic increase in the NMR intensity signal. NSFR, like many radiographic contrast media, are largely excluded from the central nervous system by the normally functioning blood-brain barrier. It is postulated that these contrast media will penetrate into the brain in pathologic conditions and thereby aid in the NMR identification of neurologic diseases. To achieve other organ-specific targetting, NSFR may be covalently conjugated to biomolecules including proteins and lipids. Aggregated particles of NSFR-protein and/or NSFR-liposomes may be diagnostically useful in NMR imaging of the liver and spleen by depicting the functional reticulo- endothelial system. These contrast-enhancing applications of NSFR would substantially add to the diagnostic utility of NMR imaging. Preliminary toxicity studies indicate safety of NSFR. Toxic doses far exceed those necessary for contrast enhancement. The long-term goal is to develop clinically useful NMR contrast agents for use in the diagnosis of human diseases.