NITROXIDE FREE RADICAL CONTRAST MEDIA FOR NMR IMAGING

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Nuclear magnetic resonance (NMR) imaging is an emerging diagnostic tool capable of providing clinically-useful images without the use of ionizing radiation. Contrast enhancing drugs, used in conjunction with NMR imaging, have been shown to supplement the information yield from images by better localizing and characterizing normal and diseased tissues. The development of NMR contrast agents is in an early stage; NMR contrast agents have been shown to be effective and useful in experimental studies, but no agent has yet met criteria of safety and efficacy for clinical use in humans. The principle aim of this continuing research program is to further test the safety, diagnostic benefits, and pharmacology of nitroxide spin labels (NSL), a group of synthetic, paramagnetic, organic molecules, applies as in vivo contrast agents for NMR imaging. Specific aims include 1) to select and synthesize candidate nonionic and polyradical NSL pharmaceuticals with superior properties of tolerance, relaxivity, and inertness, 2) to conduct extensive toxicological evaluatios of super-selected NSL's in preparation for clinical trials, 3) to continue NSL metabolic studies, including the definition of cellular and extracellular bioreduction pathways, to better apply NSL as extracellular space contrast enhancers and to identify candidate NSL's to be tested as redox-sensitive, metabolic contrast agents, 4) to synthesize and test potentially function-specific NSL contrast agents and 5) to assess the diagnostic efficacy of using NSL for image contrast enhancement in normal and diseased (tumor, inflammatory, ischemic) experimental animals. The proposed investigations require a combination of disciplines including diagnostic imaging, synthetic and analytical chemistry, NMR physics, and pharmacology. Specific techniques to be emphasized will be pulsed nuclear magnetic resonance (NMR), electron paramagnetic resonane (EPR), NMR imaging, and radiotracer detection. Experimental models of neoplastic, inflammatory, and vascular disases and obstructive uropathy will be studied by NMR before and after NSL administration to assess the diagnostic utility of contrast enhancement. The long-term goal is to develop clinically useful NMR contrast agents for use in the diagnosis of human disease.