Nitric Oxide Synthases are a family of enzymes which produce nitric oxide and citrulline from the oxidative decomposition of arginine. Three isoforms of the enzyme have been isolated. Two of these, found in brain and vascular endothelial tissue (bNOS and eNOS) are constitutive and dependent on calcium influx and the presence of calmodulin. The third (iNOS) is an inducible enzyme, not dependent on calcium/calmodulin, and found macrophages, where the nitric oxide released has cytotoxic functions. Nitric oxide formed in the CNS appears to function as a neurotransmitter, a possible retrograde messenger linked to cGMP. Neurons, which are sensitive to nitric oxide, have been found in respiratory, digestive and GU tissues. Nitric oxide generated in vascular endothelial tissues plays a role in regulation of blood pressure through vasodilation. This work involves the discovery and synthesis of compounds which inhibit any or all isoforms of the enzyme and have potential utility as imaging agents for positron emission tomography. A number of compounds from the literature are known inhibitors and a portion of ongoing research focuses on modification of one or more of these in a way to allow facile introduction of a short-lived radiolabel. Virtually all of this research nucleates around strategic synthetic design and elaboration of arginine, glutamic acid and/or ornithine into modified arginines. Another portion of this investigation has produced a new class of compounds as potential Nitric Oxide Synthase inhibitors. These are designed to irreversibly bind to the enzyme but have not yet been evaluated for biological function.
