Aging is often accompanied by a deterioration of learning and memory processes, a condition now referred to as mild cognitive impairment (MCI). Recent studies have indicated that 12% of patients afflicted with MCI will develop Alzheimer's disease, as opposed to 2% of the general population. Although the causes underlying MCI are not known, there is much evidence implicating oxidative damage. Eukarion has developed a class of low molecular weight molecules that are catalytic scavengers of reactive oxygen species (ROS), acting as mimics for the endogenous antioxidant enzymes superoxide dismutase (SOD) and catalase. These compounds are effective in many models for neurological and other classes of diseases. During Phase I of this STTR grant, two of these compounds, EUK-189 and EUK-207, were tested for their activity in preventing age-related loss of cognitive function and accumulation of oxidative stress in mice of early middle age" (8 to 11 months). Both improved cognitive performance and reduced several indicators of oxidative stress in the brain. These Phase I data support further investigation of these compounds as therapeutic agents for MCI and, potentially, for age-related neurodegenerative disease in humans. Phase II research will focus on further testing the two compounds in age-related loss of cognitive performance and on conducting key preclinical research to select one for more advanced preclinical research leading to an Investigational New Drug (IND) application for a chronic neurodegenerative disorder. Specific aims will (1) produce scale-up batches of both compounds under "near-GMP: conditions; in mice, test effects of long-term dosing, and lower doses, of compounds on (2) cognitive impairment, (3) brain oxidative stress, (4) drug and Mn levels, and (5) toxicology assessments; and (6) investigate potential chronic dosing methods for use in the clinic. (7) Based on these data, a lead compound will be selected toward the end of Phase II, and formal preclinical work will commence.