The overall goal of this project is to develop new inhibitors of phosphodiesterase 5 that are suitable for use in diseases of the central nervous system and possess the selectivity required for chronic administration to an elderly population with comorbid conditions, such as people affected by Alzheimer's disease. This project is directly derived from our previous studies demostrating that upregulation of the NO cascade and elevation of cGMP levels through inhibitors of phosphodiesterase 5 is beneficial against synaptic dysfunction and memory loss in the APP/PS1 amyloid-depositing mouse model.