Naproxen (Nap) is an NSAID used as a neuroprotective agent to treat several neurodegenerative diseases. The observed limited brain bioavailability of the drug prompted the design of several chemical delivery systems. We report the synthesis and preliminary in vitro and in vivo investigations of Nap prodrugs with dihydropyridine (I) and ascorbic acid (II) through an ester spacer to target specific brain delivery of Nap. The purpose of this study was to determine the brain bioavailability of Nap after oral administration of the prodrugs in rats. The results showed moderate oral bioavailability of prodrugs (AUC = 53-94 $h{cdot}{mu}g/mL$) in rats compared with parent Nap (AUC = 155 $h{cdot}{mu}g/mL$) at equimolar doses. Contrarily, there was a two-fold increase in Nap levels in the brain with the prodrugs compared to parent Nap. The enhanced brain bioavailability may be attributed to the specific carrier system in addition to the reduced percentage of plasma protein binding of Nap. Plasma protein binding of the tested prodrugs was investigated in vitro using equilibrium dialysis. The percentage of plasma free fraction of prodrugs (9-15%) was significantly greater than that of Nap (about 5%) when tested at 20 ${mu}M$, illustrating more available prodrug to cross the blood brain barrier. A significant decrease in gastric ulcerogenicity of the prodrugs compared with parent Nap was also noted. In conclusion, oral dihydropyridine and ascorbate prodrugs for brain site-specific delivery of Nap may be promising candidates for safe, chronic use of NSAIDs for the treatment of neurodegenerative diseases.