Five azidothymidine (AZT) prodrugs conjugated with the 1-adamantane moiety or the acyl group via an ester bond were evaluated as the brain-directed prodrug in rats. All the prodrugs showed the high lipophilicity and four of them were rapidly degraded to AZT in both plasma and brain homogenates. Adamantanecarbonyl-AZT (Ada-AZT2) was stable in both plasma and brain homogenates. After intravenous bolus administration of the prodrugs, improved brain AZT levels were observed only in acetyl-AZT (C2-AZT) and decanoyl-AZT (C10-AZT). Ada-AZT2 was highly delivered to the brain in the early time point but was rapidly cleared and the generation of AZT was not observed in the brain. The favorable nature for brain-targeted prodrugs was discussed.
