Here we prepared and evaluated two libraries of mono-N-methylated and di-N-methylated diketopiperazines (DKPs) by parallel artificial membrane permeability assay and immobilized artificial membrane chromatography in order to obtain information on the features that govern the passage of peptidic molecules across the blood-brain barrier (BBB) by passive diffusion. On the basis of the results from these two libraries, we prepared and evaluated several DKP-baicalin and DKP-dopamine constructs. The DKPs or cyclic dipeptide scaffolds can be considered a novel family of brain delivery systems (BBB-shuttles) to transport to the brain drugs and other cargos that cannot cross the BBB unaided.