A novel family of diketopiperazines as a tool for the study of transport across the blood-brain barrier (BBB) and their potential use as BBB-shuttles.

Introduction Neurodegenerative diseases such as Parkinson and Alzheimer disease, schizophrenia, epilepsy, brain tumors, HIV are pharmaceutical targets located inside the brain. In many cases there are promising compounds for their treatment, however owing to their Blood-Brain Barrier (BBB) transport problems > 98% of these potential drugs do not go to drug development stage. The BBB is a natural defense mechanism designed to keep harmful substances out of the brain. The anatomical bases of the BBB are primarily the tight junctions at the endothelial cells of the brain capillaries. Therefore, possible transport mechanisms are all transcellular. While different transport mechanisms occur at the BBB, this work has focused on the passive diffusion mechanism. We design, synthesize and evaluate the potential use of DKPs as BBB-shuttles for the delivery of cargoes that can not cross the BBB unaided.