RESUMO
Alzheimer's disease (AD) affects 10% of people older than 65 and is characterized by a progressive loss of cognitive function with an abnormal accumulation of amyloid ß (Aß ) plaques and neurofibrillary tangles (NFT) in the brain. Efforts to reduce brain Aß plaques continue to be investigated as a therapeutic approach for AD. We report here development of dual targeting agents with affinity for Aß plaque/P-glycoprotein (Pgp) and Aß plaque/α4ß 2* nicotinic acetylcholine receptors (nAChR). These novel dual agents may be able to efflux Aß plaques via the paravascular (glymphatic) pathways. Ferulic acid (FA), ferulic acid ethyl ester (FAEE), and curcumin (CUR) were used for Aß plaques, fexofenadine (FEX) was used as substrate for Pgp and nifrolidine (NIF) was used for α4ß 2* nAChRs. Aß plaque/α4ß 2* nAChR dual agent, FA-NIF (GKS-007) exhibited IC50 = 3-6 nM for α4ß 2* nAChRs in [3H]cytisine-radiolabeled thalamus and frontal cortex in rat brain slices. In postmortem human AD frontal cortex, Aß plaques labeled with [3H]PIB, FEX-CUR showed a 35% reduction in gray matter (GM)/white matter (WM) [3H]PIB binding, while CUR alone showed a 50% reduction. In vivo biodistribution studies are required of the Aß-Pgp and Aß-α4ß 2* nAChRs dual targeting agents in order to evaluate their potential as therapeutic approaches for reducing brain Aß plaques.