Drug development based on the metals hypothesis of Alzheimer's disease.

The recent report of positive results from a Phase IIa clinical trial of PBT2, a novel drug that targets amyloid-beta-metal interactions, underscores the value of abnormal transition metal metabolism as a potential therapeutic target in Alzheimer's disease. The Metals Hypothesis of Alzheimer's disease is based upon observations of the precipitation of amyloid-beta by zinc and its radicalization by copper. Both metals are markedly enriched in plaques. The Hypothesis involves the perturbance of these endogenous brain metals, and it does not consider toxicological exposure part of pathogenesis. Recent descriptions of the release of ionic zinc and copper in the cortical glutamatergic synapse, modulating the response of the NMDA receptor, may explain the vulnerability of amyloid-beta to abnormal interaction with these metal ions in the synaptic region leading to aggregation and fostering toxicity. Increasingly sophisticated medicinal chemistry approaches are being tested which correct the abnormalities without causing systemic disturbance of these essential minerals. PBT2, clioquinol and related compounds are ionophores rather than chelators. PBT2 is a once per day, orally bioavailable, second generation 8-OH quinoline derivative of clioquinol. It has performed very satisfactorily in toxicology and Phase I clinical trials and is advancing as a disease-modifying candidate drug for Alzheimer's disease.