**4.8 Clioquinol**

Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) is a quinoline metal chelator that binds selectively to zinc and copper ions (Cherny *et al.* 2001). Having a hydrophobic nature, it crosses the BBB easily. Recent research with clioquinol in neurological disorders contributed by an imbalance in metal ions has led to promising results, presenting the possibility of a new therapeutic strategy. In AD transgenic mice, treatment with clioquinol resulted in the dissolution of aberrant neocortex beta amyloid (Aβ) aggregates, which are enriched with copper and zinc ions (Cherny *et al.* 2001). In a pilot phase II clinical trial, the drug was well tolerated and led to a significant decrease in Aβ plasma levels in AD patients, providing support for future trials (Ritchie *et al.* 2003). In PD, elevated levels of iron in the substantia nigra, the brain region affected in PD, has been reported. In mice, oral administration of clioquinol antagonized the action of the Parkinson's inducing agent 1-methyl-4-phenyl-1,2,3,6-tetra-pyridine (MPTP) (Kaur *et al.* 2003). In HD, where iron, copper and zinc have been implicated, clioquinol improved the symptoms and lifespan of transgenic HD mice (Nguyen *et al.* 2005).

A second generation 8-hydroxyquinoline, PBT2, has been developed to improve the safety and efficacy of clioquinol and also its pharmaceutical properties, such as solubility and bioavailability. In preclinical *in vivo* and *in vitro* trials on transgenic AD mice, PBT2 was more effective in lowering plaque formation and reducing plaque toxicity. More importantly, it may also improve cognition.
