Inhibition of brain glutamate carboxypeptidase II (GCPII) to enhance cognitive function

Cognitive deficits are a class of symptoms present in a broad range of disorders that go largely unaddressed by current medications. Disruptions in executive function and memory can be detrimental to patient quality of life, so there is a large unmet medical need for novel therapies to improve cognitive performance. Recent research has highlighted the importance of the type II metabotropic glutamate receptor 3 (mGluR3) in patterns of persistent neuronal firing in the dorsolateral prefrontal cortex of primates, a region critical for higher order cognitive processes. The selective, endogenous agonist of the mGlu3 receptor is N-acetylaspartyl glutamate (NAAG). NAAG is hydrolyzed by the enzyme glutamate carboxypeptidase II (GCPII) which is highly upregulated in neuroinflammatory conditions. Inhibition, GCPII has been investigated as a promising therapeutic avenue in a range of preclinical models and the relationship between NAAG and cognitive function has been studied in multiple clinical populations. The following chapter summarizes the body of preclinical and clinical work supporting the inhibition of GCPII to improve cognitive deficits and the drug discovery approaches that have been utilized to improve pharmacokinetics and brain penetration for future clinical translation of GCPII inhibitor.