The proposed project focuses upon the development of a robust translational model enabling the early assessment and identification of novel, improved therapeutics for neuropsychiatric illnesses. Such a model has the potential to reduce the substantial gap between currently utilized animal models and the human central nervous system, and thus the associated time, cost and risk of drug development. The commercial value of this capability is particularly high given the increasing competitive and economic pressures faced by the drug development industry and the pipeline bottlenecks created by the lack of a means to efficiently prioritize drug leads. The proposed project combines state-of-the-art 2-[lSF]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) imaging with novel, highly representative nonhuman primate models to provide an early, insightful predictor of human therapeutic success. The initial model focuses upon schizophrenia, and the cognitive dysfunction now recognized as a core deficit of this devastating and inadequately treated disease. Given the lack of antipsychotics that can effectively address cognitive deficits, a current thrust in drug development is identification of novel antipsychotics, which have putative cognitive enhancing properties. However, the cognitive consequences of pipeline compounds cannot be fully characterized in traditional animal models, as they differ from humans in key areas of the brain involved in cognition. Further, traditional behavioral measures alone, even in representative models; lack the ability to efficiently associate effect with the underlying neural mechanisms responsible for drug success. Addressing these issues, we will combine FDG PET, modem multivariate analysis techniques tailored to this purpose, and testing of higher cognitive processes in a nonhuman primate model to discriminate among antipsychotics in order to determine the functional neural circuitry associated with their effect. Preliminary data supports our ability to discriminate between drugs of a similar therapeutic class in humans using similar techniques. A second step will be to characterize the relationship between antipsychotic effects on cognition and on regional brain metabolism, thus enabling an early means to evaluate novel compounds for their potential to address all aspects of the disease. The commercial potential for the model, validated through interactions with a broad spectrum of drug development companies, includes revenue associated with the success of collaboratively evaluated and improved drugs, as well as licensing potential of novel compounds internally discovered and preclinically validated using the model. Multiple potential pharmaceutical partners have already expressed their interest in collaborative relationships related to such a model.
