Development and Optimization of a Target Engagement Model of Brain IDO Inhibition for Alzheimer's Disease.

ABSTRACT

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO1) inhibition is a promising target as an Alzheimer's disease (AD) Disease-modifying therapy capable of downregulating immunopathic neuroinflammatory processes. METHODS: To aid in the development of IDO inhibitors as potential AD therapeutics, we optimized a lipopolysaccharide (LPS) based mouse model of brain IDO1 inhibition by examining the dosedependent and time-course of the brain kynureninetryptophan (KT) ratio to LPS via intraperitoneal dosing. RESULTS: We determined the optimal LPS dose to increase IDO1 activity in the brain, and the ideal time point to quantify the brain KT ratio after LPS administration. We then used a brain penetrant tool compound, EOS200271, to validate the model, determine the optimal dosing profile and found that a complete rescue of the KT ratio was possible with the tool compound. CONCLUSION: This LPS-based model of IDO1 target engagement is a useful tool that can be used in the development of brain penetrant IDO1 inhibitors for AD. A limitation of the present study is the lack of quantification of potential clinically relevant biomarkers in this model, which could be addressed in future studies.