Xanomeline Modulation of the Blood Oxygenation Level-Dependent Signal in Awake Rats: Development of Pharmacological Magnetic Resonance Imaging as a Translatable Pharmacodynamic Biomarker for Central Activity and Dose Selection

In vivo translational imaging techniques such as positron emission tomography (PET), single photon emission computed tomography (SPECT), are the only way to adequately determine that a drug engages its target. Unfortunately, there are far more experimental mechanisms being tested in the clinic than there are radioligands, impeding the use of this risk-mitigating approach in modern drug discovery and development. Pharmacological magnetic resonance imaging (phMRI) affords an approach to developing new biomarkers with the potential to determine central activity and dose selection in animals and humans. Using phMRI, we characterized the effects of xanomeline on ketamine-induced activations on blood-oxygen-level-dependant (BOLD) signal. In the present studies, xanomeline alone dose dependently increased the BOLD signal across several regions of interest including association, motor and sensory cortical regions. Interestingly, xanomeline dose-dependently attenuated ketamine-induced brain activation patterns, effects that were antagonized by atropine. In conclusion, the M1/M4 preferring muscarinic receptor agonist xanomeline, suppressed the effects of the N-methyl-daspartate (NMDA) channel blocker ketamine in a number of brain regions, including the association cortex, motor cortex and primary sensory cortices. The region-specific brain activations observed in this ketamine challenge phMRI study may afford a method of confirming central activity and dose selection for novel antipsychotic drugs in early clinical trials for schizophrenia, if the data obtained in animals can be recapitulated in humans.