AI Article Synopsis

  • In vivo imaging techniques like PET and SPECT are essential for confirming drug-target engagement, but the lack of radioligands limits their use in drug development.
  • Pharmacological magnetic resonance imaging (phMRI) could pave the way for new biomarkers that assess drug activity and appropriate dosages in both animals and humans.
  • In this study, xanomeline was found to increase BOLD signals in various brain areas while simultaneously reducing the brain activation caused by ketamine, suggesting its potential for early clinical trials in treating schizophrenia.

Article Abstract

In vivo translational imaging techniques, such as positron emission tomography and single-photon emission-computed tomography, are the only ways 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) offers an approach for 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 activation on blood oxygen level-dependent (BOLD) signal. In the present studies, xanomeline alone dose-dependently increased the BOLD signal across several regions of interest, including association and motor and sensory cortical regions. It is noteworthy that xanomeline dose-dependently attenuated ketamine-induced brain activation patterns, effects that were antagonized by atropine. In conclusion, the muscarinic 1/4-preferring receptor agonist xanomeline suppressed the effects of the N-methyl-D-aspartate channel blocker ketamine in a number of brain regions, including the association cortex, motor cortex, and primary sensory cortices. The region-specific brain activation observed in this ketamine challenge phMRI study may provide 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.

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Source
http://dx.doi.org/10.1124/jpet.111.188797DOI Listing

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