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

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 dosedependently 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 regionspecific 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.

The M1/M4 agonist xanomeline modulates functional connectivity and NMDAR antagonist-induced changes in the mouse brain

“…An earlier study suggested that xanomeline was able to reduce the fMRI increases in BOLD response produced by the NMDA antagonist ketamine in rats (Baker et al, 2012). Here we demonstrate that xanomeline was also able to reduce the increase in high frequency EEG activity produced by ketamine while having no effect on the reduction in lower frequency α/β activity.…”

“…While previous studies have addressed neurochemical and behavioral consequences of muscarinic modulation (Mirza et al, 2003;Raedler et al, 2007;Langmead et al, 2008) the macroscopic brain circuits and functional substrates engaged by M1/M4 agonism, and xanomeline in particular, remain poorly investigated. One previous study reported that xanomeline dose-dependently reversed the ketamine-evoked pharmacological fMRI (phMRI) signal increases in the rat brain, demonstrating a modulating effect of muscarinic agonism on an aberrant glutamatergic state considered of mechanistic relevance to schizophrenia (Baker et al, 2012). Since ketamine-challenge phMRI has been successfully translated into healthy humans and modulated by both clinically approved drugs and novel glutamatergic agents (De Simoni et al, 2013a;Doyle et al, 2013;Javitt et al, 2018aJavitt et al, , 2018bMehta et al, 2018), this observation indicates a potential translational biomarker opportunity.…”

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

“…With use of phMRI, drug action on rodent brain function has been evaluated for a range of compounds that include amphetamine (Chen et al, 2005), nicotine (Gozzi et al, 2006), remifentanil (Liu et al, 2007), and cocaine (Schwarz et al, 2004). Previous studies have also used phMRI as a means to characterize the effects of a pharmacological pretreatment (eg, 5HT-2A receptor antagonist) on a particular challenge (e.g., phencylidine) (Gozzi et al, 2008;Gozzi et al, 2010;Chin et al, 2011;Large et al, 2011;McKie et al, 2011;Baker et al, 2012). Such studies can be highly informative with regard to understanding the underlying neurobiology (receptor and brain circuit level) that drives a certain cognitive phenomenon.…”

“…A similar inconsistency has been observed for other pharmacological compounds, such as ketamine. Here, phMRI activation in the brain is the dominant effect observed in awake, naive rodents and healthy human subjects (Chin et al, 2011;Baker et al, 2012;De Simoni et al, 2012). However, in the preclinical setting, phMRI deactivation is observed in regions, such as the cerebellum, substantia nigra, and periaqueductal gray; deactivation is minimally observed in the human subgenual cingulate cortex.…”

The role of fMRI in drug development

“…The ketamine response can be blocked by antiglutamatergic compounds [88,89] and can reverse the phMRI signal evoked by some (but not all) antipsychotic agents and compounds designed to attenuate glutamate release [95,96]. Additional drug classes that induce phMRI signals include analgesics [97–101], antipsychotics [102], cognitive enhancers [103], drugs of abuse [104,105], calcium channel blockers [106,107], cyclooxygenase-2 (COX-2) inhibitors [108], muscarinic acetylcholine receptor modulators [109–111], and therapies traditionally thought to impact solely immune system activity [112]. In addition to traditional phMRI studies, pharmacological modulation of functional connectivity in animal models and humans has also been reported [113–118].…”