The [18F]FDG μPET Readout of a Brain Activation Model to Evaluate the Metabotropic Glutamate Receptor 2 Positive Allosteric Modulator JNJ-42153605

Abstract

Using [18 F]fluorodeoxyglucose m-positron emission tomography ([ 18 F]FDG mPET), we compared subanesthetic doses of memantine and ketamine on their potential to induce increases in brain activation. We also studied the reversal effect of the wellknown metabotropic glutamate receptor (mGluR)-2/3 agonist LY404039 [ (2) 18 F]FDG was injected (37 MBq i.v.) followed by a mPET/computed tomography scan. The increase due to memantine is significant for all relevant brain areas, whereas for ketamine this is not the case.Standard uptake values (SUVs) of the LY404039 pretreated and memantine-challenged group display a full reversal. Pretreatment with JNJ-42153605 also dose-dependently decreases SUV with a full reversal as well (for 10 mg/kg). Moreover, specificity of JNJ-42153605 is reached at this dose. In conclusion, this mPET experiment clearly indicates that subanesthetic doses of memantine induce significant increases of [ 18 F]FDG SUVs in discrete brain areas and that the novel mGluR2 PAM has the capacity to dose-dependently and specifically reverse memantine-induced brain activation.

( 2R,6R )-hydroxynorketamine exerts mGlu 2 receptor-dependent antidepressant actions

“…In addition, pretreatment with mGlu 2/3 agonists (64-67) or mGlu 2 receptor-selective positive allosteric modulators (68,69) prevented ketamine-induced enhancement of cortical quantitative EEG (qEEG) gamma oscillations, a marker of neuronal activation. These convergent processes have been hypothesized to involve ketamine-induced NMDAR inhibition, since mGlu 2/3 activation also prevents cortical activation induced by other noncompetitive NMDAR open channel blockers, including MK-801 (68,69), memantine (60,62), and phencyclidine (70). However, whether there are convergent actions between mGlu 2/3 receptor inhibition and (2R,6R)-HNK and if such effects are dependent on NMDAR inhibition are not known.…”

Imaging metabotropic glutamate receptor system: Application of positron emission tomography technology in drug development

“…Subanesthetic doses of N ‐methyl‐d‐aspartate receptor antagonist, memantine, have been used as on‐demand models of schizophrenia . Memantine induces long‐lasting activation as indicated by significant higher [ 18 F]FDG uptake in all relevant brain regions: caudate putamen, cingulate cortex, frontal cortex, motor cortex, parietal cortex, hippocampus and thalamus . As a selective and potent mGlu 2 PAM, JNJ42153605 can dose dependently reverse memantine induced activation in distinct brain areas and achieved specific and fully reversal at 10 mg/kg.…”

“…Under this situation, the direct RO measurement with PET may not be suitable as a translational biomarker. The dose‐efficacy relationship, however, could be established by measuring the downstream pharmacodynamic signal, such as [ 18 F]FDG/PET, through quantifying the changes in the metabolic properties.…”

“…197 In turn, the alteration of metabolism in specific brain region could be a useful biomarker for the efficacy measurement of CNS drugs. 197 Local brain metabolic activity can be measured by [ 18 F]FDG/PET. 198 The intensity of the PET signal from a specific brain region after [ 18 F]FDG administration is considered as an indirect measurement of neuronal activity.…”

“…200,201 Memantine induces long-lasting activation as indicated by significant higher [ 18 F] FDG uptake in all relevant brain regions: caudate putamen, cingulate cortex, frontal cortex, motor cortex, parietal cortex, hippocampus and thalamus. 197 As a selective and potent mGlu 2 PAM, JNJ42153605 can dose dependently reverse memantine induced activation in distinct brain areas and achieved specific and fully reversal at 10 mg/kg. 203 and to set a therapeutic window (C max at minimum ED versus C max at minimum adverse effect dose) in the early clinical development.…”