Title
The [<tex>$^{18}F$</tex>]FDG <tex>$\mu$</tex>PET readout of a brain activation model to evaluate the metabotropic glutamate receptor 2 positive allosteric modulator JNJ-42153605 The [<tex>$^{18}F$</tex>]FDG <tex>$\mu$</tex>PET readout of a brain activation model to evaluate the metabotropic glutamate receptor 2 positive allosteric modulator JNJ-42153605
Author
Faculty/Department
Faculty of Medicine and Health Sciences
Publication type
article
Publication
Baltimore, Md ,
Subject
Pharmacology. Therapy
Source (journal)
The journal of pharmacology and experimental therapeutics. - Baltimore, Md
Volume/pages
350(2014) :2 , p. 375-386
ISSN
0022-3565
ISI
000339270800019
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
Using [F-18] fluorodeoxyglucose m-positron emission tomography ([F-18]FDG mu PET), 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 well-known metabotropic glutamate receptor (mGluR)-2/3 agonist LY404039 [(-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0] hexane-4,6-dicarboxylic acid] and the novel mGluR2 positive allosteric modulator (PAM) JNJ-42153605 [3-cylcopropylmethyl-7-( 4-phenylpiperidin-1-yl)-8-trifluoromethyl [1,2,4] triazolo[4,3-a] pyridine]. First, rats (n = 12) were subjected to LY404039 (10 mg/kg s.c.) or vehicle, 30 minutes prior to saline, ketamine (30 mg/kg i.p.), or memantine (20 mg/kg i.p.). Second, rats (n - 12) were subjected to 2.5 mg/kg or 10 mg/kg mGluR2 PAM JNJ-42153605 or vehicle (s.c.), 30 minutes prior to memantine (20 mg/kg i.p.) or saline. Fifteen minutes later, [F-18] FDG was injected (37 MBq i.v.) followed by a mu PET/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 mu PET experiment clearly indicates that subanesthetic doses of memantine induce significant increases of [F-18] 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.
E-info
https://repository.uantwerpen.be/docman/iruaauth/cf3a73/14f8048.pdf
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