TY - JOUR T1 - The [<sup>18</sup>F]FDG <em>μ</em>PET Readout of a Brain Activation Model to Evaluate the Metabotropic Glutamate Receptor 2 Positive Allosteric Modulator JNJ-42153605 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 375 LP - 386 DO - 10.1124/jpet.114.213959 VL - 350 IS - 2 AU - Tine Wyckhuys AU - Leonie wyffels AU - Xavier Langlois AU - Mark Schmidt AU - Sigrid Stroobants AU - Steven Staelens Y1 - 2014/08/01 UR - http://jpet.aspetjournals.org/content/350/2/375.abstract N2 - Using [18F]fluorodeoxyglucose μ–positron emission tomography ([18F]FDG μPET), 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, [18F]FDG was injected (37 MBq i.v.) followed by a μPET/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 μPET experiment clearly indicates that subanesthetic doses of memantine induce significant increases of [18F]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. ER -