title: 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 μ-positron emission tomography ([(18)F]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, [(18)F]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 [(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.
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium (T.W., St.S.); Nuclear Medicine Department, University Hospital, Antwerp, Belgium (L.w., Si.S.); and Department of Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium (X.L., M.S.).
authors.forename: Tine
authors.initials: T
authors.lastname: Wyckhuys
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium (T.W., St.S.); Nuclear Medicine Department, University Hospital, Antwerp, Belgium (L.w., Si.S.); and Department of Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium (X.L., M.S.).
authors.forename: Leonie
authors.initials: L
authors.lastname: Wyffels
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium (T.W., St.S.); Nuclear Medicine Department, University Hospital, Antwerp, Belgium (L.w., Si.S.); and Department of Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium (X.L., M.S.).
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium (T.W., St.S.); Nuclear Medicine Department, University Hospital, Antwerp, Belgium (L.w., Si.S.); and Department of Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium (X.L., M.S.).
authors.forename: Mark
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium (T.W., St.S.); Nuclear Medicine Department, University Hospital, Antwerp, Belgium (L.w., Si.S.); and Department of Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium (X.L., M.S.).
authors.forename: Sigrid
authors.initials: S
authors.lastname: Stroobants
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium (T.W., St.S.); Nuclear Medicine Department, University Hospital, Antwerp, Belgium (L.w., Si.S.); and Department of Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium (X.L., M.S.) Steven.Staelens@uantwerpen.be.
authors.forename: Steven
authors.initials: S
authors.lastname: Staelens
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001921:Brain / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003499:Cyclic S-Oxides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019788:Fluorodeoxyglucose F18; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D008559:Memantine / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D019275:Radiopharmaceuticals; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D014227:Triazines / Q000494:pharmacology*
chemical_list: C577930:3-cyclopropylmethyl-7-(4-phenylpiperidin-1-yl)-8-trifluoromethyl(1,2,4)triazolo(4,3-a)pyridine; C517803:4-aminho-2-thiabicyclo(3.1.0)hexane-4,6-dicarboxylic acid; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003499:Cyclic S-Oxides; D011725:Pyridines; D019275:Radiopharmaceuticals; D018094:Receptors, Metabotropic Glutamate; D014227:Triazines; C108822:metabotropic glutamate receptor 2; D019788:Fluorodeoxyglucose F18; D007649:Ketamine; D008559:Memantine