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Research ArticleNeuropharmacology

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

Tine Wyckhuys, Leonie wyffels, Xavier Langlois, Mark Schmidt, Sigrid Stroobants and Steven Staelens
Journal of Pharmacology and Experimental Therapeutics August 2014, 350 (2) 375-386; DOI: https://doi.org/10.1124/jpet.114.213959
Tine Wyckhuys
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.)
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Leonie wyffels
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.)
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Xavier Langlois
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.)
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Mark Schmidt
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.)
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Sigrid Stroobants
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.)
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Steven Staelens
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.)
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Abstract

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.

Footnotes

    • Received February 13, 2014.
    • Accepted June 2, 2014.
  • This work was funded by Antwerp University, Belgium, through a full-time associate professor position for St.S., a part-time full professor position for Si.S., and a postdoctoral position for T.W.; and by Antwerp University Hospital, Belgium, through a part-time departmental position for Si.S. and a full-time position for L.w. M.S. and X.L. are with Janssen Research and Development, Beerse, Belgium.

  • Part of this work was presented as follows: Wyckhuys T, wyffels L, Langlois X, Schmidt M, Stroobants S, and Staelens S (2013) Evaluation of mGluR2 positive allosteric modulator JNJ-42153605 in an animal model of glutamatergic dysfunction using [18F]FDG microPET. Society for Neuroscience Annual Meeting; 2013 Nov 9–13; San Diego, CA.

  • dx.doi.org/10.1124/jpet.114.213959.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 350 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 350, Issue 2
1 Aug 2014
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Research ArticleNeuropharmacology

Metabotropic GluR2 PAM JNJ-42153605 Evaluation by μPET

Tine Wyckhuys, Leonie wyffels, Xavier Langlois, Mark Schmidt, Sigrid Stroobants and Steven Staelens
Journal of Pharmacology and Experimental Therapeutics August 1, 2014, 350 (2) 375-386; DOI: https://doi.org/10.1124/jpet.114.213959

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Research ArticleNeuropharmacology

Metabotropic GluR2 PAM JNJ-42153605 Evaluation by μPET

Tine Wyckhuys, Leonie wyffels, Xavier Langlois, Mark Schmidt, Sigrid Stroobants and Steven Staelens
Journal of Pharmacology and Experimental Therapeutics August 1, 2014, 350 (2) 375-386; DOI: https://doi.org/10.1124/jpet.114.213959
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