title: Dose-dependent, saturable occupancy of the metabotropic glutamate subtype 5 receptor by fenobam as measured with [11C]ABP688 PET imaging.
abstract: Fenobam is a negative allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5) with inverse agonist activity and is expected to contribute to the treatment of neuropsychiatric disorders involving dysfunction of mGluR5 including Fragile X syndrome. This study examined whether [11C]ABP688, an antagonist PET radioligand, competes with fenobam for the same binding site in the nonhuman primate brain and would allow examination of occupancy-plasma concentration relationships in the evaluation of the drug for target disorders in the human brain. Four paired PET studies with [11C]ABP688 were performed in baboons at a baseline condition and after intravenous treatment with fenobam at different dose levels (0.3-1.33 mg/kg). Total distribution volume (VT) and binding potential (BPND) using the cerebellum as a reference region were obtained by the plasma reference graphical method. Then it was examined whether occupancy follows a dose-dependent, saturating pattern that was predicted by a modified first-order Hill equation in individual regions. Baseline regional VTand BPNDvalues agreed with previously published data. Occupancy showed dose-dependent and saturating patterns in individual regions, reaching >90% occupancy at 1.33 mg/kg dose of fenobam in the majority of regions. To our knowledge, this is the first use of PET to characterize the mGluR5 therapeutic drug fenobam. This study demonstrates a proof of principle for determining the in vivo occupancy of fenobam in primates. The results indicate that [11C]ABP688 and PET may be useful for examination of occupancy of mGluR5 by fenobam, which should prove to be useful for designing future studies and treatment of human disease states. Synapse 68:565-573, 2014. © 2014 Wiley Periodicals, Inc.
authors.affiliation: Department of Radiology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: William B
authors.initials: WB
authors.lastname: Mathews
authors.affiliation: Department of Radiology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kuwabara
authors.affiliation: Department of Radiology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Kirstie
authors.initials: K
authors.lastname: Stansfield
authors.affiliation: Department of Radiology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Heather
authors.initials: H
authors.lastname: Valentine
authors.affiliation: Department of Radiology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Mohab
authors.initials: M
authors.lastname: Alexander
authors.affiliation: Department of Radiology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Radiology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: John
authors.initials: J
authors.lastname: Hilton
authors.affiliation: Department of Radiology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Dannals
authors.affiliation: Department of Radiology, Johns Hopkins University, Baltimore, Maryland.|Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland.|Department of Neuroscience, Johns Hopkins University, Baltimore, Maryland.|Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Dean F
authors.initials: DF
authors.lastname: Wong
authors.affiliation: Neurosciences Discovery, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gasparini
keywords: PET; [11C]ABP688; fenobam; glutamate; mGluR5; occupancy
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