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 VT and BPND values 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.Keywords
Funding Information
- National Institutes of Health (R33 DA016182)
- National Institutes of Health (K24 DA000412)
This publication has 48 references indexed in Scilit:
- in vivo Variation in Metabotropic Glutamate Receptor Subtype 5 Binding Using Positron Emission Tomography and [11C]ABP688Journal of Cerebral Blood Flow & Metabolism, 2011
- AFQ056, a new mGluR5 antagonist for treatment of fragile X syndromeNeurobiology of Disease, 2011
- In vivo positron emission tomography imaging with [11C]ABP688: binding variability and specificity for the metabotropic glutamate receptor subtype 5 in baboonsEuropean Journal of Nuclear Medicine and Molecular Imaging, 2011
- In vivo and in vitro Validation of Reference Tissue Models for the mGluR5 Ligand [11C]ABP688Journal of Cerebral Blood Flow & Metabolism, 2010
- Measuring Drug Occupancy in the Absence of a Reference Region: The Lassen Plot Re-VisitedJournal of Cerebral Blood Flow & Metabolism, 2009
- A pilot open label, single dose trial of fenobam in adults with fragile X syndromeJournal of Medical Genetics, 2009
- Role for metabotropic glutamate receptor 5 (mGluR5) in the pathogenesis of fragile X syndromeThe Journal of Physiology, 2008
- Correction of Fragile X Syndrome in MiceNeuron, 2007
- mGluR5 stimulates gliotransmission in the nucleus accumbensProceedings of the National Academy of Sciences, 2007
- Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEPNeuropharmacology, 2005