title: Relationship between in vivo receptor occupancy and efficacy of metabotropic glutamate receptor subtype 5 allosteric modulators with different in vitro binding profiles.
abstract: Allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu5) have exciting potential as therapeutic agents for multiple brain disorders. Translational studies with mGlu5 modulators have relied on mGlu5 allosteric site positron emission tomography (PET) radioligands to assess receptor occupancy in the brain. However, recent structural and modeling studies suggest that closely related mGlu5 allosteric modulators can bind to overlapping but not identical sites, which could complicate interpretation of in vivo occupancy data, even when PET ligands and drug leads are developed from the same chemical scaffold. We now report that systemic administration of the novel mGlu5 positive allosteric modulator VU0092273 displaced the structurally related mGlu5 PET ligand, [(18)F]FPEB, with measures of in vivo occupancy that closely aligned with its in vivo efficacy. In contrast, a close analog of VU0092273 and [(18)F]FPEB, VU0360172, provided robust efficacy in rodent models in the absence of detectable occupancy. Furthermore, a structurally unrelated mGlu5 negative allosteric modulator, VU0409106, displayed measures of in vivo occupancy that correlated well with behavioral effects, despite the fact that VU0409106 is structurally unrelated to [(18)F]FPEB. Interestingly, all three compounds inhibit radioligand binding to the prototypical MPEP/FPEB allosteric site in vitro. However, VU0092273 and VU0409106 bind to this site in a fully competitive manner, whereas the interaction of VU0360172 is noncompetitive. Thus, while close structural similarity between PET ligands and drug leads does not circumvent issues associated with differential binding to a given target, detailed molecular pharmacology analysis accurately predicts utility of ligand pairs for in vivo occupancy studies.
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Jerri M
authors.initials: JM
authors.lastname: Rook
authors.affiliation: 1] Vanderbilt University Institute of Imaging Sciences, Nashville, TN, USA [2] Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Mohammed N
authors.initials: MN
authors.lastname: Tantawy
authors.affiliation: Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Ansari
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Felts
authors.affiliation: 1] Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
authors.affiliation: 1] Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Emmitte
authors.affiliation: Department of Radiology, University of Alabama, Birmingham, AL, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Kessler
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.affiliation: 1] Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D001549:Benzamides; C581972:N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide; D010880:Piperidines; D064529:Receptor, Metabotropic Glutamate 5; D013844:Thiazoles; C575096:VU0092273; C577470:VU0409106; D009536:Niacinamide; D000661:Amphetamine; D002118:Calcium