TY - JOUR
T1 - Relationship between in vivo receptor occupancy and efficacy of metabotropic glutamate receptor subtype 5 allosteric modulators with different in vitro binding profiles
AU - Rook, Jerri M.
AU - Tantawy, Mohammed N.
AU - Ansari, Mohammad S.
AU - Felts, Andrew S.
AU - Stauffer, Shaun R.
AU - Emmitte, Kyle A.
AU - Kessler, Robert M.
AU - Niswender, Colleen M.
AU - Daniels, J. Scott
AU - Jones, Carrie K.
AU - Lindsley, Craig W.
AU - Conn, P. Jeffrey
N1 - Funding Information:
has been funded Foundation, and
Funding Information:
Disease Drug Discovery Foundation. Dr Felts has received compensation from Seaside Therapeutics. Dr Stauffer’s work has been funded by the NIH and by an industry sponsored research contract from Janssen. He is an inventor on patents that protect different classes of mGlu5PAMs. Dr Emmitte’s work has been funded by the NIH and collaborative research agreements with Seaside Therapeutics. He is an inventor on patents that protect different classes of mGlu5 NAMs. Dr Kessler’s work has been funded by Novo Nordisc and by the NIH. In addition, he is a stockholder in PHarmRx Therapeutics and a consultant for Shire Pharmaceuticals. Dr Niswender’s work has been funded by the NIH, the International Rett Syndrome Foundation and Autism Speaks. She has received licensing royalties from Johnson and Johnson, Bristol–Myers Squibb, and Seaside Therapeutics, and is an inventor on patents that protect different classes of metabotropic glutamate and muscarinic receptor allosteric modulators. Dr Daniels’ work has been funded in part by the NIH and the Molecular Libraries Probe Production Centers Network. He has received compensation from Johnson and Johnson, Bristol-Myers Squibb, Seaside Therapeutics and as a member of the scientific advisory board of the Sigma-Aldrich company and through consulting for Agios Pharmaceuticals Company and the Michael J. Fox Foundation. He is an inventor on patents that protect different classes of metabotropic glutamate and muscarinic receptor allosteric modulators. Dr Jones received research support from Bristol–Myers Squibb, Johnson and Johnson, and AstraZeneca. Dr Jones also received funding through the Michael J. Fox Foundation, the Barrus Foundation, and NIH. She is an inventor on patents that protect different classes of metabotropic glutamate and muscarinic receptor allosteric modulators. Dr Lindsley’s work has been funded by the NIH, Bristol–Myers Squibb, AstraZeneca, Michael J. Fox Foundation, as well as Seaside Therapeutics. He has consulted for AbbVie and received compensation. He is an inventor on patents that protect different classes of metabotropic glutamate and muscarinic receptor allosteric modulators. Dr Conn has been funded by NIH, Johnson and Johnson, AstraZeneca, Bristol–Myers Squibb, Michael J. Fox Foundation, and Seaside Therapeutics. He has consulted over the past 3 years for Pfizer, Cambridge, and Millipore Corporation, and received compensation. Over the past 3 years he has served on the Scientific Advisory Boards and received compensation from Seaside Therapeutics, Michael J. Fox Foundation, Stanley Center for Psychiatric Research Broad Institute (MIT/Harvard), Karuna Pharmaceuticals, Lieber Institute for Brain Development Johns Hopkins University, Clinical Mechanism and Proof of Concept Consortium, and Neurobiology Foundation for Schizophrenia and Bipolar Disorder He is an inventor on patents that protect different classes of metabotropic glutamate and muscarinic receptor allosteric modulators. Dr Tantawy, Dr Ansari, and Dr Felts declare no potential conflict of interest.
Funding Information:
We would like to thank George Wilson, Zou Yue and Ya Zhou for their technical expertise. This work was supported by NIH R01 MH062646 (PJC), R01 NS031373 (PJC) and F32 MH088234 (JMR).
Publisher Copyright:
© 2015 American College of Neuropsychopharmacology.
PY - 2015/2
Y1 - 2015/2
N2 - Allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu 5) have exciting potential as therapeutic agents for multiple brain disorders. Translational studies with mGlu 5 modulators have relied on mGlu 5 allosteric site positron emission tomography (PET) radioligands to assess receptor occupancy in the brain. However, recent structural and modeling studies suggest that closely related mGlu 5 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 mGlu 5 positive allosteric modulator VU0092273 displaced the structurally related mGlu 5 PET ligand, 18 FFPEB, with measures of in vivo occupancy that closely aligned with its in vivo efficacy. In contrast, a close analog of VU0092273 and 18 FFPEB, VU0360172, provided robust efficacy in rodent models in the absence of detectable occupancy. Furthermore, a structurally unrelated mGlu 5 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 FFPEB. 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.
AB - Allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu 5) have exciting potential as therapeutic agents for multiple brain disorders. Translational studies with mGlu 5 modulators have relied on mGlu 5 allosteric site positron emission tomography (PET) radioligands to assess receptor occupancy in the brain. However, recent structural and modeling studies suggest that closely related mGlu 5 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 mGlu 5 positive allosteric modulator VU0092273 displaced the structurally related mGlu 5 PET ligand, 18 FFPEB, with measures of in vivo occupancy that closely aligned with its in vivo efficacy. In contrast, a close analog of VU0092273 and 18 FFPEB, VU0360172, provided robust efficacy in rodent models in the absence of detectable occupancy. Furthermore, a structurally unrelated mGlu 5 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 FFPEB. 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.
UR - http://www.scopus.com/inward/record.url?scp=84922105810&partnerID=8YFLogxK
U2 - 10.1038/npp.2014.245
DO - 10.1038/npp.2014.245
M3 - Article
C2 - 25241804
AN - SCOPUS:84922105810
SN - 0893-133X
VL - 40
SP - 755
EP - 765
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 3
ER -