title: Receptor Occupancy of the κ-Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050.
abstract: The κ-opioid receptor (KOR) is thought to play an important therapeutic role in a wide range of neuropsychiatric and substance abuse disorders, including alcohol dependence. LY2456302 is a recently developed KOR antagonist with high affinity and selectivity and showed efficacy in the suppression of ethanol consumption in rats. This study investigated brain penetration and KOR target engagement after single oral doses (0.5-25 mg) of LY2456302 in 13 healthy human subjects. Three positron emission tomography scans with the KOR antagonist radiotracer (11)C-LY2795050 were conducted at baseline, 2.5 hours postdose, and 24 hours postdose. LY2456302 was well tolerated in all subjects without serious adverse events. Distribution volume was estimated using the multilinear analysis 1 method for each scan. Receptor occupancy (RO) was derived from a graphical occupancy plot and related to LY2456302 plasma concentration to determine maximum occupancy (rmax) and IC50. LY2456302 dose dependently blocked the binding of (11)C-LY2795050 and nearly saturated the receptors at 10 mg, 2.5 hours postdose. Thus, a dose of 10 mg of LY2456302 appears well suited for further clinical testing. Based on the pharmacokinetic (PK)-RO model, the rmax and IC50 of LY2456302 were estimated as 93% and 0.58 ng/ml to 0.65 ng/ml, respectively. Assuming that rmax is 100%, IC50 was estimated as 0.83 ng/ml.
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut (M.N., M.Z., S.H., N.N., S.L., J.R., Y.H., R.C.); Eli Lilly and Company, Indianapolis, Indiana (G.D., J.W., R.B., J.T.); ClinBAY, Belgium (F.V.); and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (A.N., M.R.) mika.naganawa@yale.edu.
authors.forename: Mika
authors.identifier: http://orcid.org/0000-0002-4408-2621
authors.initials: M
authors.lastname: Naganawa
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut (M.N., M.Z., S.H., N.N., S.L., J.R., Y.H., R.C.); Eli Lilly and Company, Indianapolis, Indiana (G.D., J.W., R.B., J.T.); ClinBAY, Belgium (F.V.); and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (A.N., M.R.).
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Dickinson
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut (M.N., M.Z., S.H., N.N., S.L., J.R., Y.H., R.C.); Eli Lilly and Company, Indianapolis, Indiana (G.D., J.W., R.B., J.T.); ClinBAY, Belgium (F.V.); and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (A.N., M.R.).
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Zheng
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut (M.N., M.Z., S.H., N.N., S.L., J.R., Y.H., R.C.); Eli Lilly and Company, Indianapolis, Indiana (G.D., J.W., R.B., J.T.); ClinBAY, Belgium (F.V.); and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (A.N., M.R.).
authors.forename: Shannan
authors.initials: S
authors.lastname: Henry
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut (M.N., M.Z., S.H., N.N., S.L., J.R., Y.H., R.C.); Eli Lilly and Company, Indianapolis, Indiana (G.D., J.W., R.B., J.T.); ClinBAY, Belgium (F.V.); and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (A.N., M.R.).
authors.forename: Francois
authors.initials: F
authors.lastname: Vandenhende
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut (M.N., M.Z., S.H., N.N., S.L., J.R., Y.H., R.C.); Eli Lilly and Company, Indianapolis, Indiana (G.D., J.W., R.B., J.T.); ClinBAY, Belgium (F.V.); and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (A.N., M.R.).
authors.forename: Jennifer
authors.initials: J
authors.lastname: Witcher
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut (M.N., M.Z., S.H., N.N., S.L., J.R., Y.H., R.C.); Eli Lilly and Company, Indianapolis, Indiana (G.D., J.W., R.B., J.T.); ClinBAY, Belgium (F.V.); and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (A.N., M.R.).
authors.forename: Robert
authors.initials: R
authors.lastname: Bell
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut (M.N., M.Z., S.H., N.N., S.L., J.R., Y.H., R.C.); Eli Lilly and Company, Indianapolis, Indiana (G.D., J.W., R.B., J.T.); ClinBAY, Belgium (F.V.); and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (A.N., M.R.).
authors.forename: Nabeel
authors.identifier: http://orcid.org/0000-0001-8029-0051
authors.initials: N
authors.lastname: Nabulsi
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut (M.N., M.Z., S.H., N.N., S.L., J.R., Y.H., R.C.); Eli Lilly and Company, Indianapolis, Indiana (G.D., J.W., R.B., J.T.); ClinBAY, Belgium (F.V.); and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (A.N., M.R.).
authors.forename: Shu-Fei
authors.initials: SF
authors.lastname: Lin
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut (M.N., M.Z., S.H., N.N., S.L., J.R., Y.H., R.C.); Eli Lilly and Company, Indianapolis, Indiana (G.D., J.W., R.B., J.T.); ClinBAY, Belgium (F.V.); and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (A.N., M.R.).
authors.forename: Jim
authors.initials: J
authors.lastname: Ropchan
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut (M.N., M.Z., S.H., N.N., S.L., J.R., Y.H., R.C.); Eli Lilly and Company, Indianapolis, Indiana (G.D., J.W., R.B., J.T.); ClinBAY, Belgium (F.V.); and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (A.N., M.R.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Neumeister
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut (M.N., M.Z., S.H., N.N., S.L., J.R., Y.H., R.C.); Eli Lilly and Company, Indianapolis, Indiana (G.D., J.W., R.B., J.T.); ClinBAY, Belgium (F.V.); and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (A.N., M.R.).
authors.forename: Mohini
authors.initials: M
authors.lastname: Ranganathan
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut (M.N., M.Z., S.H., N.N., S.L., J.R., Y.H., R.C.); Eli Lilly and Company, Indianapolis, Indiana (G.D., J.W., R.B., J.T.); ClinBAY, Belgium (F.V.); and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (A.N., M.R.).
authors.forename: Johannes
authors.initials: J
authors.lastname: Tauscher
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut (M.N., M.Z., S.H., N.N., S.L., J.R., Y.H., R.C.); Eli Lilly and Company, Indianapolis, Indiana (G.D., J.W., R.B., J.T.); ClinBAY, Belgium (F.V.); and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (A.N., M.R.).
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut (M.N., M.Z., S.H., N.N., S.L., J.R., Y.H., R.C.); Eli Lilly and Company, Indianapolis, Indiana (G.D., J.W., R.B., J.T.); ClinBAY, Belgium (F.V.); and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (A.N., M.R.).
authors.forename: Richard E
authors.identifier: http://orcid.org/0000-0002-9338-7966
authors.initials: RE
authors.lastname: Carson
mesh_terms: D000328:Adult; D001549:Benzamides / Q000378:metabolism* / Q000494:pharmacology; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods; D011759:Pyrrolidines / Q000378:metabolism* / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D055815:Young Adult
chemical_list: C570402:3-chloro-4-(4-((2-(3-pyridyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide; D001549:Benzamides; D002250:Carbon Radioisotopes; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa