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Research ArticleNeuropharmacology

Receptor Occupancy of the κ-Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050

Mika Naganawa, Gemma L. Dickinson, Ming-Qiang Zheng, Shannan Henry, Francois Vandenhende, Jennifer Witcher, Robert Bell, Nabeel Nabulsi, Shu-Fei Lin, Jim Ropchan, Alexander Neumeister, Mohini Ranganathan, Johannes Tauscher, Yiyun Huang and Richard E. Carson
Journal of Pharmacology and Experimental Therapeutics February 2016, 356 (2) 260-266; DOI: https://doi.org/10.1124/jpet.115.229278
Mika Naganawa
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.)
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Gemma L. Dickinson
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.)
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Ming-Qiang Zheng
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.)
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Shannan Henry
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.)
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Francois Vandenhende
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.)
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Jennifer Witcher
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.)
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Robert Bell
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.)
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Nabeel Nabulsi
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.)
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Shu-Fei Lin
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.)
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Jim Ropchan
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.)
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Alexander Neumeister
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.)
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Mohini Ranganathan
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.)
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Johannes Tauscher
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.)
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Yiyun Huang
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.)
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Richard E. Carson
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.)
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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 11C-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 11C-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.

Footnotes

    • Received October 9, 2015.
    • Accepted November 30, 2015.
  • M.N. and G.L.D. contributed equally to this study.

  • This study was supported by Eli Lilly and Company. This publication was made possible by CTSA Grant UL1 TR000142 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH.

  • dx.doi.org/10.1124/jpet.115.229278

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 356 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 356, Issue 2
1 Feb 2016
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Research ArticleNeuropharmacology

κ-Opioid Receptor Occupancy by LY2456302

Mika Naganawa, Gemma L. Dickinson, Ming-Qiang Zheng, Shannan Henry, Francois Vandenhende, Jennifer Witcher, Robert Bell, Nabeel Nabulsi, Shu-Fei Lin, Jim Ropchan, Alexander Neumeister, Mohini Ranganathan, Johannes Tauscher, Yiyun Huang and Richard E. Carson
Journal of Pharmacology and Experimental Therapeutics February 1, 2016, 356 (2) 260-266; DOI: https://doi.org/10.1124/jpet.115.229278

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Research ArticleNeuropharmacology

κ-Opioid Receptor Occupancy by LY2456302

Mika Naganawa, Gemma L. Dickinson, Ming-Qiang Zheng, Shannan Henry, Francois Vandenhende, Jennifer Witcher, Robert Bell, Nabeel Nabulsi, Shu-Fei Lin, Jim Ropchan, Alexander Neumeister, Mohini Ranganathan, Johannes Tauscher, Yiyun Huang and Richard E. Carson
Journal of Pharmacology and Experimental Therapeutics February 1, 2016, 356 (2) 260-266; DOI: https://doi.org/10.1124/jpet.115.229278
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