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

Overview

Journal J Pharmacol Exp Ther

Specialty Pharmacology

Date 2015 Dec 3

PMID 26628406

Citations 28

Authors

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

Richard E Carson

Affiliations

Soon will be listed here.

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.

Citing Articles

PET Mapping of Receptor Occupancy Using Joint Direct Parametric Reconstruction.

Marin T, Belov V, Chemli Y, Ouyang J, Najmaoui Y, El Fakhri G IEEE Trans Biomed Eng. 2024; 72(3):1057-1066.

PMID: 39446540 PMC: 11875991. DOI: 10.1109/TBME.2024.3486191.

Aticaprant, a kappa opioid receptor antagonist, and the recovered 'interest and pleasure' in the concept of major depressive disorder.

Demyttenaere K Eur Arch Psychiatry Clin Neurosci. 2024; .

PMID: 38969753 DOI: 10.1007/s00406-024-01851-7.

Novel medications for problematic alcohol use.

Heilig M, Witkiewitz K, Ray L, Leggio L J Clin Invest. 2024; 134(11).

PMID: 38828724 PMC: 11142745. DOI: 10.1172/JCI172889.

Efficacy and safety of aticaprant, a kappa receptor antagonist, adjunctive to oral SSRI/SNRI antidepressant in major depressive disorder: results of a phase 2 randomized, double-blind, placebo-controlled study.

Schmidt M, Kezic I, Popova V, Melkote R, Van Der Ark P, Pemberton D Neuropsychopharmacology. 2024; 49(9):1437-1447.

PMID: 38649428 PMC: 11251157. DOI: 10.1038/s41386-024-01862-x.

Development and Optimization of C-Labeled Radiotracers: A Review of the Modern Quality Control Design Process.

Myburgh P, Sai K ACS Pharmacol Transl Sci. 2023; 6(11):1616-1631.

PMID: 37974626 PMC: 10644505. DOI: 10.1021/acsptsci.3c00200.

References

Salinas C, Weinzimmer D, Searle G, Labaree D, Ropchan J, Huang Y . Kinetic analysis of drug-target interactions with PET for characterization of pharmacological hysteresis. J Cereb Blood Flow Metab. 2013; 33(5):700-7. PMC: 3652698. DOI: 10.1038/jcbfm.2012.208. View

Deehan Jr G, McKinzie D, Carroll F, McBride W, Rodd Z . The long-lasting effects of JDTic, a kappa opioid receptor antagonist, on the expression of ethanol-seeking behavior and the relapse drinking of female alcohol-preferring (P) rats. Pharmacol Biochem Behav. 2012; 101(4):581-7. PMC: 3327789. DOI: 10.1016/j.pbb.2012.03.006. View

Naganawa M, Zheng M, Henry S, Nabulsi N, Lin S, Ropchan J . Test-retest reproducibility of binding parameters in humans with 11C-LY2795050, an antagonist PET radiotracer for the κ opioid receptor. J Nucl Med. 2015; 56(2):243-8. PMC: 4322754. DOI: 10.2967/jnumed.114.147975. View

Innis R, Cunningham V, Delforge J, Fujita M, Gjedde A, Gunn R . Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007; 27(9):1533-9. DOI: 10.1038/sj.jcbfm.9600493. View

Lowe S, Wong C, Witcher J, Gonzales C, Dickinson G, Bell R . Safety, tolerability, and pharmacokinetic evaluation of single- and multiple-ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects. J Clin Pharmacol. 2014; 54(9):968-78. DOI: 10.1002/jcph.286. View

Cunningham V, Rabiner E, Slifstein M, Laruelle M, Gunn R . Measuring drug occupancy in the absence of a reference region: the Lassen plot re-visited. J Cereb Blood Flow Metab. 2009; 30(1):46-50. PMC: 2949110. DOI: 10.1038/jcbfm.2009.190. View

Papademetris X, Jackowski M, Rajeevan N, DiStasio M, Okuda H, Constable R . BioImage Suite: An integrated medical image analysis suite: An update. Insight J. 2014; 2006:209. PMC: 4213804. View

Abanades S, Van der Aart J, Barletta J, Marzano C, Searle G, Salinas C . Prediction of repeat-dose occupancy from single-dose data: characterisation of the relationship between plasma pharmacokinetics and brain target occupancy. J Cereb Blood Flow Metab. 2010; 31(3):944-52. PMC: 3063628. DOI: 10.1038/jcbfm.2010.175. View

Ichise M, Liow J, Lu J, Takano A, Model K, Toyama H . Linearized reference tissue parametric imaging methods: application to [11C]DASB positron emission tomography studies of the serotonin transporter in human brain. J Cereb Blood Flow Metab. 2003; 23(9):1096-112. DOI: 10.1097/01.WCB.0000085441.37552.CA. View

10.

Walker B, Koob G . Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol dependence. Neuropsychopharmacology. 2007; 33(3):643-52. PMC: 2739278. DOI: 10.1038/sj.npp.1301438. View

11.

Kim S, Zheng M, Nabulsi N, Labaree D, Ropchan J, Najafzadeh S . Determination of the in vivo selectivity of a new κ-opioid receptor antagonist PET tracer 11C-LY2795050 in the rhesus monkey. J Nucl Med. 2013; 54(9):1668-74. PMC: 5824998. DOI: 10.2967/jnumed.112.118877. View

12.

Naganawa M, Zheng M, Nabulsi N, Tomasi G, Henry S, Lin S . Kinetic modeling of (11)C-LY2795050, a novel antagonist radiotracer for PET imaging of the kappa opioid receptor in humans. J Cereb Blood Flow Metab. 2014; 34(11):1818-25. PMC: 4269759. DOI: 10.1038/jcbfm.2014.150. View

13.

Hilton J, Yokoi F, Dannals R, Ravert H, Szabo Z, Wong D . Column-switching HPLC for the analysis of plasma in PET imaging studies. Nucl Med Biol. 2000; 27(6):627-30. DOI: 10.1016/s0969-8051(00)00125-6. View

14.

Jin X, Mulnix T, Gallezot J, Carson R . Evaluation of motion correction methods in human brain PET imaging--a simulation study based on human motion data. Med Phys. 2013; 40(10):102503. PMC: 3785538. DOI: 10.1118/1.4819820. View

15.

Holmes C, Hoge R, Collins L, Woods R, Toga A, Evans A . Enhancement of MR images using registration for signal averaging. J Comput Assist Tomogr. 1998; 22(2):324-33. DOI: 10.1097/00004728-199803000-00032. View

16.

Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N . Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage. 2002; 15(1):273-89. DOI: 10.1006/nimg.2001.0978. View

17.

Zheng M, Nabulsi N, Kim S, Tomasi G, Lin S, Mitch C . Synthesis and evaluation of 11C-LY2795050 as a κ-opioid receptor antagonist radiotracer for PET imaging. J Nucl Med. 2013; 54(3):455-63. PMC: 3775344. DOI: 10.2967/jnumed.112.109512. View

18.

Mitch C, Quimby S, Diaz N, Pedregal C, de la Torre M, Jimenez A . Discovery of aminobenzyloxyarylamides as κ opioid receptor selective antagonists: application to preclinical development of a κ opioid receptor antagonist receptor occupancy tracer. J Med Chem. 2011; 54(23):8000-12. DOI: 10.1021/jm200789r. View

19.

Rorick-Kehn L, Witkin J, Statnick M, Eberle E, McKinzie J, Kahl S . LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders. Neuropharmacology. 2013; 77:131-44. DOI: 10.1016/j.neuropharm.2013.09.021. View

20.

Rorick-Kehn L, Witcher J, Lowe S, Gonzales C, Weller M, Bell R . Determining pharmacological selectivity of the kappa opioid receptor antagonist LY2456302 using pupillometry as a translational biomarker in rat and human. Int J Neuropsychopharmacol. 2015; 18(2). PMC: 4368892. DOI: 10.1093/ijnp/pyu036. View