ArticleThe Journal of pharmacology and experimental therapeutics2016
Receptor Occupancy of the κ-Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050.
Article in The Journal of pharmacology and experimental therapeutics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed.
- 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.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Trial
- Modulatory effects of orexin and dynorphin on stress-related alcohol seeking and relapse: pivotal role of the posterior paraventricular nucleus of the thalamus.Frontiers in pharmacology · 2026Review
- Application of the research domain criteria in early-phase clinical development of transdiagnostic neurotherapeutics: A multidisciplinary perspective.Neuroscience applied · 2026Review
- Aticaprant, a kappa opioid receptor antagonist, and the recovered 'interest and pleasure' in the concept of major depressive disorder.European archives of psychiatry and clinical neuroscience · 2025Review
- Kappa opioid receptors diminish spontaneous dopamine signals in awake mice through multiple mechanisms.Neuropharmacology · 2025Article
- PET Mapping of Receptor Occupancy Using Joint Direct Parametric Reconstruction.IEEE transactions on bio-medical engineering · 2025Article
- Novel medications for problematic alcohol use.The Journal of clinical investigation · 2024Review
- Development and Optimization ofACS pharmacology & translational science · 2023Review
- Preclinical evaluation of a brain penetrant PARP PET imaging probe in rat glioblastoma and nonhuman primates.European journal of nuclear medicine and molecular imaging · 2023Article
- The opioid system in depression.Neuroscience and biobehavioral reviews · 2022Review
- Strategic, feasibility, economic, and cultural aspects of phase 0 approaches: Is it time to change the drug development process in order to increase productivity?Clinical and translational science · 2022Review
- Kappa Opioid Receptor Ligands and Pharmacology: Diphenethylamines, a Class of Structurally Distinct, Selective Kappa Opioid Ligands.Handbook of experimental pharmacology · 2022Review
- Kappa Opioid Receptor Antagonists as Potential Therapeutics for Mood and Substance Use Disorders.Handbook of experimental pharmacology · 2022Article
- The Role of Dynorphin and the Kappa Opioid Receptor in Schizophrenia and Major Depressive Disorder: A Translational Approach.Handbook of experimental pharmacology · 2022Review
- Kappa Opioid Receptors in the Pathology and Treatment of Major Depressive Disorder.Handbook of experimental pharmacology · 2022Review
- Imaging Kappa Opioid Receptors in the Living Brain with Positron Emission Tomography.Handbook of experimental pharmacology · 2022Review
- Evaluation of Specific Binding of [ACS medicinal chemistry letters · 2021Article
- The Use, Standardization, and Interpretation of Brain Imaging Data in Clinical Trials of Neurodegenerative Disorders.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Review
- New agents and perspectives in the pharmacological treatment of major depressive disorder.Progress in neuro-psychopharmacology & biological psychiatry · 2021Review
- The kappa opioid receptor antagonist aticaprant reverses behavioral effects from unpredictable chronic mild stress in male mice.Psychopharmacology · 2020Article
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Authors and funding
15 authors.
Funding
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.
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