The kappa opioid receptors (KORs) have been implicated in a number of neuropsychiatric disorders including depression, anxiety and stress-related disorders, addictions, as well as Alzheimer's disease. The availability of validated PET imaging agents will provide non-invasive biomarker to investigate the KOR and gain insights into the function and dysfunction of this receptor in these disorders. Until recently there were no PET radiotracers for use in humans to image KOR, although tracers for other opioid receptors have been available. We are the first to have conducted the initial test of a pair of selective KOR agonist ([11C]GR103545) and antagonist ([11C]LY2795050) tracers in humans for the in vivo quantification of KORs. This is significant, as an antagonist tracer measures the total receptor availability, while an agonist tracer measures only the availability of receptors configured in the high affinity state, which is the functional, or active state. Therefore, the availability of an agonist/antagonist pair of PET tracers will, for the first time, allow the simultaneous assessment of both total KOR receptor expression, and, as importantly, the portion of KOR configured in its functional state, which may change in disease conditions. Building upon our initial human experience, the first major goal of this proposal is to establish the reliability and validity of [11C]GR103545 and [11C]LY2795050 as PET imaging agents for the quantification of KOR in humans. The validation and successful application of selective PET imaging agents for the KOR will have broad impact in the investigation and elucidation of the opioid system and the KORs, in gaining further understanding in the involvement of this receptor subtype in brain disorders, and in the development of novel therapeutics for a wide range of pathological conditions. Many psychiatric disorders, chief among them depression, anxiety and addictions, display strong sex differences in prevalence, time course, and/or treatment response. Understanding sex differences in neuroreceptor expression and function will provide insights into the biochemical processes of these disorders and inform treatment development of sex-specific pharmacotherapies. PET imaging is a powerful tool in this investigation, as it allows the investigation of receptor availability in the living human subjects. Therefore, the second major goal of this application is to use the validated KOR-selective PET tracers to investigate the effects of sex and age on the availability of total receptor, and the portion configured in the functional, high affinity state, in the living brain. We also will explore whether there is an age effect on KOR given that the regional densities of most receptors and transporters decrease with age. It is noteworthy, however, that 5 opioid receptor densities were shown to increase with age, and thus it may be possible that the regulation of opioid receptors is distinctly different from that of other receptor types. The investigation in this proposal will help provide answer to this question.

Public Health Relevance

This grant application proposes to validate the kappa opiate receptor radiotracers carbon-11 GR103545 and carbon-11 LY2795050 as a positron emission tomography (PET) imaging biomarkers for use in biomedical imaging research. The kappa opiate receptor is believed to be involved in a number of psychiatric disorders, addictive behaviors, and other diseases of the brain, therefore the availability of validated PET imaging biomarkers will provide the biomedical research community with a non-invasive way of investigating the function and regulation of the kappa opiate receptor protein under normal conditions, as well as its possible dysfunction in diseases. Furthermore, PET imaging biomarkers can be used to investigate whether a drug reaches its intended target and produces therapeutic efficacy, and determine the most appropriate doses with minimal side effects, therefore aiding in the development of new and effective treatments for various psychiatric disorders, addictions, and other diseases of the brain.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1-NT-B (09))
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Meinecke, Douglas L
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Yale University
Schools of Medicine
New Haven
United States
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Vijay, Aishwarya; Cavallo, Dana; Goldberg, Alissa et al. (2018) PET imaging reveals lower kappa opioid receptor availability in alcoholics but no effect of age. Neuropsychopharmacology 43:2539-2547
Cai, Zhengxin; Li, Songye; Pracitto, Richard et al. (2017) Fluorine-18-Labeled Antagonist for PET Imaging of Kappa Opioid Receptors. ACS Chem Neurosci 8:12-16
Vijay, Aishwarya; Wang, Shuo; Worhunsky, Patrick et al. (2016) PET imaging reveals sex differences in kappa opioid receptor availability in humans, in vivo. Am J Nucl Med Mol Imaging 6:205-14
Naganawa, Mika; Zheng, Ming-Qiang; Henry, Shannan et al. (2015) Test-retest reproducibility of binding parameters in humans with 11C-LY2795050, an antagonist PET radiotracer for the ? opioid receptor. J Nucl Med 56:243-8
Naganawa, Mika; Jacobsen, Leslie K; Zheng, Ming-Qiang et al. (2014) Evaluation of the agonist PET radioligand [¹¹C]GR103545 to image kappa opioid receptor in humans: kinetic model selection, test-retest reproducibility and receptor occupancy by the antagonist PF-04455242. Neuroimage 99:69-79