Retest imaging of [11C]NOP-1A binding to nociceptin/orphanin FQ peptide (NOP) receptors in the brain of healthy humans

doi:10.1016/j.neuroimage.2013.10.068

NeuroImage

Volume 87, 15 February 2014, Pages 89-95

https://doi.org/10.1016/j.neuroimage.2013.10.068 Get rights and content

Highlights

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We report reproducibility and reliability for [¹¹C]NOP-1A binding in human brain.
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Reproducibility was moderately good across most brain regions and modeling methods.
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Reliability was moderately good across most brain regions and modeling methods.
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[¹¹C]NOP-1A is useful to compare NOP receptor binding within and between subjects.

Abstract

[¹¹C]NOP-1A is a novel high-affinity PET ligand for imaging nociceptin/orphanin FQ peptide (NOP) receptors. Here, we report reproducibility and reliability measures of binding parameter estimates for [¹¹C]NOP-1A binding in the brain of healthy humans.

After intravenous injection of [¹¹C]NOP-1A, PET scans were conducted twice on eleven healthy volunteers on the same (10/11 subjects) or different (1/11 subjects) days. Subjects underwent serial sampling of radial arterial blood to measure parent radioligand concentrations. Distribution volume (V_T; a measure of receptor density) was determined by compartmental (one- and two-tissue) modeling in large regions and by simpler regression methods (graphical Logan and bilinear MA1) in both large regions and voxel data. Retest variability and intraclass correlation coefficient (ICC) of V_T were determined as measures of reproducibility and reliability respectively.

Regional [¹¹C]NOP-1A uptake in the brain was high, with a peak radioactivity concentration of 4–7 SUV (standardized uptake value) and a rank order of putamen > cingulate cortex > cerebellum. Brain time–activity curves fitted well in 10 of 11 subjects by unconstrained two-tissue compartmental model. The retest variability of V_T was moderately good across brain regions except cerebellum, and was similar across different modeling methods, averaging 12% for large regions and 14% for voxel-based methods. The retest reliability of V_T was also moderately good in most brain regions, except thalamus and cerebellum, and was similar across different modeling methods averaging 0.46 for large regions and 0.48 for voxels having gray matter probability > 20%. The lowest retest variability and highest retest reliability of V_T were achieved by compartmental modeling for large regions, and by the parametric Logan method for voxel-based methods.

Moderately good reproducibility and reliability measures of V_T for [¹¹C]NOP-1A make it a useful PET ligand for comparing NOP receptor binding between different subject groups or under different conditions in the same subject.

Introduction

Positron emission tomography (PET) is used to measure binding site occupancy of medications and differences in the receptor density between groups by comparing the measurements within or between subjects. The sensitivity and specificity of the PET studies are influenced by variation in quantification. In this regard, the test–retest imaging, wherein the same subject undergoes two identical scans, is useful to assess both within subject variations as reproducibility or between subject variations as reliability of the outcome measures (Laruelle, 1999).

Our laboratory recently developed carbon-11-labeled NOP-1A ([¹¹C]NOP-1A) as a promising PET radioligand for in vivo imaging of nociceptin/orphanin FQ peptide (NOP) receptors (Pike et al., 2011). [¹¹C]NOP-1A has high affinity, binds selectively to the NOP receptor as an antagonist, and has appropriate lipophilicity (log D = 3.41) for blood–brain barrier permeability. After [¹¹C]NOP-1A injection in monkeys, about 60% of brain radioactivity reflects specific (i.e., displaceable) binding to NOP receptors (Kimura et al., 2011). We used [¹¹C]NOP-1A to visualize NOP receptors in human brain for the first time, and quantified them as total distribution volume (V_T), which is proportional to receptor density (Lohith et al., 2012). V_T values were measured both in large brain regions by compartmental modeling and in individual voxels by simpler regression analyses. In addition, V_T values were well identified across brain regions and stable over time, which is consistent with radiometabolites not entering the brain.

However, by doing a single scan in each subject (Lohith et al., 2012), the precision of measuring binding can only be estimated mathematically based on standard errors (i.e. identifiability) to measure V_T. In the current study, we sought to determine the reproducibility and reliability of V_T by scanning each subject twice, i.e. test and retest scans. Reproducibility was measured as retest variability, and reliability was measured as intraclass correlation coefficient (ICC) (Laruelle, 1999). Retest variability and reliability were studied not only in large brain regions but also at the voxel level, because such parametric images are useful for localizing brain regions with altered binding in patient and control groups. Because voxel-wise analyses are prone to underestimate V_T, we compared two parametric methods (i.e., graphical Logan and MA1) with different sensitivities to underestimation. Furthermore, based on the results obtained we sought to determine the necessary sample size for alterations in a prospective between-subject receptor density studies.

Section snippets

Radioligand preparation

[¹¹C]NOP-1A was labeled by [¹¹C] methylation of an N-desmethyl precursor, as previously described (Pike et al., 2011). The radioligand was prepared according to our Investigational New Drug Application (114,313), which was submitted to the U.S. Food and Drug Administration; a copy is available at http://pdsp.med.unc.edu/snidd/IND/nop1a.html. The radioligand was obtained with high radiochemical purity (> 99%) and a specific activity of 128 ± 34 GBq/μmol at the time of injection (n = 22 batches).

Subjects

Eleven

Pharmacologic effects

The injected radioactivity (n = 22 injections in 11 subjects) of [¹¹C]NOP-1A was 691 ± 126 MBq (range, 228–760 MBq). The injected mass dose was 81 ± 32 pmol/kg (range, 25–155 pmol/kg). The injected radioactivity and mass dose did not differ statistically between the test and retest scans (Table 1). There were no adverse or clinically detectable pharmacologic effects in any subject during test or retest scans. No significant changes were observed in vital signs or electrocardiograms or the results of

Discussion

The present study sought to determine the reproducibility and reliability of measuring NOP binding by comparing V_T values from 2 [¹¹C]NOP-1A PET scans in the same subject. Reproducibility (measured as retest variability) and reliability (measured as ICC) of V_T were moderately good, but not excellent. We confirmed these measures both at regional-level using compartmental modeling and at voxel-level using simpler regression methods such as Logan and bilinear MA1. The Logan voxel-wise method tends

Conclusion

The present study confirms that [¹¹C]NOP-1A has high brain uptake and regional distribution in human brain consistent with that of NOP receptors. [¹¹C]NOP-1A can quantify NOP receptor binding in terms of distribution volume both at the regional level using compartmental model and at the voxel level using simpler regression analyses. The absolute value, reproducibility, and reliability of V_T were comparable among different models, with compartmental model providing the most reproducible and

Acknowledgments

This study was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) and by a Cooperative Research and Development Agreement with Eli Lilly & Co. We thank Denise Rallis-Frutos, Gerald L. Hodges, Kimberly Jenko, David Clark, Jeih-San Liow, Robert L. Gladding, Paolo Zanotti-Fregonara, and the staff of the PET Department for assistance in completing the studies, and PMOD Technologies (Zurich, Switzerland) for providing

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Imaging Nociceptin Opioid Peptide Receptors in Alcohol Use Disorder With [11C]NOP-1A and Positron Emission Tomography: Findings From a Second Cohort
2023, Biological Psychiatry
Nociceptin, which binds to the nociceptin opioid peptide receptor (NOP), regulates stress and reward in addiction. In a previous [¹¹C]NOP-1A positron emission tomography (PET) study, we found no differences in NOP in non–treatment-seeking individuals with alcohol use disorder (AUD) relative to healthy control subjects Here, we evaluated NOP in treatment-seeking individuals with AUD to document its relationship with relapse to alcohol.
[¹¹C]NOP-1A distribution volume (V_T) was measured in recently abstinent individuals with AUD and healthy control subjects (n = 27/group) using an arterial input function–based kinetic analysis in brain regions that regulate reward and stress behaviors. Recent heavy drinking before PET was quantified using hair ethyl glucuronide (≥30 pg/mg was defined as heavy drinking). To document relapse, 22 subjects with AUD were followed with urine ethyl glucoronide tests (3/week) for 12 weeks after PET, where they were incentivized with money to abstain.
There were no differences in [¹¹C]NOP-1A V_T between individuals with AUD and healthy control subjects. Individuals with AUD who drank heavily before the study had significantly lower V_T than those with no recent heavy drinking history. Significant negative correlations between V_T and the number of drinking days and the number of drinks consumed per drinking day in the 30 days before enrollment were also present. Individuals with AUD who relapsed (and dropped out) had significantly lower V_T than those who abstained for 12 weeks.
Lower NOP V_T in heavy drinking AUD predicted relapse to alcohol during a 12-week follow-up period. The results of this PET study support the need to investigate medications that act at NOP to prevent relapse in individuals with AUD.
Contribution of the opioid system to depression and to the therapeutic effects of classical antidepressants and ketamine
2023, Life Sciences
Major depressive disorder (MDD) afflicts approximately 5 % of the world population, and about 30–50 % of patients who receive classical antidepressant medications do not achieve complete remission (treatment resistant depressive patients). Emerging evidence suggests that targeting opioid receptors mu (MOP), kappa (KOP), delta (DOP), and the nociceptin/orphanin FQ receptor (NOP) may yield effective therapeutics for stress-related psychiatric disorders. As depression and pain exhibit significant overlap in their clinical manifestations and molecular mechanisms involved, it is not a surprise that opioids, historically used to alleviate pain, emerged as promising and effective therapeutic options in the treatment of depression. The opioid signaling is dysregulated in depression and numerous preclinical studies and clinical trials strongly suggest that opioid modulation can serve as either an adjuvant or even an alternative to classical monoaminergic antidepressants. Importantly, some classical antidepressants require the opioid receptor modulation to exert their antidepressant effects. Finally, ketamine, a well-known anesthetic whose extremely efficient antidepressant effects were recently discovered, was shown to mediate its antidepressant effects via the endogenous opioid system. Thus, although opioid system modulation is a promising therapeutical venue in the treatment of depression further research is warranted to fully understand the benefits and weaknesses of such approach.
The opioid system in depression
2022, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
Selective radioligands for imaging brain NOP receptors with PET, including 11C-NOP-1A and 18F-MK-0911, have been developed (Lohith et al., 2012; Pike et al., 2011). 11C-NOP-1A PET has demonstrated regional distribution in the healthy human brain with cortical and subcortical structures such as the caudate and thalamus having higher uptake (Lohith et al., 2014), however studies are yet to apply 11C-NOP-1A to examine NOP receptor density in depressed patients. Nonetheless, the 11C-NOP-1A tracer has proven useful for the assessment between NOP receptor occupancy, dose, and plasma concentration of the NOP antagonist LY2940094, helping to determine an appropriate dosing strategy (40 mg/daily) to achieve sustainably high NOP receptor occupancy suitable to test clinical efficacy (Raddad et al., 2016).
Opioid receptors are widely distributed throughout the brain and play an essential role in modulating aspects of human mood, reward, and well-being. Accumulating evidence indicates the endogenous opioid system is dysregulated in depression and that pharmacological modulators of mu, delta, and kappa opioid receptors hold potential for the treatment of depression. Here we review animal and clinical data, highlighting evidence to support: dysregulation of the opioid system in depression, evidence for opioidergic modulation of behavioural processes and brain regions associated with depression, and evidence for opioidergic modulation in antidepressant responses. We evaluate clinical trials that have examined the safety and efficacy of opioidergic agents in depression and consider how the opioid system may be involved in the effects of other treatments, including ketamine, that are currently understood to exert antidepressant effects through non-opioidergic actions. Finally, we explore key neurochemical and molecular mechanisms underlying the potential therapeutic effects of opioid system engagement, that together provides a rationale for further investigation into this relevant target in the treatment of depression.
Acute Elevations in Cortisol Increase the In Vivo Binding of [11C]NOP-1A to Nociceptin Receptors: A Novel Imaging Paradigm to Study the Interaction Between Stress- and Antistress-Regulating Neuropeptides
2020, Biological Psychiatry
Citation Excerpt :
The magnetic resonance–PET image alignment was performed using a normalized mutual information algorithm. ROIs included the amygdala, hippocampus, midbrain, ventral striatum, caudate, putamen, dorsolateral prefrontal cortex, orbital frontal cortex, medial prefrontal cortex, anterior cingulate cortex, and cerebellum (22). ROIs were generated for each subject based on the Automated Anatomical Labeling–Volumes of Interest atlas using the built-in brain parcellation workflow within PMOD’s Neuro Tool (PNEURO module).
An imbalance between neuropeptides that promote stress and resilience, such as corticotropin-releasing factor and nociceptin, has been postulated to underlie relapse in addiction. The objective of this study was to develop a paradigm to image the in vivo interaction between stress-promoting neuropeptides and nociceptin (NOP) receptors in humans.
[¹¹C]NOP-1A positron emission tomography was used to measure the binding to NOP receptors at baseline (BASE) and following an intravenous hydrocortisone challenge (CORT) in 19 healthy control subjects. Hydrocortisone was used as a challenge because in microdialysis studies it has been shown to increase corticotropin-releasing factor release in extrahypothalamic brain regions such as the amygdala. [¹¹C]NOP-1A total distribution volume (V_T) in 11 regions of interest were measured using a 2-tissue compartment kinetic analysis. The primary outcome measure was hydrocortisone-induced ΔV_T calculated as (V_{T CORT} − V_{T BASE})/V_{T BASE}.
Hydrocortisone led to an acute increase in plasma cortisol levels. Regional [¹¹C]NOP-1A V_T was on average 11% to 16% higher in the post-hydrocortisone condition compared with the baseline condition (linear mixed model, condition, p = .005; region, p < .001; condition × region, p < .001). Independent Student's t tests in all regions of interest were statistically significant and survived multiple comparison correction. Hydrocortisone-induced ΔV_T was significantly negatively correlated with baseline V_T in several regions of interest.
Hydrocortisone administration increases NOP receptor availability. Increased NOP in response to elevated cortisol might suggest a compensatory mechanism in the brain to counteract corticotropin-releasing factor and/or stress. The [¹¹C]NOP-1A and hydrocortisone imaging paradigm should allow for the examination of interactions between stress-promoting neuropeptides and NOP in addictive disorders.
Decreased Nociceptin Receptors Are Related to Resilience and Recovery in College Women Who Have Experienced Sexual Violence: Therapeutic Implications for Posttraumatic Stress Disorder
2019, Biological Psychiatry
Citation Excerpt :
PET imaging sessions were conducted with the Siemens Biograph64 mCT scanner (Siemens Healthineers). The injected dose and mass of [11C]NOP-1A were restricted to 12 mCi and ≤4.2 μg (29). Following a low-dose computed tomography scan of the brain acquired for attenuation correction, subjects received an intravenous bolus injection of [11C]NOP-1A, and emission data were collected for 70 minutes (17).
Posttraumatic stress disorder (PTSD) is a stress disorder that develops in only some individuals following a traumatic event. Data suggest that a substantial fraction of women recover after sexual violence. Thus, the investigation of stress and antistress neuropeptides in this sample has the potential to inform the neurochemistry of resilience following trauma. Nociceptin is an antistress neuropeptide in the brain that promotes resilience in animal models of PTSD.
[¹¹C]NOP-1A positron emission tomography was used to measure the in vivo binding to nociceptin receptors in 18 college women who had experienced sexual violence irrespective of whether they met DSM-5 diagnostic criteria for PTSD. [¹¹C]NOP-1A data from 18 healthy control subjects were also included to provide a contrast with the sexual violence group. [¹¹C]NOP-1A total distribution volume (V_T) in the regions of interest were measured with kinetic analysis using the arterial input function. The relationships between regional V_T and Clinician-Administered PTSD Scale for DSM-5 total symptom and subscale severity were examined using correlational analyses.
No differences in [¹¹C]NOP-1A V_T were noted between the sexual violence and control groups. V_T in the midbrain and cerebellum were positively correlated with PTSD total symptom severity in the past month before positron emission tomography. Intrusion/re-experiencing and avoidance subscale symptoms drove this relationship. Stratification of subjects by a DSM-5 PTSD diagnosis and contrasting their V_T with that in control subjects showed no group differences.
Decreased midbrain and cerebellum nociceptin receptors are associated with less severe PTSD symptoms. Medications that target nociceptin should be explored to prevent and treat PTSD.
Nociceptin Receptors in Alcohol Use Disorders: A Positron Emission Tomography Study Using [11C]NOP-1A
2018, Biological Psychiatry
Citation Excerpt :
To determine the plasma activity representing unmetabolized parent compound ([11C]NOP-1A), seven samples (collected at 4, 8, 12, 20, 30, 40, and 60 minutes) were further processed using high-performance liquid chromatography methods previously described (13). The seven measured parent fractions for [11C]NOP-1A were fitted using a Hill model (28,29) consistent with that reported in prior validation studies (17,19). Plasma free fraction was determined using ultrafiltration, as previously described (30,31).
The neuropeptide transmitter nociceptin, which binds to the nociceptin/orphanin FQ peptide (NOP) receptor, is a core component of the brain's antistress system. Nociceptin exerts its antistress effect by counteracting the functions of corticotropin-releasing factor, the primary stress-mediating neuropeptide in the brain. Basic investigations support a role for medications that target nociceptin receptors in the treatment of alcohol use disorders. Thus, it is of high interest to measure the in vivo status of NOP receptors in individuals with alcohol use disorders.
Here, we used [¹¹C]NOP-1A and positron emission tomography to measure the in vivo binding to NOP receptors in 15 alcohol-dependent humans as identified by DSM-IV and 15 healthy control subjects matched for age, sex, and smoking status. Alcohol-dependent individuals with no comorbid psychiatric, medical, or drug abuse disorders were scanned following 2 weeks of outpatient monitored abstinence (confirmed with three times per week urine alcohol metabolite testing). [¹¹C]NOP-1A distribution volume in regions of interest (including the amygdala, hippocampus, and midbrain, striatal, and prefrontal cortical subdivisions) was measured with kinetic analysis using the arterial input function.
Regional [¹¹C]NOP-1A distribution volume in alcohol dependence was not significantly different compared with healthy control subjects. No relationship between [¹¹C]NOP-1A distribution volume and other clinical measures (including duration and severity of alcohol abuse, craving, and anxiety or depressive symptoms) were significant after correction for the multiple hypotheses tested.
The results of this study do not support alterations in the binding to NOP receptors in alcohol dependence. However, this finding does not necessarily rule out alterations in nociceptin transmission in alcohol dependence.

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^☆: Disclosures: This study was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) and by a Cooperative Research and Development Agreement with Eli Lilly & Co.

¹: This work was performed during Dr. Lohith's postdoctoral fellowship at NIH.

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Retest imaging of [11C]NOP-1A binding to nociceptin/orphanin FQ peptide (NOP) receptors in the brain of healthy humans☆

Highlights

Abstract

Introduction

Section snippets

Radioligand preparation

Subjects

Pharmacologic effects

Discussion

Conclusion

Acknowledgments

Neuropsychopharmacology

J. Pharm. Sci.

Neuroimage

Nucl. Med. Biol.

Neuroimage

Neuroimage

Neuroimage

Role of nociceptin/orphanin FQ and NOP receptors in the response to acute and repeated restraint stress in rats

J. Neuroendocrinol.

In vivo variation in metabotropic glutamate receptor subtype 5 binding using positron emission tomography and [11C]ABP688

J. Cereb. Blood Flow Metab.

Reduced metabotropic glutamate receptor 5 density in major depression determined by [(11)C]ABP688 PET and postmortem study

Am. J. Psychiatry

Effects of temporal sampling, glucose metabolic rates, and disruptions of the blood–brain barrier on the FDG model with and without a vascular compartment: studies in human brain tumors with PET

J. Cereb. Blood Flow Metab.

Measurement of central mu-opioid receptor binding in vivo with PET and [11C]carfentanil: a test–retest study in healthy subjects

Eur. J. Nucl. Med. Mol. Imaging

Retest imaging of [¹¹C]NOP-1A binding to nociceptin/orphanin FQ peptide (NOP) receptors in the brain of healthy humans☆