Publications by authors named "Hiroto Kuwabara"

83 Publications

Molecular imaging of beta-amyloid deposition in late-life depression.

Neurobiol Aging 2021 May 15;101:85-93. Epub 2021 Jan 15.

Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Late-life depression (LLD) is associated with an increased risk of all-cause dementia and may involve Alzheimer's disease pathology. Twenty-one LLD patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for a current major depressive episode and 21 healthy controls underwent clinical and neuropsychological assessments, magnetic resonance imaging to measure gray matter volumes, and high-resolution positron emission tomography to measure beta-amyloid (Aβ) deposition. Clinical and neuropsychological assessments were repeated after 10-12 weeks of Citalopram or Sertraline treatment (LLD patients only). LLD patients did not differ from healthy controls in baseline neuropsychological function, although patients improved in both depressive symptoms and visual-spatial memory during treatment. Greater Aβ in the left parietal cortex was observed in LLD patients compared with controls. Greater Aβ was correlated with greater depressive symptoms and poorer visual-spatial memory, but not with improvement with treatment. The study of LLD patients with prospective measurements of mood and cognitive responses to antidepressant treatment is an opportunity to understand early neurobiological mechanisms underlying the association between depression and subsequent cognitive decline.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.01.002DOI Listing
May 2021

Molecular Imaging of the Serotonin Transporter Availability and Occupancy by Antidepressant Treatment in Late-Life Depression.

Neuropharmacology 2021 Jan 12:108447. Epub 2021 Jan 12.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.

Patients with late-life depression (LLD) have a more variable response to pharmacotherapy relative to patients with mid-life depression. Degeneration of the serotonergic system and lower occupancy of the initial target for antidepressant medications, the serotonin transporter (5-HTT) may contribute to variability in treatment response. The focus of this study was to test the hypotheses that lower cortical and limbic 5-HTT availability in LLD patients relative to controls and less 5-HTT occupancy by antidepressant medications would be associated with less improvement in mood and cognition with treatment in the LLD patients. Twenty LLD patients meeting DSM-IV criteria for a current major depressive episode and 20 non-depressed controls underwent clinical and neuropsychological assessments, magnetic resonance imaging to measure grey matter volumes and high-resolution positron emission tomography (PET) scanning to measure 5-HTT before and after 10-12 weeks of treatment with citalopram or sertraline (patients only). Prior to treatment, 5-HTT was lower in LLD patients relative to controls in cortical and limbic (amygdala) regions. Grey matter volumes were not significantly different between groups. 5-HTT occupancy was detected throughout cortical, striatal, thalamic and limbic (amygdala, hippocampus) regions. The magnitude of 5-HTT occupancy by antidepressants was 70% or greater across cortical and sub-cortical regions, consistent with the magnitude of 5-HTT occupancy observed in mid-life depressed patients. Greater regional 5-HTT occupancy correlated with greater improvement in depressive symptoms and visual-spatial memory performance. These data support the hypothesis that serotonin degeneration and variability in 5-HTT occupancy may contribute to heterogeneity in treatment response in LLD patients.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108447DOI Listing
January 2021

Correction to: An open-label, positron emission tomography study of the striatal D/D receptor occupancy and pharmacokinetics of single-dose oral brexpiprazole in healthy participants.

Eur J Clin Pharmacol 2021 Jan 4. Epub 2021 Jan 4.

Section of High Resolution Brain PET, Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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http://dx.doi.org/10.1007/s00228-020-03071-zDOI Listing
January 2021

An open-label, positron emission tomography study of the striatal D/D receptor occupancy and pharmacokinetics of single-dose oral brexpiprazole in healthy participants.

Eur J Clin Pharmacol 2021 May 16;77(5):717-725. Epub 2020 Nov 16.

Section of High Resolution Brain PET, Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Purpose: The aim of this Phase 1, open-label, positron emission tomography (PET) study was to determine the degree of striatal D/D receptor occupancy induced by the serotonin-dopamine activity modulator, brexpiprazole, at different single dose levels in the range 0.25-6 mg.

Methods: Occupancy was measured at 4 and 23.5 h post-dose using the D/D receptor antagonist [C]raclopride. The pharmacokinetics, safety and tolerability of brexpiprazole were assessed in parallel.

Results: Fifteen healthy participants were enrolled (mean age 33.9 years; 93.3% male). Mean D/D receptor occupancy in the putamen and caudate nucleus increased with brexpiprazole dose, leveled out at 77-88% with brexpiprazole 5 mg and 6 mg at 4 h post-dose, and remained at a similar level at 23.5 h post-dose (74-83%). Estimates of maximum obtainable receptor occupancy (O) were 89.2% for the putamen and 95.4% for the caudate nucleus; plasma concentrations predicted to provide 50% of O (EC) were 8.13 ng/mL and 7.75 ng/mL, respectively. Brexpiprazole area under the concentration-time curve (AUC) and maximum plasma concentration (C) increased approximately proportional to dose. No notable subjective or objective adverse effects were observed in this cohort.

Conclusion: By extrapolating the observed single-dose D/D receptor occupancy data in healthy participants, multiple doses of brexpiprazole 2 mg/day and above are expected to result in an efficacious brexpiprazole concentration, consistent with clinically active doses in schizophrenia and major depressive disorder.

Trial Registration: ClinicalTrials.gov NCT00805454 December 9, 2008.
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http://dx.doi.org/10.1007/s00228-020-03021-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032567PMC
May 2021

Ethnic disparities in pain processing among healthy adults: μ-opioid receptor binding potential as a putative mechanism.

Pain 2020 04;161(4):810-820

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Although ethnic differences in pain perception are well documented, the underlying mechanism for these outcomes has not been established. µ-opioid receptor (MOR) function might contribute to this disparity, given that MORs play a key role in pain sensitivity and modulation. However, no study has characterized ethnic differences in MOR physiology. This study sought to address this knowledge gap by examining differences in µ-selective agonist binding potential (BPND; [C]-Carfentanil) between 27 non-Hispanic black (NHB) and 27 demographically similar, non-Hispanic white participants. Participants completed questionnaires and two 90-minute high-resolution research tomograph positron emission tomography (PET) imaging sessions. During PET imaging, a capsaicin or control cream was applied to individuals' arms, and pain ratings were collected. Bonferroni-corrected PET volumes of interest analyses revealed significantly greater [C]-Carfentanil BPND among NHB participants in bilateral ventral striatum ([left]: F1,52 = 16.38, P < 0.001; [right]: F1,52 = 21.76, P < 0.001), bilateral dorsolateral prefrontal cortex ([left] F1,52 = 17.3, P < 0.001; [right]: F1,52 = 14.17, P < 0.001), bilateral subgenual anterior cingulate cortex ([left]: F1,52 = 10.4, P = 0.002; [right]: F1,52 = 12.91, P = 0.001), and right insula (F1,52 = 11.0, P = 0.002). However, there were no significant main effects of condition or ethnicity × condition interaction effects across models, likely attributable to individual variability in the direction of change within groups. BPND values were significantly correlated with pain ratings collected during the capsaicin condition (r range = 0.34-0.46, P range = 0.01-0.001). Results suggest that NHB individuals might have generally greater unoccupied MOR density than non-Hispanic white peers. Findings have implications for physiological differences underlying ethnicity-related pain disparities. If replicated, these results further emphasize the need for tailored treatments in historically underserved populations.
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http://dx.doi.org/10.1097/j.pain.0000000000001759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085427PMC
April 2020

The Relationship of Varenicline Agonism of α4β2 Nicotinic Acetylcholine Receptors and Nicotine-Induced Dopamine Release in Nicotine-Dependent Humans.

Nicotine Tob Res 2020 05;22(6):892-899

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.

Introduction: Cigarette smoking continues to be one of the most important behavioral causes of morbidity and mortality in the world. Varenicline, an α4β2 nicotinic acetylcholine receptor (nAChR) partial agonist, has been shown to increase smoking quit rates compared with nicotine-based products. This human laboratory, double-blind, placebo-controlled study examined varenicline and placebo effects on α4β2-nAChRs occupancy, nicotine-induced change in [11C]raclopride non-displaceable binding potential (BPND), and behavioral measures of cigarette smoking, nicotine craving, and withdrawal.

Methods: Current nicotine dependent daily smokers (N = 17) were randomized to varenicline 1 mg twice daily or placebo for 13 days. Using positron emission tomography), we characterized α4β2-nAChRs occupancy using [18F]AZAN and dopamine receptor binding using [11C]raclopride as well as behavioral measures of cigarettes smoked, craving, and nicotine withdrawal.

Results: Varenicline compared with placebo resulted in significant reductions in [18F]AZAN BPND in multiple brain regions including thalamus, midbrain, putamen, and ventral striatum. Following administration of a controlled-dose nicotine cigarette, dopamine release was significantly suppressed in the ventral striatum in the varenicline-treated compared with the placebo group. There was a significant relationship between α4β2-nAChRs BPND measured in thalamus during the [18F]AZAN scan and nicotine-induced change in raclopride BPND in the ventral striatum.

Conclusion: This is the first human study to demonstrate a direct relationship between the extent of varenicline occupancy of α4β2-nAChRs and the magnitude of dopamine release following nicotine use.

Implications: It has remained unclear how nicotinic receptor blockade through partial agonist medications such as varenicline promotes smoking cessation. One hypothesized mechanism is downstream dampening of the mesolimbic reward dopamine system. For the first time in human smokers, we observed a direct relationship between the extent of varenicline blockade of α4β2-nACh nicotinic receptors and the magnitude of dopamine release following smoking. This has mechanistic and therapeutic implications for improving smoking cessation interventions.
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http://dx.doi.org/10.1093/ntr/ntz080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529151PMC
May 2020

Comparison of Quantitative and Qualitative Oxygen Extraction Fraction (OEF) in Acute Stroke Patients with Large Vessel Occlusion.

Adv Exp Med Biol 2018 ;1072:45-51

Department of Neurosurgery, University of New Mexico, Albuquerque, NM, USA.

The superficial temporal artery-middle cerebral artery bypass (STA-MCA) bypass surgery developed by Donaghy and Yarsagil in 1967 provided relief for patients with acute stroke and large vessel occlusive vascular disease. Early reports showed low morbidity and good outcomes. However, a large clinical trial in 1985 reported a failure of extracranial-intracranial (EC/IC) bypass to show benefit in reducing the risk of stroke compared to best medical treatment. Problems with the study included cross overs to surgery from best medical treatment, patients unwilling to be randomized and chose EC/IC surgery, and loss of patients to follow-up. Most egregious is the fact that the study did not attempt to identify and select the patients at high risk for a second stroke. Based on these shortcomings of the EC/IC bypass study, a carotid occlusion surgery study (COSS) was proposed by Dr. William Powers and colleagues using qualitative hemispheric oxygen extraction fraction (OEF) by positron emission tomography (PET) between the contralateral and ipsilateral hemispheres with a ratio of 1.16 indicative of hemodynamic compromise. To increase patient enrollment, several compromises were made mid study. First. The ratio threshold was lowered to 1.12 and the level of occlusion in the carotid reduced from 70% to 60%. Despite these compromises the study was closed for futility, apparently because the stroke rate in the medically treated group was too low. Thus, the question as to the benefit of EC/IC bypass surgery remains unresolved. In our NIH funded study Quantitative Occlusive Vascular Disease Study (QUOVADIS), we used quantitative OEF to evaluate stroke risk and compared it to the qualitative count-rate ratio method used in the COSS study and found that these two methods did not identify the same patients at increased risk for stroke, which may explain the reason for the failure of the COSS study as our results show that qualitative OEF ratios do not identify the same patients as quantitative OEF.
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http://dx.doi.org/10.1007/978-3-319-91287-5_8DOI Listing
January 2019

Evaluation of F-RO-948 PET for Quantitative Assessment of Tau Accumulation in the Human Brain.

J Nucl Med 2018 12 10;59(12):1877-1884. Epub 2018 Aug 10.

Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.

The availability of tau PET radioligands enables quantitative assessment of tau density and distribution in the human brain. We evaluated the kinetics of a novel radioligand, F-RO-948 (previously referred to as F-RO6958948), and its ability to identify tau positivity in individual patients with mild Alzheimer disease (AD). Eleven subjects with amyloid-positive mild AD, 5 amyloid-negative older control subjects (OC), and 5 younger control subjects (YC) completed 1 or 2 (4 AD and 5 OC) PET scans with F-RO-948 for 90, 120, or 200 min. The kinetics of the radioligand was evaluated with standard compartmental and noncompartmental models (with plasma data in 70% of cases), tissue-reference methods, and SUV ratio. These approaches were applied to assess the ability of F-RO-948 to discriminate AD subjects from OC subjects. The plasma reference graphical analysis appeared to be the optimal method of quantification for F-RO-948, yielding strictly time-consistent values of distribution volume and distribution volume ratio at 90 min against the analyses at 120 and 200 min. The reference tissue graphical analysis and SUV ratio were cross-validated against plasma reference graphical analysis. Test-retest evaluation showed excellent reproducibility. A proposed novel index of tau load, the regional tau-positive fraction, showed high values in the medial and lateral temporal and parietal regions in AD and successfully separated AD subjects from OC and YC subjects with a significant margin. F-RO-948 appears to be a promising radioligand for quantitative imaging of tau in the brain of AD patients.
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http://dx.doi.org/10.2967/jnumed.118.214437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278898PMC
December 2018

Characterization of 3 Novel Tau Radiopharmaceuticals, C-RO-963, C-RO-643, and F-RO-948, in Healthy Controls and in Alzheimer Subjects.

J Nucl Med 2018 12 4;59(12):1869-1876. Epub 2018 May 4.

Pharma Research and Early Development, Hoffmann-La Roche, Basel, Switzerland.

C-RO-963, C-RO-643, and F-RO-948 (previously referred to as C-RO6924963, C-RO6931643, and F-RO6958948, respectively) have been reported as promising PET tracers for tau imaging based on in vitro and preclinical PET data. Here we describe the first, to our knowledge, human evaluation of these novel radiotracers. Amyloid PET-positive Alzheimer disease (AD) subjects and younger controls each received 2 different tau tracers. Dynamic 90-min scans were obtained after bolus injection of C-RO-963, C-RO-643, or F-RO-948. Arterial blood sampling was performed on 11 healthy controls and 11 AD subjects. Regions were defined on MR images, and PET data were quantified by plasma reference graphical analysis (for total distribution volume) and target cerebellum ratio (SUV ratios of 60- to 90-min frames). SUV ratio images were also analyzed voxelwise. Five older controls each underwent 2 scans with F-RO-948 for evaluation of test-retest variability. Four AD subjects underwent a repeated F-RO-948 scan 6-22 mo after the first scan. Six additional healthy controls (3 men and 3 women; age range, 41-67 y) each underwent 1 whole-body dosimetry scan with F-RO-948. In younger controls, SUV was observed in the temporal lobe with values of approximately 3.0 for C-RO-963, 1.5 for C-RO-643, and 3.5 for F-RO-948. Over all brain regions and subjects, the trend was for F-RO-948 to have the highest SUV, followed by C-RO-963 and then C-RO-643. Regional analysis of SUV ratio and total distribution volume for C-RO-643 and F-RO-948 clearly discriminated the AD group from the healthy control groups. Compartmental modeling confirmed that C-RO-643 had lower brain entry than either C-RO-963 or F-RO-948 and that F-RO-948 showed better contrast between (predicted) areas of high versus low tau accumulation. Thus, our subsequent analysis focused on F-RO-948. Both voxelwise and region-based analysis of F-RO-948 binding in healthy controls versus AD subjects revealed multiple areas where AD subjects significantly differed from healthy controls. Of 22 high-binding regions, 13 showed a significant group difference (after ANOVA, = 45, < 10). Voxelwise analysis also revealed a set of symmetric clusters where AD subjects had higher binding than healthy controls (threshold of < 0.001, cluster size > 50). F-RO-948 demonstrates characteristics superior to C-RO-643 and C-RO-963 for characterization of tau pathology in AD. Regional binding data and kinetic properties of F-RO-948 compare favorably with other existing tau PET tracers.
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http://dx.doi.org/10.2967/jnumed.118.209916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278896PMC
December 2018

Brain PET Imaging of α7-nAChR with [18F]ASEM: Reproducibility, Occupancy, Receptor Density, and Changes in Schizophrenia.

Int J Neuropsychopharmacol 2018 07;21(7):656-667

Russell H. Morgan Department of Radiology and Radiological Sciences, Baltimore, Maryland.

Background: The α7 nicotinic acetylcholine receptor increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The highly cortical distribution of α7 nicotinic acetylcholine receptor suggests a role in cognition.

Methods: We expanded the first-in-human PET imaging of α7 nicotinic acetylcholine receptor with [18F]ASEM from 5 to 21 healthy nonsmoking volunteers and added a feasibility study in 6 male patients with schizophrenia. Study aims included: (1) confirmation of test-retest reproducibility of [18F]ASEM binding, (2) demonstration of specificity by competition with DMXB-A, an α7 nicotinic acetylcholine receptor partial agonist, (3) estimation of [18F]ASEM binding potentials and α7 nicotinic acetylcholine receptor density in vivo in humans, and (4) demonstrating the feasibility of studying α7 nicotinic acetylcholine receptor as a target for schizophrenia.

Results: Test-retest PET confirmed reproducibility (>90%) (variability ≤7%) of [18F]ASEM volume of distribution (VT) estimates in healthy volunteers. Repeated sessions of PET in 5 healthy subjects included baseline and effect of inhibition after oral administration of 150 mg DMXB-A. From reduction of binding potentials, we estimated the dose-dependent occupancy of α7 nicotinic acetylcholine receptor by DMXB-A at 17% to 49% for plasma concentrations at 60 to 200 nM DMXB-A. In agreement with evidence postmortem, α7 nicotinic acetylcholine receptor density averaged 0.67 to 0.82 nM and inhibitor affinity constant averaged 170 to 385 nM. Median VT in a feasibility study of 6 patients with schizophrenia was lower than in healthy volunteers in cingulate cortex, frontal cortex, and hippocampus (P = 0.02, corrected for multiple comparions, Mann-Whitney test).

Conclusions: The current results confirm the reproducibility of [18F]ASEM VT estimates and the specificity of the tracer for α7 nicotinic acetylcholine receptor. Preliminary findings from our feasibility study of [18F]ASEM binding in patients with schizophrenia are suggestive and provide guidance for future studies with more subjects.
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http://dx.doi.org/10.1093/ijnp/pyy021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030963PMC
July 2018

F-XTRA PET for Enhanced Imaging of the Extrathalamic α4β2 Nicotinic Acetylcholine Receptor.

J Nucl Med 2018 10 1;59(10):1603-1608. Epub 2018 Mar 1.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland

Reduced density of the α4β2 nicotinic acetylcholine receptor (α4β2-nAChR) in the cortex and hippocampus of the human brain has been reported in aging and patients with neurodegenerative disease. This study assessed the pharmacokinetic behavior of F-(-)-JHU86428 (F-XTRA), a new radiotracer for in vivo PET imaging of the α4β2-nAChR, particularly in extrathalamic regions of interest in which the α4β2-nAChR is less densely expressed than in thalamus. F-XTRA was also used to evaluate the α4β2-nAChR in the hippocampus in human aging. Seventeen healthy nonsmoker adults (11 men, 6 women; age, 30-82 y) underwent PET neuroimaging over 90 or 180 min in a high-resolution research tomograph after bolus injection of F-XTRA. Methods to quantify binding of F-XTRA to the α4β2-nAChR in the human brain were compared, and the relationship between age and binding in the hippocampus was tested. F-XTRA rapidly entered the brain, and time-activity curves peaked within 10 min after injection for extrathalamic regions and at approximately 70 min in the thalamus. The 2-tissue-compartment model (2TCM) predicted the regional time-activity curves better than the 1-tissue-compartment model, and total distribution volume (V) was well identified by the 2TCM in all ROIs. V values estimated using Logan analysis with metabolite-corrected arterial input were highly correlated with those from the 2TCM in all regions, and values from 90-min scan duration were on average within 5% of those values from 180 min of data. Parametric images of V were consistent with the known distribution of the α4β2-nAChR across the brain. Finally, an inverse correlation between V in the hippocampus and age was observed. Our results extend support for use of F-XTRA with 90 min of emission scanning in quantitative human neuroimaging of the extrathalamic α4β2-nAChR, including in studies of aging.
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http://dx.doi.org/10.2967/jnumed.117.205492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167533PMC
October 2018

Metabotropic glutamate receptor 5 tracer [F]-FPEB displays increased binding potential in postcentral gyrus and cerebellum of male individuals with autism: a pilot PET study.

Cerebellum Ataxias 2018 12;5. Epub 2018 Feb 12.

1Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, 420 Delaware St SE, MMC 392, Minneapolis, MN 55455 USA.

Background: Autism is a neurodevelopmental disorder that is first manifested during early childhood. Postmortem experiments have identified significantly elevated expression of metabotropic glutamate receptor 5 (mGluR5) in cerebellar vermis and prefrontal cortex of individuals with autism.

Methods: In the current study we employed the mGluR5 tracer [F]-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ([F]-FPEB) to quantify mGluR5 binding in vivo in adults with autism vs. healthy controls using positron emission tomography (PET).

Results: We identified significantly higher [F]-FPEB binding potential in the postcentral gyrus and cerebellum of individuals with autism. There was a significant negative correlation between age and [F]-FPEB binding potential in the cerebellum but not in the postcentral gyrus. In the precuneus, [F]-FPEB binding potential correlated positively with the lethargy subscale score for the Aberrant Behavioral Checklist (ABC). In cerebellum, there were significant negative correlations between [F]-FPEB binding potential and ABC total score, ABC hyperactivity subscale score, and the ABC inappropriate speech subscale score.

Conclusions: These novel findings demonstrate for the first time that mGluR5 binding is altered in critical brain areas of subjects with autism, suggesting abnormal glutamate signaling in these regions. Finally, the correlations between altered [F]-FPEB binding potential in the cerebellum and precuneus suggest that some autistic symptoms may be influenced by abnormal glutamate signaling.
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http://dx.doi.org/10.1186/s40673-018-0082-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810020PMC
February 2018

The distribution of the alpha7 nicotinic acetylcholine receptor in healthy aging: An in vivo positron emission tomography study with [F]ASEM.

Neuroimage 2018 01 7;165:118-124. Epub 2017 Oct 7.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, USA. Electronic address:

Altered function of the alpha7 nicotinic acetylcholine receptor (α7-nAChR) is implicated in several neuropsychiatric diseases. Nevertheless, studies of the human cerebral α7-nAChR even in healthy aging are limited in number and to postmortem tissue.

Methods: The distribution of the cerebral α7-nAChR was estimated in nine brain regions in 25 healthy volunteers (ages 21-86 years; median 57 years, interquartile range 52 years) using [F]ASEM with positron emission tomography (PET) imaging. Regional total distribution volume (V) measurements were calculated using the Logan method from each subject's 90 min dynamic PET data and their metabolite-corrected plasma input function. Spearman's rank or Pearson's correlation analysis was used depending on the normality of the data. Correlation between age and regional 1) volume relative to intracranial volume (volume ratio) and 2) [F]ASEM V was tested. Correlation between regional volume ratio and [F]ASEM V was also evaluated. Finally, the relationship between [F]ASEM V and neuropsychological measures was investigated in a subpopulation of 15 elderly healthy participants (those 50 years of age and older). Bonferroni correction for multiple comparisons was applied to statistical analyses.

Results: A negative correlation between tissue volume ratio and age was observed in six of the nine brain regions including striatum and five cortical (temporal, occipital, cingulate, frontal, or parietal) regions. A positive correlation between [F]ASEM V and age was observed in all nine brain regions of interest (ROIs). There was no correlation between [F]ASEM V and volume ratio in any ROI after controlling for age. Regional [F]ASEM V and neuropsychological performance on each of eight representative subtests were not correlated among the well-performing subpopulation of elderly healthy participants.

Conclusions: Our results suggest an increase in cerebral α7-nAChR distribution over the course of healthy aging that should be tested in future longitudinal studies. The preservation of the α7-nAChR in the aging human brain supports the development of therapeutic agents that target this receptor for use in the elderly. Further study of the relationship between α7-nAChR availability and cognitive impairment over aging is needed.
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http://dx.doi.org/10.1016/j.neuroimage.2017.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738927PMC
January 2018

Preclinical Evaluation of F-RO6958948, C-RO6931643, and C-RO6924963 as Novel PET Radiotracers for Imaging Tau Aggregates in Alzheimer Disease.

J Nucl Med 2018 04 28;59(4):675-681. Epub 2017 Sep 28.

Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.

Tau aggregates and amyloid-β (Aβ) plaques are key histopathologic features in Alzheimer disease (AD) and are considered targets for therapeutic intervention as well as biomarkers for diagnostic in vivo imaging agents. This article describes the preclinical in vitro and in vivo characterization of 3 novel compounds-RO6958948, RO6931643, and RO6924963-that bind specifically to tau aggregates and have the potential to become PET tracers for future human use. RO6958948, RO6931643, and RO6924963 were identified as high-affinity competitors at the H-T808 binding site on native tau aggregates in human late-stage AD brain tissue. Binding of tritiated compounds to brain tissue sections of AD patients and healthy controls was analyzed by macro- and microautoradiography and by costaining of tau aggregates and Aβ plaques on the same tissue section using specific antibodies. All 3 tracer candidates were radiolabeled with a PET nuclide and tested in vivo in tau-naïve baboons to assess brain uptake, distribution, clearance, and metabolism. H-RO6958948, H-RO6931643, and H-RO6924963 bound with high affinity and specificity to tau aggregates, clearly lacking affinity for concomitant Aβ plaques in human AD Braak V tissue sections. The specificity of all 3 radioligands for tau aggregates was supported, first, by binding patterns in AD sections comparable to the tau-specific radioligand H-T808; second, by very low nonspecific binding in brain tissue devoid of tau pathology, excluding significant radioligand binding to any other central nervous system target; and third, by macroscopic and microscopic colocalization and quantitative correlation of radioligand binding and tau antibody staining on the same tissue section. RO6958948, RO6931643, and RO6924963 were successfully radiolabeled with a PET nuclide at high specific activity, radiochemical purity, and yield. After intravenous administration of F-RO6958948, C-RO6931643, and C-RO6924963 to baboons, PET scans indicated good brain entry, rapid washout, and a favorable metabolism pattern. F-RO6958948, C-RO6931643, and C-RO6924963 are promising PET tracers for visualization of tau aggregates in AD. Head-to-head comparison and validation of these tracer candidates in AD patients and healthy controls will be reported in due course.
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http://dx.doi.org/10.2967/jnumed.117.196741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932750PMC
April 2018

Identification of Three Novel Radiotracers for Imaging Aggregated Tau in Alzheimer's Disease with Positron Emission Tomography.

J Med Chem 2017 09 12;60(17):7350-7370. Epub 2017 Jul 12.

Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. , CH-4070 Basel, Switzerland.

Aggregates of tau and beta amyloid (Aβ) plaques constitute the histopathological hallmarks of Alzheimer's disease and are prominent targets for novel therapeutics as well as for biomarkers for diagnostic in vivo imaging. In recent years much attention has been devoted to the discovery and development of new PET tracers to image tau aggregates in the living human brain. Access to a selective PET tracer to image and quantify tau aggregates represents a unique tool to support the development of any novel therapeutic agent targeting pathological forms of tau. The objective of the study described herein was to identify such a novel radiotracer. As a result of this work, we discovered three novel PET tracers (2-(4-[C]methoxyphenyl)imidazo[1,2-a]pyridin-7-amine 7 ([C]RO6924963), N-[C]methyl-2-(3-methylphenyl)imidazo[1,2-a]pyrimidin-7-amine 8 ([C]RO6931643), and [F]2-(6-fluoropyridin-3-yl)pyrrolo[2,3-b:4,5-c']dipyridine 9 ([F]RO6958948)) with high affinity for tau neurofibrillary tangles, excellent selectivity against Aβ plaques, and appropriate pharmacokinetic and metabolic properties in mice and non-human primates.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00632DOI Listing
September 2017

Linking dopaminergic reward signals to the development of attentional bias: A positron emission tomographic study.

Neuroimage 2017 08 30;157:27-33. Epub 2017 May 30.

Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; Department of Psychological and Brain Sciences, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA; F.M. Kirby Research Center, Kennedy Krieger Institute, 707 N. Broadway, Baltimore, MD 21205, USA.

The attention system is shaped by reward history, such that learned reward cues involuntarily draw attention. Recent research has begun to uncover the neural mechanisms by which learned reward cues compete for attention, implicating dopamine (DA) signaling within the dorsal striatum. How these elevated priority signals develop in the brain during the course of learning is less well understood, as is the relationship between value-based attention and the experience of reward during learning. We hypothesized that the magnitude of the striatal DA response to reward during learning contributes to the development of a learned attentional bias towards the cue that predicted it, and examined this hypothesis using positron emission tomography with [C]raclopride. We measured changes in dopamine release for rewarded versus unrewarded visual search for color-defined targets as indicated by the density and distribution of the available D/D receptors. We then tested for correlations of individual differences in this measure of reward-related DA release to individual differences in the degree to which previously reward-associated but currently task-irrelevant stimuli impair performance in an attention task (i.e., value-driven attentional bias), revealing a significant relationship in the right anterior caudate. The degree to which reward-related DA release was right hemisphere lateralized was also predictive of later attentional bias. Our findings provide support for the hypothesis that value-driven attentional bias can be predicted from reward-related DA release during learning.
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http://dx.doi.org/10.1016/j.neuroimage.2017.05.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600829PMC
August 2017

Density of available striatal dopamine receptors predicts trait impulsiveness during performance of an attention-demanding task.

J Neurophysiol 2017 07 29;118(1):64-68. Epub 2017 Mar 29.

Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland.

The density (measured at binding potential) of available striatal D/D receptors has been shown to predict trait impulsiveness. This relationship is highly robust and well replicated. In each case, however, the availability of dopamine receptors was measured at rest. More broadly, the extent to which relationships between dopamine receptor availability and behavioral traits hold when participants perform a cognitive task is unclear. Furthermore, the performance of a cognitive task engages fundamentally different neural networks than are maximally engaged during the resting state. This complicates interpretation of previously observed correlations, which could be influenced by two distinct factors. The first is variation in available receptor density, which reflects a stable trait of the individual. The second is variation in context-specific dopamine release, which differentially displaces some dopamine radiotracers (such as raclopride) across individuals. Using an existing data set, we related trait impulsiveness, as measured using the Barratt Impulsiveness Scale (BIS-11), to the density (binding potential) of available striatal D/D receptors as measured using positron emission tomography (PET) with [C]raclopride. Importantly, the PET scan was completed while participants performed an attention-demanding visual search task. We replicate robust correlations between this measure of receptor availability and trait impulsiveness previously demonstrated during the resting state, extending this relationship to periods of active task engagement. Our results support the idea that this relationship depends on striatal D/D receptor density and not on context-dependent dopamine release. Several studies have demonstrated a relationship between the density of available striatal D/D receptors and trait impulsiveness. However, in each case, the availability of dopamine receptors was measured during the resting state. This complicates interpretation of previously observed correlations, which could be influenced by either stable variation in receptor density or context-dependent dopamine release. We present evidence uniquely consistent with the former interpretation, providing clarity to the nature of this brain-behavior relationship.
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http://dx.doi.org/10.1152/jn.00125.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494363PMC
July 2017

Imaging α4β2 Nicotinic Acetylcholine Receptors (nAChRs) in Baboons with [F]XTRA, a Radioligand with Improved Specific Binding in Extra-Thalamic Regions.

Mol Imaging Biol 2017 04;19(2):280-288

Department of Radiology, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA.

Purpose: Currently available positron-emitting radiotracers for imaging of the α4β2 subtype of nicotinic acetylcholine receptors (nAChRs) exhibit high and moderate specific binding in the thalamus and extra-thalamic brain regions, respectively. In many neuropsychiatric disorders, α4β2-nAChRs are altered in the extra-thalamic brain regions, but not necessarily in the thalamus. The purpose of this study was to evaluate [F]XTRA, a new α4β2-nAChR positron emission tomography (PET) radioligand with improved specific binding in extra-thalamic brain regions, in non-human primates.

Procedures: The regional distribution of [F]XTRA in the brain of Papio anubis baboons was evaluated in baseline and blocking experiments. Various PET modeling procedures were used for determination of volume of distribution (V ), binding potential (BP), and receptor occupancy. Radiation dosimetry for [F]XTRA was studied in male CD-1 mice and extrapolated to human dosimetry estimates using OLINDA/EXM software.

Results: [F]XTRA was synthesized using an automated radiochemistry module with 25 % decay-corrected radiochemical yield. [F]XTRA readily enters the baboon brain and specifically labels α4β2-nAChRs. Mathematical modeling demonstrates high binding potential values (BP = 7 and 1.3 in the thalamus and frontal cortex, respectively). A PET scanning time of 90-120 min was sufficient to obtain stable V values in the extra-thalamic regions. The extrapolated human effective dose was 0.041 mSv/MBq (0.15 Rem/mCi).

Conclusion: [F]XTRA exhibits improved specific binding in the baboon brain including extra-thalamic regions and it is considered radiologically acceptable for human studies. Further evaluations of [F]XTRA in human subjects are under way.
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http://dx.doi.org/10.1007/s11307-016-0999-9DOI Listing
April 2017

Development of a High-Affinity PET Radioligand for Imaging Cannabinoid Subtype 2 Receptor.

J Med Chem 2016 09 23;59(17):7840-55. Epub 2016 Aug 23.

Johns Hopkins School of Medicine , Department of Radiology, Baltimore, 21287 United States.

Cannabinoid receptors type 2 (CB2) represent a target with increasing importance for neuroimaging due to its upregulation under various pathological conditions. Encouraged by preliminary results obtained with [(11)C](Z)-N-(3-(2-methoxyethyl)-4,5-dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethyl-cyclopropanecarboxamide ([(11)C]A-836339, [(11)C]1) in a mouse model of acute neuroinflammation (induced by lipopolysaccharide, LPS), we designed a library of fluorinated analogues aiming for an [(18)F]-labeled radiotracer with improved CB2 binding affinity and selectivity. Compound (Z)-N-(3-(4-fluorobutyl)-4,5-dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (29) was selected as the ligand with the highest CB2 affinity (Ki = 0.39 nM) and selectivity over those of CB1 (factor of 1000). [(18)F]29 was prepared starting from the bromo precursor (53). Specific binding was shown in vitro, whereas fast metabolism was observed in vivo in CD-1 mice. Animal PET revealed a brain uptake comparable to that of [(11)C]1. In the LPS-treated mice, a 20-30% higher uptake in brain was found in comparison to that in nontreated mice (n = 3, P < 0.05).
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http://dx.doi.org/10.1021/acs.jmedchem.6b00554DOI Listing
September 2016

The Role of Dopamine in Value-Based Attentional Orienting.

Curr Biol 2016 Feb 11;26(4):550-5. Epub 2016 Feb 11.

Department of Psychological and Brain Sciences, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, USA.

Reward learning gives rise to strong attentional biases. Stimuli previously associated with reward automatically capture visual attention regardless of intention. Dopamine signaling within the ventral striatum plays an important role in reward learning, representing the expected reward initiated by a cue. How dopamine and the striatum may be involved in maintaining behaviors that have been shaped by reward learning, even after reward expectancies have changed, is less well understood. Nonspecific measures of brain activity have implicated the striatum in value-based attention. However, the neurochemical mechanisms underlying the attentional priority of learned reward cues remain unexplored. Here, we investigated the contribution of dopamine to value-based attention using positron emission tomography (PET) with [(11)C]raclopride. We show that, in the explicit absence of reward, the magnitude of attentional capture by previously reward-associated but currently task-irrelevant distractors is correlated across individuals with changes in available D2/D3 dopamine receptors (presumably due to intrasynaptic dopamine) linked to distractor processing within the right caudate and posterior putamen. Our findings provide direct evidence linking dopamine signaling within the striatum to the involuntary orienting of attention, and specifically to the attention-grabbing quality of learned reward cues. These findings also shed light on the neurochemical basis of individual susceptibility to value-driven attentional capture, which is known to play a role in addiction. More broadly, the present study highlights the value and feasibility of using PET to relate changes in the release of a neurotransmitter to learning-dependent changes in healthy adults.
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http://dx.doi.org/10.1016/j.cub.2015.12.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767677PMC
February 2016

Family history of alcoholism is related to increased D /D receptor binding potential: a marker of resilience or risk?

Addict Biol 2017 Jan 29;22(1):218-228. Epub 2015 Sep 29.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.

The aim of this study was to examine the relationship between family history of alcohol use disorder and striatal dopamine using positron emission tomography imaging. Participants were 84 healthy, 18- to 30-year-old, social drinkers recruited via fliers and newspaper advertisements. At assessment, participants completed measures of lifetime personal and family substance use and psychiatric symptoms. Participants underwent two consecutive positron emission tomography scans using the D /D dopamine receptor radioligand [ C]raclopride. Scans were preceded by intravenous saline and amphetamine 0.3 mg/kg, providing measures of baseline [ C]raclopride binding potential (BP ) and change in [ C]raclopride (ΔBP ). Subjective ratings of stimulant drug effects were collected during scans. Subjects were classified as family history positive (FHP) if they reported any first-degree relative with alcohol use disorder (AUD) and family history negative (FHN) if no first-degree relatives had history of AUD. Participants were predominantly White (69.0 percent) and male (62.1 percent). Baseline [ C]raclopride BP was generally higher in FHP compared with FHN subjects across striatal subdivisions. There were no differences in ΔBP across regions. Negative subjective drug effects were more pronounced in FHP than in FHN subjects. While FHN subjects evidenced the expected positive relationship between ΔBP and positive subjective drug effects, this relationship was disrupted in FHP subjects. There are key differences in dopamine status and subjective stimulant drug experiences as a function of family AUD history. These findings have important implications for understanding risk for AUD development in FHP offspring.
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http://dx.doi.org/10.1111/adb.12300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811753PMC
January 2017

GM1 ganglioside in Parkinson's disease: Pilot study of effects on dopamine transporter binding.

J Neurol Sci 2015 Sep 16;356(1-2):118-23. Epub 2015 Jun 16.

Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States; Department of Psychiatry and Behavior Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States; Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.

Objective: GM1 ganglioside has been suggested as a treatment for Parkinson's disease (PD), potentially having symptomatic and disease modifying effects. The current pilot imaging study was performed to examine effects of GM1 on dopamine transporter binding, as a surrogate measure of disease progression, studied longitudinally.

Methods: Positron emission tomography (PET) imaging data were obtained from a subset of subjects enrolled in a delayed start clinical trial of GM1 in PD [1]: 15 Early-start (ES) subjects, 14 Delayed-start (DS) subjects, and 11 Comparison (standard-of-care) subjects. Treatment subjects were studied over a 2.5 year period while Comparison subjects were studied over 2 years. Dynamic PET scans were performed over 90 min following injection of [(11)C]methylphenidate. Regional values of binding potential (BPND) were analyzed for several striatal volumes of interest.

Results: Clinical results for this subset of subjects were similar to those previously reported for the larger study group. ES subjects showed early symptomatic improvement and slow symptom progression over the study period. DS and Comparison subjects were initially on the same symptom progression trajectory but diverged once DS subjects received GM1 treatment. Imaging results showed significant slowing of BPND loss in several striatal regions in GM1-treated subjects and in some cases, an increased BPND in some striatal regions was detected after GM1 use.

Interpretation: Results of this pilot imaging study provide additional data to suggest a potential disease modifying effect of GM1 on PD. These results need to be confirmed in a larger number of subjects.
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http://dx.doi.org/10.1016/j.jns.2015.06.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545312PMC
September 2015

Risky decision-making and ventral striatal dopamine responses to amphetamine: a positron emission tomography [(11)C]raclopride study in healthy adults.

Neuroimage 2015 Jun 18;113:26-36. Epub 2015 Mar 18.

The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Recent functional magnetic resonance imaging (fMRI) studies have provided compelling evidence that corticolimbic brain regions are integrally involved in human decision-making. Although much less is known about molecular mechanisms, there is growing evidence that the mesolimbic dopamine (DA) neurotransmitter system may be an important neural substrate. Thus far, direct examination of DA signaling in human risk-taking has centered on gambling disorder. Findings from several positron emission tomography (PET) studies suggest that dysfunctions in mesolimbic DA circuits may play an important role in gambling behavior. Nevertheless, interpretation of these findings is currently hampered by a need for better understanding of how individual differences in regional DA function influence normative decision-making in humans. To further our understanding of these processes, we used [(11)C]raclopride PET to examine associations between ventral striatal (VS) DA responses to amphetamine (AMPH) and risky decision-making in a sample of healthy young adults with no history of psychiatric disorder, Forty-five male and female subjects, ages 18-29 years, completed a computerized version of the Iowa Gambling Task. Participants then underwent two 90-minute PET studies with high specific activity [(11)C]raclopride. The first scan was preceded by intravenous saline; the second, by intravenous AMPH (0.3mg/kg). Findings of primary analyses showed that less advantageous decision-making was associated with greater right VS DA release; the relationship did not differ as a function of gender. No associations were observed between risk-taking and left VS DA release or baseline D2/D3 receptor availability in either hemisphere. Overall, the results support notions that variability in striatal DA function may mediate inter-individual differences in risky decision-making in healthy adults, further suggesting that hypersensitive DA circuits may represent a risk pathway in this population.
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http://dx.doi.org/10.1016/j.neuroimage.2015.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433778PMC
June 2015

Mu Opioid Receptor Binding Correlates with Nicotine Dependence and Reward in Smokers.

PLoS One 2014 10;9(12):e113694. Epub 2014 Dec 10.

National Institute on Drug Abuse, Rockville, United States of America.

The rewarding effects of nicotine are associated with activation of nicotine receptors. However, there is increasing evidence that the endogenous opioid system is involved in nicotine's rewarding effects. We employed PET imaging with [11C]carfentanil to test the hypotheses that acute cigarette smoking increases release of endogenous opioids in the human brain and that smokers have an upregulation of mu opioid receptors (MORs) when compared to nonsmokers. We found no significant changes in binding potential (BPND) of [11C]carfentanil between the placebo and the active cigarette sessions, nor did we observe differences in MOR binding between smokers and nonsmokers. Interestingly, we showed that in smokers MOR availability in bilateral superior temporal cortices during the placebo condition was negatively correlated with scores on the Fagerström Test for Nicotine Dependence (FTND). Also in smokers, smoking-induced decreases in [11C]carfentanil binding in frontal cortical regions were associated with self-reports of cigarette liking and wanting. Although we did not show differences between smokers and nonsmokers, the negative correlation with FTND corroborates the role of MORs in superior temporal cortices in nicotine addiction and provides preliminary evidence of a role of endogenous opioid signaling in frontal cortex in nicotine reward.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0113694PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262264PMC
October 2017

Human brain imaging of α7 nAChR with [(18)F]ASEM: a new PET radiotracer for neuropsychiatry and determination of drug occupancy.

Mol Imaging Biol 2014 Oct;16(5):730-8

Department of Radiology, School of Medicine, The Johns Hopkins University, Baltimore, MD, USA,

Purpose: Using the α7-nAChR radiotracer, [(18)F]ASEM, we present the first successful human positron emission tomography (PET) studies. Rodent occupancy with three clinically employed α7-nAChR drugs confirms the specificity of the radiotracer.

Procedures: Five healthy male subjects were imaged for 90 min following IV [(18)F]ASEM. Two subjects were scanned for the second time (test/retest; TRV). Mouse biodistribution of [(18)F]ASEM was carried out in CD1 mice injected with using human equivalent doses of DMXB-A, EVP-6124, and varenicline to block specific binding.

Results: [(18)F]ASEM readily entered the brain and peaked at 15 min post-injection with reversible kinetics and a peak %SUV of about 400 %. The regional human brain distribution of [(18)F]ASEM matched previous in vitro data and baboon PET results. The precuneus, parietal, occipital, cingulate cortexes, putamen, and thalamus showed high values of distribution volume (>20 ml/ml) and binding potentials >1 with TRV averaged 10.8 ± 5.1 %. In mouse distribution studies, there was significant dose-dependent blockade in the mouse brain with DMXB-A as well as the other two α7-nAChR drugs.

Conclusions: The characteristics of [(18)F]ASEM are consistent with the ability to quantify α7-nAChR in the human brain. [(18)F]ASEM is suitable for imaging neuropsychiatric disorders and target engagement (receptor occupancy) of potential α7-nAChR drugs.
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http://dx.doi.org/10.1007/s11307-014-0779-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344036PMC
October 2014

Dose-dependent, saturable occupancy of the metabotropic glutamate subtype 5 receptor by fenobam as measured with [ C]ABP688 PET imaging.

Synapse 2014 Dec 19;68(12):565-573. Epub 2014 Aug 19.

Neurosciences Discovery, Novartis Pharma AG, Basel, Switzerland.

Fenobam is a negative allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5) with inverse agonist activity and is expected to contribute to the treatment of neuropsychiatric disorders involving dysfunction of mGluR5 including Fragile X syndrome. This study examined whether [ C]ABP688, an antagonist PET radioligand, competes with fenobam for the same binding site in the nonhuman primate brain and would allow examination of occupancy-plasma concentration relationships in the evaluation of the drug for target disorders in the human brain. Four paired PET studies with [ C]ABP688 were performed in baboons at a baseline condition and after intravenous treatment with fenobam at different dose levels (0.3-1.33 mg/kg). Total distribution volume (V ) and binding potential (BP ) using the cerebellum as a reference region were obtained by the plasma reference graphical method. Then it was examined whether occupancy follows a dose-dependent, saturating pattern that was predicted by a modified first-order Hill equation in individual regions. Baseline regional V and BP values agreed with previously published data. Occupancy showed dose-dependent and saturating patterns in individual regions, reaching >90% occupancy at 1.33 mg/kg dose of fenobam in the majority of regions. To our knowledge, this is the first use of PET to characterize the mGluR5 therapeutic drug fenobam. This study demonstrates a proof of principle for determining the in vivo occupancy of fenobam in primates. The results indicate that [ C]ABP688 and PET may be useful for examination of occupancy of mGluR5 by fenobam, which should prove to be useful for designing future studies and treatment of human disease states. Synapse 68:565-573, 2014. © 2014 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/syn.21775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320023PMC
December 2014

18F-ASEM, a radiolabeled antagonist for imaging the α7-nicotinic acetylcholine receptor with PET.

J Nucl Med 2014 Apr 20;55(4):672-7. Epub 2014 Feb 20.

Department of Radiology, Johns Hopkins School of Medicine, Baltimore, Maryland.

Unlabelled: The α7-nicotinic cholinergic receptor (α7-nAChR) is a key mediator of brain communication and has been implicated in a wide variety of central nervous system disorders. None of the currently available PET radioligands for α7-nAChR are suitable for quantitative PET imaging, mostly because of insufficient specific binding. The goal of this study was to evaluate the potential of (18)F-ASEM ((18)F-JHU82132) as an α7-nAChR radioligand for PET.

Methods: The inhibition binding assay and receptor functional properties of ASEM were assessed in vitro. The brain regional distribution of (18)F-ASEM in baseline and blockade were evaluated in DISC1 mice (dissection) and baboons (PET).

Results: ASEM is an antagonist for the α7-nAChR with high binding affinity (Ki = 0.3 nM). (18)F-ASEM readily entered the baboon brain and specifically labeled α7-nAChR. The in vivo specific binding of (18)F-ASEM in the brain regions enriched with α7-nAChRs was 80%-90%. SSR180711, an α7-nAChR-selective partial agonist, blocked (18)F-ASEM binding in the baboon brain in a dose-dependent manner, suggesting that the binding of (18)F-ASEM was mediated by α7-nAChRs and the radioligand was suitable for drug evaluation studies. In the baboon baseline studies, the brain regional volume of distribution (VT) values for (18)F-ASEM were 23 (thalamus), 22 (insula), 18 (hippocampus), and 14 (cerebellum), whereas in the binding selectivity (blockade) scan, all regional VT values were reduced to less than 4. The range of regional binding potential values in the baboon brain was from 3.9 to 6.6. In vivo cerebral binding of (18)F-ASEM and α7-nAChR expression in mutant DISC1 mice, a rodent model of schizophrenia, was significantly lower than in control animals, which is in agreement with previous postmortem human data.

Conclusion: (18)F-ASEM holds promise as a radiotracer with suitable imaging properties for quantification of α7-nAChR in the human brain.
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http://dx.doi.org/10.2967/jnumed.113.132068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112566PMC
April 2014

History of childhood adversity is positively associated with ventral striatal dopamine responses to amphetamine.

Psychopharmacology (Berl) 2014 Jun 22;231(12):2417-33. Epub 2014 Jan 22.

Department of Family and Community Health, University of Maryland School of Nursing, 655 W. Lombard Street, Baltimore, MD, 21201, USA,

Rationale: Childhood exposure to severe or chronic trauma is an important risk factor for the later development of adult mental health problems, such as substance abuse. Even in nonclinical samples of healthy adults, persons with a history of significant childhood adversity seem to experience greater psychological distress than those without this history. Evidence from rodent studies suggests that early life stress may impair dopamine function in ways that increase risks for drug abuse. However, the degree to which these findings translate to other species remains unclear.

Objectives: This study was conducted to examine associations between childhood adversity and dopamine and subjective responses to amphetamine in humans.

Methods: Following intake assessment, 28 healthy male and female adults, aged 18-29 years, underwent two consecutive 90-min positron emission tomography studies with high specific activity [(11)C]raclopride. The first scan was preceded by intravenous saline; the second by amphetamine (AMPH 0.3 mg/kg).

Results: Consistent with prior literature, findings showed positive associations between childhood trauma and current levels of perceived stress. Moreover, greater number of traumatic events and higher levels of perceived stress were each associated with higher ventral striatal dopamine responses to AMPH. Findings of mediation analyses further showed that a portion of the relationship between childhood trauma and dopamine release may be mediated by perceived stress.

Conclusions: Overall, results are consistent with preclinical findings suggesting that early trauma may lead to enhanced sensitivity to psychostimulants and that this mechanism may underlie increased vulnerability for drug abuse.
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http://dx.doi.org/10.1007/s00213-013-3407-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040334PMC
June 2014

Recent PET radioligands with optimal brain kinetics for imaging nicotinic acetylcholine receptors.

J Labelled Comp Radiopharm 2013 Mar-Apr;56(3-4):159-66

Division of Nuclear Medicine, Department of Radiology, Johns Hopkins University, Baltimore, MD, USA.

Cerebral neuronal nicotinic acetylcholine receptors (nAChRs) are implicated in various neurophysiological processes and in the pathophysiology and/or treatment strategies of various disorders. Positron emission tomography (PET) imaging of nAChR and, especially, the most prominent cerebral subtype α4β2-nAChR is important in smoking, epilepsy, attention deficit hyperactivity disorder, depression, schizophrenia, cognition, behavior, memory, and in research involving aging, cognitive impairments, and dementia. Most human α4β2-nAChR PET imaging has been performed with 2-[(18) F]FA, but slow brain kinetics is the substantial drawback of 2-[(18) F]FA that precludes widespread PET imaging research of nAChR in humans. Development of a better PET radioligand for α4β2-nAChR was a focus of substantial investigation that has been thoroughly reviewed (up to 2009) previously. This article attempts to summarize the peer-reviewed publications of the most recent development and preclinical studies of novel α4β2-nAChR PET radioligands with improved brain kinetics and first human studies with one of these radioligands ([(18) F]AZAN).
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http://dx.doi.org/10.1002/jlcr.3020DOI Listing
July 2014

individual variation in sleep quality and duration is related to cerebral mu opioid receptor binding potential during tonic laboratory pain in healthy subjects.

Pain Med 2013 Dec 18;14(12):1882-92. Epub 2013 Sep 18.

Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

Objective: Although poor sleep is a consequence of pain, sleep disturbance reciprocally induces hyperalgesia and exacerbates clinical pain. Conceptual models of chronic pain implicate dysfunctional supraspinal pain processing mechanisms, mediated in part by endogenous opioid peptides. Our preliminary work indicates that sleep disruption impairs psychophysical measures of descending pain modulation, but few studies have investigated whether insufficient sleep may be associated with alterations in endogenous opioid systems. This preliminary, exploratory investigation sought to examine the relationship between sleep and functioning of the cerebral mu opioid system during the experience of pain in healthy participants.

Subjects And Design: Twelve healthy volunteers participated in a 90-minute positron emission tomography imaging scan using [11C]Carfentanil, a mu opioid receptors agonist. During the session, pain responses to a 10% topical capsaicin cream were continuously rated on a 0-100 scale. Participants also completed the Pittsburgh Sleep Quality Index (PSQI).

Results: Poor sleep quality (PSQI) was positively and significantly associated with greater binding potential (BP) in regions within the frontal lobes. In addition, sleep duration was negatively associated with BP in these areas as well as the temporal lobe and anterior cingulate.

Conclusions: These findings suggest that poor sleep quality and short sleep duration are associated with endogenous opioid activity in these brain regions during the application of a noxious stimulus. Elucidating the role of the endogenous opioid system in mediating some of the associations between sleep and pain could significantly improve our understanding of the pathophysiology of chronic pain and might advance clinical practice by suggesting interventions that could buffer the adverse effects of poor sleep on pain.
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http://dx.doi.org/10.1111/pme.12231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104524PMC
December 2013