A copy of this work was available on the public web and has been preserved in the Wayback Machine. The capture dates from 2019; you can also visit the original URL.
The file type is
Objectives. Although serotonergic mechanisms have been implicated in pathological gambling (PG), no ligand-based imaging studies have assessed serotonin receptors in individuals with PG. Given its role in substance addictions and its abundance in brain regions implicated in PG, we evaluated serotonin 1B receptors (5-HT 1B Rs) in PG. Methods. Ten medication-free subjects with PG (mean Ϯ SD age ϭ 36.3 Ϯ 9.4 years, nine men) and ten control comparison (CC) subjects (mean Ϯ SD age ϭ 35.8 Ϯ 9.9doi:10.3109/15622975.2011.598559 pmid:21936763 pmcid:PMC3595502 fatcat:kyvrdp44ovfzta5skaglhwv3jq
more »... , nine men) underwent [ 11 C]P943 positron emission scanning on a high resolution research tomograph. Results. 5-HT 1B R BP ND values were similar in PG and CC subjects ( P Ͼ 0.1). Among PG subjects, scores on the South Oaks Gambling Screen (SOGS) correlated positively with 5-HT 1B R BP ND values in the ventral striatum ( r ϭ 0.66; P ϭ 0.04), putamen ( r ϭ 0.67; P ϭ 0.03) and anterior cingulate cortex ( r ϭ 0.73; P ϭ 0.02). Conclusions. These fi ndings provide the fi rst evidence that PG severity in humans is linked to increased levels of 5-HT 1B Rs in regions previously implicated in functional neuroimaging studies of PG. These fi ndings indicate a potential role for serotonergic function in the ventral striatum and anterior cingulate cortex contributing to problem gambling severity and warrant further studies to investigate whether numbers of available 5-HT 1B Rs might represent a vulnerability factor for PG or develop in relationship to problem gambling.
GR103545 is a potent and selective kappa-opioid receptor agonist. Previous studies in non-human primates demonstrated favorable properties of [ 11 C]GR103545 as a positron emission tomography tracer for in vivo imaging of cerebral kappa-opioid receptor. Nonetheless, advancement of [ 11 C]GR103545 to imaging studies in humans was hampered by difficulties of its multiple-step radiosynthesis, which produces a final product with low specific activity (SA), which in turn could induce undesirabledoi:10.1016/j.nucmedbio.2010.08.014 pmid:21315277 fatcat:3slw63oeofctrpalaguxmuqlke
more »... iological side effects resulting from the mass associated with an injected amount of radioactivity. We report herein an alternative radiosynthesis of [ 11 C]GR103545 with higher SA and radiochemical yields. Methods: The TRACERLab FXC automated synthesis module was used to carry out the two-step, one-pot procedure. In the first step, the desmethoxycarbonyl precursor was converted to the carbamic acid intermediate desmethyl-GR103545 via transcarboxylation with the zwitterionic carbamic complex, 1,8-diazabicyclo[5.4.0]undec-7-ene-carbon dioxide, in the presence and/or absence of cesium carbonate and tetrabutylammonium triflate. In the second step, the intermediate was radiolabeled at the carboxyl oxygen with [ 11 C]methyl trifluoromethanesulfonate to give [ 11 C]GR103545. Results: This novel synthesis produced [ 11 C]GR103545 with ≥90% chemical and radiochemical purities and an SA of 290.45±99.9 MBq/nmol at the end of synthesis (n=26). Injectable radioactivity was 1961±814 GBq/μmol with 43 min of average synthesis time from the end of beam. Conclusion: We have developed a practical one-pot method for the routine production of [ 11 C]GR103545 with reliably high SA and radiochemical yield, thus allowing the advancement of this radiotracer to imaging applications in humans.
Purpose Neuronal damage and synapse loss in the spinal cord (SC) have been implicated in spinal cord injury (SCI) and neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS). Current standards of diagnosis for SCI include CT or MRI imaging to evaluate injury severity. The current study explores the use of PET imaging with [11C]UCB-J, which targets the synaptic vesicle protein 2A (SV2A), in the human spinal cord, as a way to visualize synaptic density and integrity in vivo.doi:10.1186/s40658-022-00464-0 pmid:35503134 pmcid:PMC9065222 fatcat:g6ghkjnblja2lj27b6k2gddqhq
more »... s First, simulations of baseline and blocking [11C]UCB-J HRRT scans were performed, based on SC dimensions and SV2A distribution to predict VT, VND, and VS values. Next, human baseline and blocking [11C]UCB-J HRRT images were used to estimate these values in the cervical SC (cSC). Simulation results had excellent agreement with observed values of VT, VND, and VS from the real human data, with baseline VT, VND, and VS of 3.07, 2.15, and 0.92 mL/cm3, respectively, with a BPND of 0.43. Lastly, we explored full SC imaging with whole-body images. Using automated SC regions of interest (ROIs) for the full SC, cSC, and thoracic SC (tSC), the distribution volume ratio (DVR) was estimated using the brain gray matter as a reference region to evaluate SC SV2A density relative to the brain. In full body imaging, DVR values of full SC, cSC, and tSC were 0.115, 0.145, and 0.112, respectively. Therefore, measured [11C]UCB-J uptake, and thus SV2A density, is much lower in the SC than in the brain. Conclusions The results presented here provide evidence for the feasibility of SV2A PET imaging in the human SC, however, specific binding of [11C]UCB-J is low. Ongoing and future work include further classification of SV2A distribution in the SC as well as exploring higher-affinity PET radioligands for SC imaging.
Dopamine D 2/3 receptor signaling is critical for flexible adaptive behavior; however, it is unclear whether D 2 , D 3 , or both receptor subtypes modulate precise signals of feedback and reward history that underlie optimal decision making. Here, PET with the radioligand [ 11 C]-(ϩ)-PHNO was used to quantify individual differences in putative D 3 receptor availability in rodents trained on a novel threechoice spatial acquisition and reversal-learning task with probabilistic reinforcement.doi:10.1523/jneurosci.3253-15.2016 pmid:27335404 pmcid:PMC4916249 fatcat:4f4rnswvbrh4nbhkk6yfh55bly
more »... ng of [ 11 C]-(ϩ)-PHNO in the midbrain was negatively related to the ability of rats to adapt to changes in rewarded locations, but not to the initial learning. Computational modeling of choice behavior in the reversal phase indicated that [ 11 C]-(ϩ)-PHNO binding in the midbrain was related to the learning rate and sensitivity to positive, but not negative, feedback. Administration of a D 3 -preferring agonist likewise impaired reversal performance by reducing the learning rate and sensitivity to positive feedback. These results demonstrate a previously unrecognized role for D 3 receptors in select aspects of reinforcement learning and suggest that individual variation in midbrain D 3 receptors influences flexible behavior. Our combined neuroimaging, behavioral, pharmacological, and computational approach implicates the dopamine D 3 receptor in decision-making processes that are altered in psychiatric disorders. Flexible decision-making behavior is dependent upon dopamine D 2/3 signaling in corticostriatal brain regions. However, the role of D 3 receptors in adaptive, goal-directed behavior has not been thoroughly investigated. By combining PET imaging with the D 3 -preferring radioligand [ 11 C]-(ϩ)-PHNO, pharmacology, a novel three-choice probabilistic discrimination and reversal task and computational modeling of behavior in rats, we report that naturally occurring variation in [ 11 C]-(ϩ)-PHNO receptor availability relates to specific aspects of flexible decision making. We confirm these relationships using a D 3 -preferring agonist, thus identifying a unique role of midbrain D 3 receptors in decision-making processes.
The serotonin 5-HT 1B receptors regulate the release of serotonin and are involved in various disease states, including depression and schizophrenia. The goal of the study was to evaluate a high affinity and high selectivity antagonist, [ 11 C]P943, as a positron emission tomography (PET) tracer for imaging the 5-HT 1B receptor. [ 11 C]P943 was synthesized via N-methylation of the precursor with [ 11 C]methyl iodide or [ 11 C]methyl triflate using automated modules. The average radiochemicaldoi:10.1016/j.nucmedbio.2009.10.007 pmid:20152720 pmcid:PMC3780362 fatcat:4b3r3jt7qvaqrfnudleoxjq4ry
more »... ld was approx. 10% with radiochemical purity of N99% and specific activity of 8.8±3.6 mCi/nmol at the end-of-synthesis (n=37). PET imaging was performed in non-human primates with a high-resolution research tomograph scanner with a bolus/infusion paradigm. Binding potential (BP ND ) was calculated using the equilibrium ratios of regions to cerebellum. The tracer uptake was highest in the globus pallidus and occipital cortex, moderate in basal ganglia and thalamus, and lowest in the cerebellum, which is consistent with the known brain distribution of 5-HT 1B receptors. Infusion of tracer at different specific activities (by adding various amount of unlabeled P943) reduced BP ND values in a dose-dependent manner, demonstrating the saturability of the tracer binding. Blocking studies with GR127935 (2 mg/kg iv), a selective 5-HT 1B /5-HT 1D antagonist, resulted in reduction of BP ND values by 42-95% across regions; for an example, in occipital region from 0.71 to 0.03, indicating a complete blockade. These results demonstrate the saturability and specificity of [ 11 C]P943 for 5-HT 1B receptors, suggesting its suitability as a PET radiotracer for in vivo evaluations of the 5-HT 1B receptor system in humans. Published by Elsevier Inc.
Animal studies indicate that the kappa-opioid receptor/dynorphin system plays an important role in cocaine binges and stress-induced relapse. Our goal was to investigate changes in kappa-opioid receptor (KOR) availability in the human brain using positron emission tomography (PET), before and after a cocaine binge. We also investigated the correlation between KOR and stress-induced cocaine self-administration. PET imaging was performed with the KOR selective agonist [11C]GR103545. Subjects withdoi:10.1038/s41386-019-0398-4 pmid:31026862 pmcid:PMC6785004 fatcat:2zbznis6c5ekhdusfw5rvli3vu
more »... cocaine-use disorder (CUD) underwent PET scans and performed two types of cocaine self-administration sessions in the laboratory as follows: (1) choice sessions following a cold pressor test, to induce stress, and (2) binge dosing of cocaine. This allowed us investigate the following: (1) the association between KOR binding and a laboratory model of stress-induced relapse and (2) the change in KOR binding following a 3-day cocaine binge, which is thought to represent a change in endogenous dynorphin. A group of matched healthy controls was included to investigate between group differences in KOR availability. A significant association between [11C]GR103545 binding and cocaine self-administration was seen: greater KOR availability was associated with more choices for cocaine. In addition, the 3-day cocaine binge significantly reduced [11C]GR103545 binding by 18% in the striatum and 14% across brain regions. No difference in [11C]GR103545 binding was found between the CUD subjects and matched controls. In the context of previous studies, these findings add to the growing evidence that pharmacotherapies targeting the KOR have the potential to significantly impact treatment development for cocaine-use disorder.
Type 1 diabetes mellitus (T1DM) is characterized by a loss of β-cells in the islets of Langerhans of the pancreas and subsequent deficient insulin secretion in response to hyperglycemia. Development of an in vivo test to measure β-cell mass (BCM) would greatly enhance the ability to track diabetes therapies. β-cells and neurologic tissues have common cellular receptors and transporters, therefore, we screened brain radioligands for their ability to identify β-cells. Methods: We examined adoi:10.2967/jnumed.117.197285 pmid:29371405 fatcat:xu27kw6tcjfwjpmui25mv5vmam
more »... gene atlas for endocrine pancreas receptor targets and cross-referenced these targets with brain radioligands that were available at our institution. Twelve healthy control subjects and 2 T1DM subjects underwent dynamic PET/CT scans with 6 tracers. Results: The D 2 /D 3 receptor agonist radioligand 11 C-(1)-4propyl-9-hydroxynaphthoxazine (PHNO) was the only radioligand to demonstrate sustained uptake in the pancreas with high contrast versus abdominal organs such as the kidneys, liver, and spleen, based on the first 30 min of data. Mean SUV from 20 to 30 min demonstrated high uptake of 11 C-(1)-PHNO in healthy controls (SUV, 13.8) with a 71% reduction in a T1DM subject with undetectable levels of Cpeptide (SUV, 4.0) and a 20% reduction in a T1DM subject with fasting C-peptide level of 0.38 ng/mL (SUV, 11.0). SUV in abdominal organs outside the pancreas did not show measurable differences between the control and T1DM subjects, suggesting that the changes in SUV of 11 C-(1)-PHNO may be specific to changes in the pancreas between healthy controls and T1DM subjects. When D 3 and D 2 antagonists were used in nonhuman primates, specific pancreatic binding (SUVR-1) of 11 C-PHNO was reduced by 57% and 38%, respectively. Conclusion: 11 C-(1)-PHNO is a potential marker of BCM, with 2:1 binding of D 3 receptors over D 2 receptors. Further in vitro and in vivo studies to establish D 2 /D 3 receptor specificity to βcells is warranted to characterize 11 C-(1)-PHNO as a candidate for clinical measurement of BCM in healthy control and diabetic subjects.
In vivo characterization of the brain pharmacokinetics of novel compounds provides important information for drug development decisions involving dose selection and the determination of administration regimes. In this context, the compound-target affinity is the key parameter to be estimated. However, if compounds exhibit a dynamic lag between plasma and target bound concentrations leading to pharmacological hysteresis, care needs to be taken to ensure the appropriate modeling approach is useddoi:10.1038/jcbfm.2012.208 pmid:23385202 pmcid:PMC3652698 fatcat:2zmnomzydjeghdrrxonlp36hqe
more »... o that the system is characterized correctly and that the resultant estimates of affinity are correct. This work focuses on characterizing different pharmacokinetic models that relate the plasma concentration to positron emission tomography outcomes measurements (e.g., volume of distribution and target occupancy) and their performance in estimating the true in vivo affinity. Measured (histamine H3 receptor antagonist-GSK189254) and simulated data sets enabled the investigation of different modeling approaches. An indirect pharmacokinetic-receptor occupancy model was identified as a suitable model for the calculation of affinity when a compound exhibits pharmacological hysteresis.
Annals of Neurology
Objective: Several interventions promote axonal growth and functional recovery when initiated shortly after central nervous system injury, including blockade of myelin-derived inhibitors with soluble Nogo receptor (NgR1, RTN4R) decoy protein. We examined the efficacy of this intervention in the much more prevalent and refractory condition of chronic spinal cord injury. Methods: We eliminated the NgR1 pathway genetically in mice by conditional gene targeting starting 8 weeks after spinaldoi:10.1002/ana.22527 pmid:22162062 pmcid:PMC3238798 fatcat:5dywlsxkq5hflaconee4emgece
more »... ion injury and monitored locomotion in the open field and by video kinematics over the ensuing 4 months. In a separate pharmacological experiment, intrathecal NgR1 decoy protein administration was initiated 3 months after spinal cord contusion injury. Locomotion and raphespinal axon growth were assessed during 3 months of treatment between 4 and 6 months after contusion injury. Results: Conditional deletion of NgR1 in the chronic state results in gradual improvement of motor function accompanied by increased density of raphespinal axons in the caudal spinal cord. In chronic rat spinal contusion, NgR1 decoy treatment from 4 to 6 months after injury results in 29% (10 of 35) of rats recovering weight-bearing status compared to 0% (0 of 29) of control rats (p < 0.05). Open field Basso, Beattie, and Bresnahan locomotor scores showed a significant improvement in the NgR-treated group relative to the control group (p < 0.005, repeated measures analysis of variance). An increase in raphespinal axon density caudal to the injury is detected in NgR1 decoy-treated animals by immunohistology and by positron emission tomography using a serotonin reuptake ligand. Interpretation: Antagonizing myelin-derived inhibitors signaling with NgR1 decoy augments recovery from chronic spinal cord injury.
Sex differences exist in the neurochemical mechanisms underlying tobacco smoking and smoking-related behaviors. Men tend to smoke for the reinforcing effects of nicotine, whereas women tend to smoke for stress and mood regulation, and have a harder time maintaining long-term abstinence. The mesolimbic dopamine (DA) system drives the reinforcing effects of tobacco smoking, whereas the mesocortical DA system-including the dorsolateral prefrontal cortex (dlPFC)-is critical for stress-relateddoi:10.1038/s41386-019-0456-y pmid:31269510 pmcid:PMC6897943 fatcat:xiochangnndn7cl26taggpasee
more »... ive functioning and inhibitory control. This study is the first to investigate dlPFC D2/3-type receptor (D2R) availability and amphetamine-induced cortical DA release in smokers and nonsmokers. Forty-nine subjects (24 tobacco smokers (12 females) and 25 sex- and age-matched nonsmokers) participated in two same-day [11C]FLB457 positron emission tomography (PET) scans before and 3-hours after amphetamine administration (0.4-0.5 mg/kg, PO). D2R availability (non-displaceable binding potential; BPND) was measured pre- and post-amphetamine. The percent fractional change in BPND (%ΔBPND) between pre- and post-amphetamine, an index of DA release, was compared between male and female smokers and nonsmokers. Smokers showed significantly lower dlPFC D2R availability (BPND = 0.77 ± 0.05) than nonsmokers (BPND = 0.92 ± 0.04), p = 0.016, driven by males. Female smokers showed significantly less amphetamine-induced DA release in dlPFC (%ΔBPND = 1.9 ± 3.0%) than male smokers (%ΔBPND = 14.0 ± 4.3%), p < 0.005, and female nonsmokers (%ΔBPND = 9.3 ± 3.3%), p < 0.005. This study shows that in the prefrontal cortex, smokers have lower D2R availability than nonsmokers and that female vs. male smokers have a blunted amphetamine-induced DA release. These findings demonstrate that tobacco smoking differentially affects the mesocortical DA system in men vs. women, suggesting a potential target for gender-specific treatments.
The ability to quantify synaptic density in vivo in human adults and adolescents is of vital importance to understanding neuropsychiatric disorders. Here, we performed whole-body scans to determine organ radiation dosimetry of 11C-UCB-J in humans.doi:10.1186/s13550-020-00670-w pmid:32666239 fatcat:mbcseogu4zf77hybcwtpt2ynr4
Background-Preclinical evidence implicates the 5-HT 1B receptor in cocaine's effects. This study explores 5-HT 1B in humans by examining receptor availability in vivo with primary cocainedependent (CD) subjects using positron emission tomography (PET). Methods-Fourteen medically healthy CD subjects (mean age=41±6 yrs) were compared to 14 age-matched healthy control subjects (41±8 yrs) with no past or current history of cocaine or other illicit substance abuse. Participants received an MRI anddoi:10.1016/j.biopsych.2013.11.022 pmid:24433854 pmcid:PMC4037398 fatcat:5o2yz3jmxng2laa6xz3po22asm
more »... en a PET scan with the highly selective 5HT 1B tracer, [ 11 C]P943, for purposes of quantifying regional binding potential (BP ND ). Voxelbased morphometry (VBM) and gray matter masking (GMM) were also employed to control for potential partial volume effects. Results-[ 11 C]P943 PET imaging data in nine candidate regions (amygdala, anterior cingulate cortex, caudate, frontal cortex, hypothalamus, pallidum, putamen, thalamus and ventral striatum) showed significant or nearly significant reductions of BP ND in CD subjects in three regions,
Annals of Neurology
Parkinson disease is characterized by motor and nonmotor symptoms, reduced striatal dopamine signaling, and loss of dopamine neurons in the substantia nigra. It is now known that the pathological process in Parkinson disease may begin decades before the clinical diagnosis and include a variety of neuronal alterations in addition to the dopamine system. This study examined the density of all synapses with synaptic vesicle glycoprotein 2A (SV2A) in Parkinson disease subjects with mild bilateraldoi:10.1002/ana.25682 pmid:31953875 pmcid:PMC7065227 fatcat:o4kiupv6mnd4pehukaln4nh3xu
more »... sease (n = 12) and matched normal controls (n = 12) using in vivo high-resolution positron emission tomographic imaging as well as postmortem autoradiography in an independent sample with Parkinson disease (n = 15) and normal controls (n = 13) in the substantia nigra and putamen. A group-by-brain region interaction effect (F10, 22 = 3.52, p = 0.007) was observed in the primary brain areas with in vivo SV2A binding. Post hoc analyses revealed that the Parkinson disease group exhibited lower SV2A in the substantia nigra (-45%; p < 0.001), red nucleus (-31%; p = 0.03), and locus coeruleus (-17%; p = 0.03). Exploratory analyses also revealed lower SV2A binding in clinically relevant cortical areas. Using autoradiography, we confirmed lower SV2A in the substantia nigra (-17%; p < 0.005) and nonsignificant findings in the putamen (-4%; p = 0.06). This work provides the first evidence of synaptic loss in brainstem nuclei involved in the pathogenesis of Parkinson disease in living patients. SV2A imaging holds promise for understanding synaptic changes central to the disease. Ann Neurol 2020;87:329-338.
Detecting fluctuations in synaptic dopamine levels in extrastriatal brain regions with [ 11 C]FLB 457 and positron emission tomography (PET) is a valuable tool for studying dopaminergic dysfunction in psychiatric disorders. The evaluation of reference region modeling approaches would eliminate the need to obtain arterial input function data. Our goal was to explore the use of reference region models to estimate amphetamine-induced changes in [ 11 C]FLB 457 dopamine D2/D3 binding. Six healthydoi:10.1038/jcbfm.2014.237 pmid:25564239 pmcid:PMC4420880 fatcat:xogwetr53vh6nfubnpjihwuxhi
more »... acco smokers were imaged with [ 11 C]FLB 457 at baseline and at 3 hours after amphetamine (0.4 to 0.5 mg/kg, per os) administration. Simplified reference tissue models, SRTM and SRTM2, were evaluated against the 2-tissue compartmental model (2TC) to estimate [ 11 C]FLB 457 binding in extrastriatal regions of interest (ROIs), using the cerebellum as a reference region. No changes in distribution volume were observed in the cerebellum between scan conditions. SRTM and SRTM2 underestimated binding, compared with 2TC, in ROIs by 26% and 9%, respectively, with consistent bias between the baseline and postamphetamine scans. Postamphetamine, [ 11 C]FLB 457 binding significantly decreased across several brain regions as measured with SRTM and SRTM2; no significant change was detected with 2TC. These data support the sensitivity of [ 11 C]FLB 457 for measuring amphetamine-induced dopamine release in extrastriatal regions with SRTM and SRTM2. Positron emission tomography images were aligned to the MR via a rigid registration with mutual information. Each MR image was normalized Reference region modeling approaches for C-11 FLB 457 CM Sandiego et al
Reactive oxygen species (ROS) play important roles in cell signaling and homeostasis. However, an abnormally high level of ROS is toxic, and is implicated in a number of diseases. Positron emission tomography (PET) imaging of ROS can assist in the detection of these diseases. For the purpose of clinical translation of [ 18 F]6-(4-((1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-5-methyl-5,6-dihydrophenanthridine-3,8-diamine ([ 18 F]DHMT), a promising ROS PET radiotracer, we firstdoi:10.3390/molecules21121696 pmid:27941676 pmcid:PMC5505691 fatcat:yfbx4ophujdchjhvqipsb4h4te
more »... ly optimized the large-scale radiosynthesis conditions and then implemented them in an automated synthesis module. Our manual synthesis procedure afforded [ 18 F]DHMT in 120 min with overall radiochemical yield (RCY) of 31.6% ± 9.3% (n = 2, decay-uncorrected) and specific activity of 426 ± 272 GBq/µmol (n = 2). Fully automated radiosynthesis of [ 18 F]DHMT was achieved within 77 min with overall isolated RCY of 6.9% ± 2.8% (n = 7, decay-uncorrected) and specific activity of 155 ± 153 GBq/µmol (n = 7) at the end of synthesis. This study is the first demonstration of producing 2-[ 18 F]fluoroethyl azide by an automated module, which can be used for a variety of PET tracers through click chemistry. It is also the first time that [ 18 F]DHMT was successfully tested for PET imaging in a healthy beagle dog.
« Previous Showing results 1 — 15 out of 62 results