"Ro15-4513"

Test-retest reproducibility of quantitative binding measures of [11C]Ro15-4513, a PET ligand for GABAA receptors containing alpha5 subunits Alteration of γ-aminobutyric acid "A" (GABA) receptor-mediated neurotransmission has been associated with various neurological and psychiatric disorders. [C]Ro15-4513 is a PET ligand with high affinity for α5-subunit-containing GABA receptors, which are highly expressed in limbic regions of the human brain (Sur et al., 1998). We quantified the test-retest reproducibility of measures of [C]Ro15-4513 binding derived from six different quantification methods (12 variants). Five healthy males (median age 40 years, range 38-49 years) had a 90-min PET scan on two occasions (median interval 12 days, range 11-30 days), after injection of a median dose of 441

Quantification of [11C]Ro15-4513 GABAAα5 specific binding and regional selectivity in humans. [C]Ro15-4513 has been introduced as a positron emission tomography radioligand to image the GABAα5 receptor subtype thought to be important in learning, memory and addiction. However, the in vivo selectivity of the ligand remains unknown and a full assessment of different analysis approaches has yet to be performed. Using human heterologous competition data, with [C]Ro15-4513 and the highly selective GABAα5 selective negative allosteric modulator Basmisanil (RG1662), we quantify the GABAα5 selectivity of [C]Ro15-4513, assess the validity of reference tissues and evaluate the performance of four different kinetic analysis methods. The results show that [C]Ro15-4513 has high but not complete selectivity

Using [11C]Ro15 4513 PET to characterise GABA-benzodiazepine receptors in opiate addiction: Similarities and differences with alcoholism The importance of the GABA-benzodiazepine receptor complex and its subtypes are increasingly recognised in addiction. Using the α1/α5 benzodiazepine receptor PET radioligand [(11)C]Ro15 4513, we previously showed reduced binding in the nucleus accumbens and hippocampus in abstinent alcohol dependence. We proposed that reduced [(11)C]Ro15 4513 binding in the nucleus accumbens was a marker of addiction whilst the reduction in hippocampus and positive relationship with memory was a consequence of chronic alcohol abuse. To examine this further we assessed [(11)C]Ro15 4513 binding in another addiction, opiate dependence, and used spectral analysis to estimate

Acute increases in synaptic GABA detectable in the living human brain: A [(11)C]Ro15-4513 PET study. The inhibitory γ-aminobutyric acid (GABA) neurotransmitter system is associated with the regulation of normal cognitive functions and dysregulation has been reported in a number of neuropsychiatric disorders including anxiety disorders, schizophrenia and addictions. Investigating the role of GABA in both health and disease has been constrained by difficulties in measuring acute changes in synaptic GABA using neurochemical imaging. The aim of this study was to investigate whether acute increases in synaptic GABA are detectable in the living human brain using the inverse agonist GABA-benzodiazepine receptor (GABA-BZR) positron emission tomography (PET) tracer, [(11)C]Ro15-4513. We examined

Alcohol Selectivity of β3-Containing GABAA Receptors: Evidence for a Unique Extracellular Alcohol/Imidazobenzodiazepine Ro15-4513 Binding Site at the α+β− Subunit Interface in αβ3δ GABAA Receptors GABAA receptors (GABARs) have long been the focus for acute alcohol actions with evidence for behaviorally relevant low millimolar alcohol actions on tonic GABA currents and extrasynaptic α4/6 containing GABA receptors contain a unique ethanol site at the α4/6+β3- subunit interface. This site is homologous to the classical benzodiazepine binding site and we propose that it not only binds ethanol at relevant concentrations (EC50-17 mM), but also has high affinity for a few selected benzodiazepine site ligands including alcohol antagonistic iBZs (Ro15-4513, RY023, RY024, RY80) which have in common

Characterisation of the contribution of the GABA-benzodiazepine α1 receptor subtype to [(11)C]Ro15-4513 PET images. This positron emission tomography (PET) study aimed to further define selectivity of [(11)C]Ro15-4513 binding to the GABARα5 relative to the GABARα1 benzodiazepine receptor subtype. The impact of zolpidem, a GABARα1-selective agonist, on [(11)C]Ro15-4513, which shows selectivity for GABARα5, and the nonselective benzodiazepine ligand [(11)C]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [(11)C]Ro15-4513 time-activity curves was used to describe distribution volume (V(T)) differences in regions populated by different GABA receptor subtypes. Those with low α5 were best fitted by one-tissue compartment models; and those with high α5 required

The brain GABA-benzodiazepine receptor alpha-5 subtype in autism spectrum disorder: A pilot [11C]Ro15-4513 positron emission tomography study GABA (gamma-amino-butyric-acid) is the primary inhibitory neurotransmitter in the human brain. It has been proposed that the symptoms of autism spectrum disorders (ASDs) are the result of deficient GABA neurotransmission, possibly including reduced expression of GABAA receptors. However, this hypothesis has not been directly tested in living adults with ASD. In this preliminary investigation, we used Positron Emission Tomography (PET) with the benzodiazepine receptor PET ligand [(11)C]Ro15-4513 to measure α1 and α5 subtypes of the GABAA receptor levels in the brain of three adult males with well-characterized high-functioning ASD compared with three

. [18F]FFMZ also has faster kinetics than [11C]FMZ [167]. Static images can be obtained as early as 10 to 15 min of the injection 197 to 370 MBq of [18F]FMZ. Binding of FMZ is, however, more indicative of the expression of α1 rather than α5 subunits of the GABA-A receptor with potential impact of benzodiazepine receptor binding medications [168]. New tracers like [11C]Ro15-4513 have approximately nanomolar affinity for GABAA receptors, with approximately 10–15 times higher affinity for those receptors containing α5 than for those that do not. Clinical validity has not been demonstrated for [11C]Ro15-4513. However, a recent study in MRI-negative TLE produced, from a single injection, two parametric maps (one each for α1 and α5) via bandpass analysis showing bilaterally increased α5 binding, likely

. Transcriptional activation of the human HMG1 gene in cisplatin-resistant human. Cancer Cells. 2001;1592–7. * Noguchi J, Suzuki K. Automated synthesis of the ultra high specific activity of [11C]Ro15-4513 and its application in an extremely low concentration region to an ARG study. Nucl Med Biol. 2003;30(3):335–43. CAS PubMed Article Google Scholar * Oswald LM, Wong DF, McCaul M, Zhou Y

exposure. Quantitative receptor autoradiography was used to measure receptor density in the dorsal hippocampus CA1, ventral hippocampus CA1, and ventral subiculum. Specifically, [H]-Ro15-4513 was used to quantify the density of α5GABA receptors (α5GABAR), [H]-flumazenil to quantify α1-3;5GABAR, and [H]-MK801 to quantify NMDA receptors. MAM rats exhibited anxiety and schizophrenia-relevant behaviors

stimulation of pyramidal cells, it is of interest to determine whether the dopaminergic system regulates GABA release directly in cortical paralimbic regions. Here, we test the hypothesis that the regulation of the GABA-ergic system by the dopaminergic system becomes attenuated in problem gamblers resulting in addictive behaviors and impaired self-awareness. [ C]Ro15-4513 PET, a marker of benzodiazepine α1

, ranging from 4.5% to 8.7%. Pretreatment with flumazenil (a subtype nonselective ligand, 0.2 mg/kg, intravenous [IV], n = 1), Ro15-4513 (an α-selective ligand, 0.03 mg/kg, IV, n = 2), and zolpidem (an α-selective ligand, 1.7 mg/kg, IV, n = 1) led to blockade of [C]ADO binding by 96.5%, 52.5%, and 76.5%, respectively, indicating the in vivo binding specificity of the radiotracer. Using the nondisplaceable

demonstrated in humans. We here hypothesize that dopamine challenge stimulates the GABA system directly in the medial prefrontal/anterior cingulate region in the human brain. Positron emission tomography (PET) with the GABA receptor α1/α5 subtype ligand [(11)C] Ro15-4513 was used to detect changes in GABA receptor availability after clinical oral doses of levodopa in a double blind controlled study. We here provide the first direct evidence for such coupling in the cerebral cortex, in particular in the medial prefrontal anterior cingulate region, by showing that exogenous dopamine decreases [(11)C] Ro15-4513 binding widely in the human brain compatible with a fall in α1 subtype availability in GABA complexes due to increased GABA activity.

with greater impulsivity. There is also evidence of GABAergic dysregulation in substance addiction and in impulsivity. This study therefore investigated GABA receptor availability in 15 individuals with GD and 19 healthy volunteers (HV) using [ C]Ro15-4513, a relatively selective α5 benzodiazepine receptor PET tracer and its relationship with impulsivity. We found significantly higher [ C]Ro15-4513 total distribution volume (V ) in the right hippocampus in the GD group compared with HV. We found higher levels of the 'Negative Urgency' construct of impulsivity in GD, and these were positively associated with higher [ C]Ro15-4513 V in the amygdala in the GD group; no such significant correlations were evident in the HV group. These results contrast with reduced binding of GABAergic PET ligands described

independent mechanism for the development of abuse treatment pharmacotherapeutics. We tested the hypothesis that the GABAA receptor benzodiazepine-site (BDZ) negative modulator Ro15-4513 would reduce the reward-related effects of three pharmacologically dissimilar drugs; toluene vapor, d-methamphetamine, and diazepam using intracranial self-stimulation (ICSS) in mice. We also examined whether Ro15-4513 attenuated dopamine release produced by d-methamphetamine in an in vivo microdialysis procedure. Ro15-4513 abolished ICSS reward facilitation produced by all three abused drugs at Ro15-4513 doses which had no effect on ICSS when administered alone. In contrast, the BDZ antagonist flumazenil only attenuated the ICSS-facilitating effects of diazepam. Administration of the same dose of Ro15-4513 which

and plays an important role in mediating alcohol-seeking behaviors. Here we describe the long-lasting alterations of γ-aminobutyric acid type A receptors (GABA(A)Rs) of medium spiny neurons (MSNs) in the NAcc after chronic intermittent ethanol (CIE) treatment, a rat model of alcohol dependence. CIE treatment and withdrawal (>40 days) produced decreases in the ethanol and Ro15-4513 potentiation