Contribution of specific binding to the central benzodiazepine site to the brain concentrations of two novel benzodiazepine site ligands

2007 ◽  
Vol 28 (6) ◽  
pp. 275-282 ◽  
Author(s):  
Andrew Pike ◽  
Susan M. Cook ◽  
Alan P. Watt ◽  
Paul Scott-Stevens ◽  
Thomas W. Rosahl ◽  
...  
Keyword(s):  
Specific Binding ◽  
The Brain ◽  
Benzodiazepine Site

scholarly journals Improved in vivo PET imaging of the adenosine A2A receptor in the brain using [18F]FLUDA, a deuterated radiotracer with high metabolic stability

2021 ◽  
Author(s):  
Thu Hang Lai ◽  
Magali Toussaint ◽  
Rodrigo Teodoro ◽  
Sladjana Dukić-Stefanović ◽  
Daniel Gündel ◽  
...  
Keyword(s):  
Specific Binding ◽  
Radiochemical Yield ◽  
Toxicity Study ◽  
In Vivo Evaluation ◽  
One Pot ◽  
Specific Binding Ratio ◽  
Mri Studies ◽  
The Brain

Abstract Purpose The adenosine A2A receptor has emerged as a therapeutic target for multiple diseases, and thus the non-invasive imaging of the expression or occupancy of the A2A receptor has potential to contribute to diagnosis and drug development. We aimed at the development of a metabolically stable A2A receptor radiotracer and report herein the preclinical evaluation of [18F]FLUDA, a deuterated isotopologue of [18F]FESCH. Methods [18F]FLUDA was synthesized by a two-step one-pot approach and evaluated in vitro by autoradiographic studies as well as in vivo by metabolism and dynamic PET/MRI studies in mice and piglets under baseline and blocking conditions. A single-dose toxicity study was performed in rats. Results [18F]FLUDA was obtained with a radiochemical yield of 19% and molar activities of 72–180 GBq/μmol. Autoradiography proved A2A receptor–specific accumulation of [18F]FLUDA in the striatum of a mouse and pig brain. In vivo evaluation in mice revealed improved stability of [18F]FLUDA compared to that of [18F]FESCH, resulting in the absence of brain-penetrant radiometabolites. Furthermore, the radiometabolites detected in piglets are expected to have a low tendency for brain penetration. PET/MRI studies confirmed high specific binding of [18F]FLUDA towards striatal A2A receptor with a maximum specific-to-non-specific binding ratio in mice of 8.3. The toxicity study revealed no adverse effects of FLUDA up to 30 μg/kg, ~ 4000-fold the dose applied in human PET studies using [18F]FLUDA. Conclusions The new radiotracer [18F]FLUDA is suitable to detect the availability of the A2A receptor in the brain with high target specificity. It is regarded ready for human application.

scholarly journals Potential for imaging the high-affinity state of the 5-HT1B receptor: a comparison of three PET radioligands with differing intrinsic activity

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Anton Lindberg ◽  
Ryosuke Arakawa ◽  
Tsuyoshi Nogami ◽  
Sangram Nag ◽  
Magnus Schou ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Specific Binding ◽  
Occipital Cortex ◽  
Intrinsic Activity ◽  
High Affinity ◽  
G Protein Coupled ◽  
Dose Dependent ◽  
The Brain ◽  
Agonist Affinity States ◽  
Different Doses

Abstract Background Over the last decade, a few radioligands have been developed for PET imaging of brain 5-HT1B receptors. The 5-HT1B receptor is a G-protein-coupled receptor (GPCR) that exists in two different agonist affinity states. An agonist ligand is expected to be more sensitive towards competition from another agonist, such as endogenous 5-HT, than an antagonist ligand. It is of interest to know whether the intrinsic activity of a PET radioligand for the 5-HT1B receptor impacts on its ability to detect changes in endogenous synaptic 5-HT density. Three high-affinity 11C-labeled 5-HT1B PET radioligands with differing intrinsic activity were applied to PET measurements in cynomolgus monkey to evaluate their sensitivity to be displaced within the brain by endogenous 5-HT. For these experiments, fenfluramine was pre-administered at two different doses (1.0 and 5.0 mg/kg, i.v.) to induce synaptic 5-HT release. Results A dose-dependent response to fenfluramine was detected for all three radioligands. At the highest dose of fenfluramine (5.0 mg/kg, i.v.), reductions in specific binding in the occipital cortex increased with radioligand agonist efficacy, reaching 61% for [11C]3. The most antagonistic radioligand showed the lowest reduction in specific binding. Conclusions Three 5-HT1B PET radioligands were identified with differing intrinsic activity that could be used in imaging high- and low-affinity states of 5-HT1B receptors using PET. From this limited study, radioligand sensitivity to endogenous 5-HT appears to depend on agonist efficacy. More extensive studies are required to substantiate this suggestion.

Influnce of the beta-adrenergic agonist clenbuterol on plasma catecholamines and lymphocyte beta-receptors

1986 ◽  
Vol 1 (3) ◽  
pp. 234-236
Author(s):  
B. Bondy ◽  
M. Ackenheil ◽  
G. Laakmann ◽  
H.T. Munz
Keyword(s):  
Specific Binding ◽  
Plasma Catecholamines ◽  
Adrenergic System ◽  
Plasma Norepinephrine ◽  
Adrenergic Agonists ◽  
Adrenergic Agonist ◽  
Beta Receptors ◽  
Β Receptor ◽  
Beta Adrenergic Agonist ◽  
The Brain

SummaryThe influence of subchronic application of the β-adrenergic agonist clenbuterol on plasma norepinephrine (NE), epinephrine (E) and β-receptors on lymphocytes was investigated in 8 male, healthy volunteers. Treatment with clenbuterol (0.04 mg/day) for 6 days induced significant reduction of β-receptor specific binding in 7 of the 8 subjects with a mean decrease of 40% (p < 0.01) with no changes in affinity. Concomitantly an increase in the plasma NE concentration was observed (mean 50%, p < 0.01), but no significant overall alteration of E concentration. Our results suggest that β-adrenergic agonists exercise a similar effect on the peripheral adrenergic system and on the adrenergic system in the brain.

scholarly journals Mechanistic Insights in NeuroD Potentiation of Mineralocorticoid Receptor Signaling

2019 ◽  
Vol 20 (7) ◽  
pp. 1575 ◽  
Author(s):  
Lisa van Weert ◽  
Jacobus Buurstede ◽  
Hetty Sips ◽  
Isabel Mol ◽  
Tanvi Puri ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Mood Disorders ◽  
Chromatin Remodeling ◽  
Mineralocorticoid Receptor ◽  
Protective Factor ◽  
Specific Binding ◽  
Transcription Factor Family ◽  
Direct Stimulation ◽  
The Brain ◽  
Stimulation Of

Mineralocorticoid receptor (MR)-mediated signaling in the brain has been suggested as a protective factor in the development of psychopathology, in particular mood disorders. We recently identified genomic loci at which either MR or the closely related glucocorticoid receptor (GR) binds selectively, and found members of the NeuroD transcription factor family to be specifically associated with MR-bound DNA in the rat hippocampus. We show here using forebrain-specific MR knockout mice that GR binding to MR/GR joint target loci is not affected in any major way in the absence of MR. Neurod2 binding was also independent of MR binding. Moreover, functional comparison with MyoD family members indicates that it is the chromatin remodeling aspect of NeuroD, rather than its direct stimulation of transcription, that is responsible for potentiation of MR-mediated transcription. These findings suggest that NeuroD acts in a permissive way to enhance MR-mediated transcription, and they argue against competition for DNA binding as a mechanism of MR- over GR-specific binding.

scholarly journals The neurobiology and evolution of cannabinoid signalling

2001 ◽  
Vol 356 (1407) ◽  
pp. 381-408 ◽  
Author(s):  
Maurice R. Elphick ◽  
Michaelà Egertova
Keyword(s):  
G Protein ◽  
Cannabinoid Receptors ◽  
Cannabis Sativa ◽  
Specific Binding ◽  
Acid Amide ◽  
Presynaptic Terminals ◽  
Smooth Muscle Contractility ◽  
Signalling System ◽  
G Protein Coupled ◽  
The Brain

The plant Cannabis sativa has been used by humans for thousands of years because of its psychoactivity. The major psychoactive ingredient of cannabis is δ 9 –tetrahydrocannabinol, which exerts effects in the brain by binding to a G–protein–coupled receptor known as the CB 1 cannabinoid receptor. The discovery of this receptor indicated that endogenous cannabinoids may occur in the brain, which act as physiological ligands for CB 1 . Two putative endocannabinoid ligands, arachidonylethanolamide (‘anandamide’) and 2–arachidonylglycerol, have been identified, giving rise to the concept of a cannabinoid signalling system. Little is known about how or where these compounds are synthesized in the brain and how this relates to CB 1 expression. However, detailed neuroanatomical and electrophysiological analysis of mammalian nervous systems has revealed that the CB 1 receptor is targeted to the presynaptic terminals of neurons where it acts to inhibit release of ‘classical’ neurotransmitters. Moreover, an enzyme that inactivates endocannabinoids, fatty acid amide hydrolase, appears to be preferentially targeted to the somatodendritic compartment of neurons that are postsynaptic to CB 1 –expressing axon terminals. Based on these findings, we present here a model of cannabinoid signalling in which anandamide is synthesized by postsynaptic cells and acts as a retrograde messenger molecule to modulate neurotransmitter release from presynaptic terminals. Using this model as a framework, we discuss the role of cannabinoid signalling in different regions of the nervous system in relation to the characteristic physiological actions of cannabinoids in mammals, which include effects on movement, memory, pain and smooth muscle contractility. The discovery of the cannabinoid signalling system in mammals has prompted investigation of the occurrence of this pathway in non–mammalian animals. Here we review the evidence for the existence of cannabinoid receptors in non–mammalian vertebrates and invertebrates and discuss the evolution of the cannabinoid signalling system. Genes encoding orthologues of the mammalian CB 1 receptor have been identified in a fish, an amphibian and a bird, indicating that CB 1 receptors may occur throughout the vertebrates. Pharmacological actions of cannabinoids and specific binding sites for cannabinoids have been reported in several invertebrate species, but the molecular basis for these effects is not known. Importantly, however, the genomes of the protostomian invertebrates Drosophila melanogaster and Caenorhabditis elegans do not contain CB 1 orthologues, indicating that CB 1 –like cannabinoid receptors may have evolved after the divergence of deuterostomes (e.g. vertebrates and echinoderms) and protostomes. Phylogenetic analysis of the relationship of vertebrate CB 1 receptors with other G–protein–coupled receptors reveals that the paralogues that appear to share the most recent common evolutionary origin with CB 1 are lysophospholipid receptors, melanocortin receptors and adenosine receptors. Interestingly, as with CB 1 , each of these receptor types does not appear to have Drosophila orthologues , indicating that this group of receptors may not occur in protostomian invertebrates. We conclude that the cannabinoid signalling system may be quite restricted in its phylogenetic distribution, probably occurring only in the deuterostomian clade of the animal kingdom and possibly only in vertebrates.

scholarly journals Follistatin (FS) in human cerebrospinal fluid and regulation of FS expression in a mouse model of meningitis

2000 ◽  
pp. 809-816 ◽  
Author(s):  
U Michel ◽  
S Ebert ◽  
O Schneider ◽  
Y Shintani ◽  
S Bunkowski ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Specific Binding ◽  
In Situ Hybridisation ◽  
Viral Meningitis ◽  
Csf Analysis ◽  
Mrna And Protein Expression ◽  
Leukocyte Counts ◽  
The Brain

OBJECTIVE: Follistatin (FS) is the specific binding protein of activin and expression of both factors is regulated by inflammatory agents. Therefore, FS concentrations were determined in cerebrospinal fluid (CSF) of patients with bacterial and viral meningitis or multiple sclerosis (MS), as well as in the CSF of patients without meningial inflammation or autoimmune diseases. Furthermore, a mouse pneumococcal meningitis model was used to localise the cellular sources of FS in brains of normal and meningitic mice. METHODS: FS concentrations in CSF were determined by ELISA; FS in mice was localised by in situ hybridisation and immunohistochemistry. RESULTS: FS concentrations were > or =0.4 microg/l in 22 of 66 CSF samples of meningitis patients versus 2 of 27 CSF samples from patients with multiple sclerosis (P<0.05) and 2 of 41 CSF specimen from patients without neuroinflammatory diseases (P<0.01). In the CSF of patients with meningitis, the concentration of FS was correlated with total protein (P<0.005) and lactate concentrations (P<0.05), but not with leukocyte counts, interval between onset of disease and CSF analysis, or clinical outcome. The CSF-to-serum ratios of FS and albumin also correlated significantly (P<0.0005). In some patients with meningitis the CSF-to-serum ratios suggested that the elevated FS in CSF did not originate from serum alone. FS was localised in mice brains to neurones of the hippocampus, dentate gyrus, neocortex, and to the choroid plexus. Analyses of brains and other organs from uninfected and infected animals sacrificed 6-36 h after infection did not reveal any obvious differences in the distribution and intensity of FS mRNA and protein expression. CONCLUSIONS: The concentration of FS in humans is elevated during meningitis. In some patients the increase is caused by a release of FS from brain into CSF. Data from the mouse meningitis model suggest that increased CSF concentrations of FS in meningitis appear not to be accompanied by an elevated number of cells containing FS mRNA or protein in the brain.

scholarly journals Chronic Developmental Lead Exposure increases μ-Opiate Receptor Levels in the Adolescent Rat Brain

2020 ◽  
Author(s):  
Damaris Albores-Garcia ◽  
Jennifer L McGlothan ◽  
Zoran Bursac ◽  
Tomás R. Guilarte
Keyword(s):  
Rat Brain ◽  
Early Adolescence ◽  
Drugs Of Abuse ◽  
Specific Binding ◽  
Biological Effects ◽  
The United States ◽  
Female Rats ◽  
Opioid Use ◽  
Male And Female Rats ◽  
The Brain

AbstractOpioid use and abuse has reached epidemic proportion in the United States resulting in a significant numbers of deaths due to overdose. While environmental factors are implicated in opioid addiction, less is known about the role of exposure to environmental pollutants on the brain opioid system. Human and preclinical studies have suggested an association between childhood lead (Pb2+) intoxication and proclivity to substance abuse and delinquent behavior. Opioid receptors are involved in the biological effects of opioids and other drugs of abuse. In this study, we examine the effect of chronic developmental Pb2+ exposure on μ-opioid receptor (MOR) levels in the rat brain using [3H]-D-Ala2-MePhe4-Gly-ol5 enkephalin ([3H]-DAMGO) quantitative receptor autoradiography.Our results indicate that chronic developmental Pb2+ exposure increases the levels of [3H]-DAMGO specific binding to MOR in several limbic regions of the brain in male and female rats during the pre-adolescence (PN14) and early-adolescence (PN28) period. These changes were less pronounced in late-adolescence (PN50) and adult (PN120) animals. Our findings are important because the pre-adolescence and early adolescence period is a time in which there is higher engagement in reward and drug seeking behaviors in humans.In summary, we show that chronic exposure to Pb2+ an ubiquitous and well-known environmental contaminant and neurotoxicant, alters MOR levels in brain regions associated with addiction circuits in the adolescent period with important implications to opioid drug use and abuse.

scholarly journals Specific Binding Sites for Endothelin in the Brain, Spinal Cord, Heart and Kidney

1990 ◽  
Vol 31 (4) ◽  
pp. 567-567
Author(s):  
Masami Niwa ◽  
Tsutomu Kawaguchi ◽  
Tetsu Maeda ◽  
Hidefumi Yamasaki ◽  
Masaki Kurihara ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Binding Sites ◽  
Specific Binding ◽  
Specific Binding Sites ◽  
The Brain

scholarly journals Modeling the Effect of Binding Kinetics in Spatial Drug Distribution in the Brain

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Nelson Kashaju ◽  
Mark Kimathi ◽  
Verdiana G. Masanja
Keyword(s):  
Specific Binding ◽  
Extracellular Fluid ◽  
Drug Distribution ◽  
Drug Binding ◽  
Binding Kinetics ◽  
Binding Parameter ◽  
Specific Binding Sites ◽  
Distribution Process ◽  
Parameter Values ◽  
The Brain

A 3-dimensional mathematical model is developed to determine the effect of drug binding kinetics on the spatial distribution of a drug within the brain. The key components, namely, transport across the blood-brain barrier (BBB), drug distribution in the brain extracellular fluid (ECF), and drug binding kinetics are coupled with the bidirectional bulk flow of the brain ECF to enhance the visualization of drug concentration in the brain. The model is developed based on the cubical volume of a brain unit, which is a union of three subdomains: the brain ECF, the BBB, and the blood plasma. The model is a set of partial differential equations and the associated initial and boundary conditions through which the drug distribution process in the mentioned subdomains is described. Effects of drug binding kinetics are investigated by varying the binding parameter values for both nonspecific and specific binding sites. All variations of binding parameter values are discussed, and the results show the improved visualization of the effect of binding kinetics in the drug distribution within the brain. For more realistic visualization, we suggest incorporating more brain components that make up the large volume of the brain tissue.

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