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Christer Halldin - One of the best experts on this subject based on the ideXlab platform.
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an in vivo study of a rat fluid percussion induced traumatic brain injury model with 11c pbr28 and 18f flumazenil pet imaging
International Journal of Molecular Sciences, 2021Co-Authors: Krishna Kanta Ghosh, Christer Halldin, Parasuraman Padmanabhan, Changtong Yang, Zhimin Wang, Mathangi Palanivel, Jan CarlstedtdukeAbstract:Traumatic brain injury (TBI) modelled by lateral fluid percussion-induction (LFPI) in rats is a widely used experimental rodent model to explore and understand the underlying cellular and molecular alterations in the brain caused by TBI in humans. Current improvements in imaging with positron emission tomography (PET) have made it possible to map certain features of TBI-induced cellular and molecular changes equally in humans and animals. The PET imaging technique is an apt supplement to nanotheranostic-based treatment alternatives that are emerging to tackle TBI. The present study aims to investigate whether the two Radioligands, [11C]PBR28 and [18F]flumazenil, are able to accurately quantify in vivo molecular-cellular changes in a rodent TBI-model for two different biochemical targets of the processes. In addition, it serves to observe any palpable variations associated with primary and secondary injury sites, and in the affected versus the contralateral hemispheres. As [11C]PBR28 is a Radioligand of the 18 kD translocator protein, the up-regulation of which is coupled to the level of neuroinflammation in the brain, and [18F]flumazenil is a Radioligand for GABAA-benzodiazepine receptors, whose level mirrors interneuronal activity and eventually cell death, the use of the two Radioligands may reveal two critical features of TBI. An up-regulation in the [11C]PBR28 uptake triggered by the LFP in the injured (right) hemisphere was noted on day 14, while the uptake of [18F]flumazenil was down-regulated on day 14. When comparing the left (contralateral) and right (LFPI) hemispheres, the differences between the two in neuroinflammation were obvious. Our results demonstrate a potential way to measure the molecular alterations in a rodent-based TBI model using PET imaging with [11C]PBR28 and [18F]flumazenil. These Radioligands are promising options that can be eventually used in exploring the complex in vivo pharmacokinetics and delivery mechanisms of nanoparticles in TBI treatment.
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the metabotropic glutamate receptor 5 Radioligand 11c azd9272 identifies unique binding sites in primate brain
Neuropharmacology, 2018Co-Authors: Katarina Varnäs, Sjoerd J. Finnema, Vladimir Stepanov, Akihiro Takano, Anders Jureus, Peter Johnstrom, Patrick Raboisson, Nahid Amini, Christer HalldinAbstract:Abstract The metabotropic glutamate receptor 5 (mGluR5) is a target for drug development and for imaging studies of the glutamate system in neurological and psychiatric disorders. [ 11 C]AZD9272 is a selective mGluR5 PET Radioligand that is structurally different from hitherto applied mGluR5 Radioligands. In the present investigation we compared the binding patterns of radiolabeled AZD9272 and other mGluR5 Radioligands in the non-human primate (NHP) brain. PET studies were undertaken using [ 11 C]AZD9272 and the commonly applied mGluR5 Radioligand [ 11 C]ABP688. Autoradiography studies were performed in vitro using [ 3 H]AZD9272 and the standard mGluR5 Radioligands [ 3 H]M-MTEP and [ 3 H]ABP688 in NHP tissue. Competition binding studies were undertaken in vivo and in vitro using different mGluR5 selective compounds as inhibitors. In comparison to other mGluR5 Radioligands radiolabeled AZD9272 displayed a distinct regional distribution pattern with high binding in ventral striatum, midbrain, thalamus and cerebellum. While the binding of [ 11 C]AZD9272 was almost completely inhibited by the structurally unique mGluR5 compound fenobam (2.0 mg/kg; 98% occupancy), it was only partially inhibited (46% and 20%, respectively) by the mGluR5 selective compounds ABP688 and MTEP, at a dose (2.0 mg/kg) expected to saturate the mGluR5. Autoradiography studies using [ 3 H]AZD9272 confirmed a distinct pharmacologic profile characterized by preferential sensitivity to fenobam. The distinctive binding in ventral striato-pallido-thalamic circuits and shared pharmacologic profile with the pro-psychotic compound fenobam warrants further examination of [ 11 C]AZD9272 for potential application in psychiatric neuroimaging studies.
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Fenfluramine Reduces [11C]Cimbi-36 Binding to the 5-HT2A Receptor in the Nonhuman Primate Brain.
The International Journal of Neuropsychopharmacology, 2017Co-Authors: Kai-chun Yang, Gitte M Knudsen, Vladimir Stepanov, Stefan Martinsson, Anders Ettrup, Lars Farde, Christer Halldin, Akihiro Takano, Sjoerd J. FinnemaAbstract:Background: [11C]Cimbi-36 is a serotonin 2A receptor agonist positron emission tomography Radioligand that has recently been examined in humans. The binding of agonist Radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist Radioligands. In the current study, we compared the effect of serotonin releaser fenfluramine on the binding of [11C]Cimbi-36, [11C]MDL 100907 (a serotonin 2A receptor antagonist Radioligand), and [11C]AZ10419369 (a serotonin 1B receptor partial agonist Radioligand with established serotonin sensitivity) in the monkey brain. Methods: Eighteen positron emission tomography measurements, 6 for each Radioligand, were performed in 3 rhesus monkeys before or after administration of 5.0 mg/kg fenfluramine. Binding potential values were determined with the simplified reference tissue model using cerebellum as the reference region. Results: Fenfluramine significantly decreased [11C]Cimbi-36 (26-62%) and [11C]AZ10419369 (35-58%) binding potential values in most regions (P < 0.05). Fenfluramine-induced decreases in [11C]MDL 100907 binding potential were 8% to 30% and statistically significant in 3 regions. Decreases in [11C]Cimbi-36 binding potential were larger than for [11C]AZ10419369 in neocortical and limbic regions (~35%) but smaller in striatum and thalamus (~40%). Decreases in [11C]Cimbi-36 binding potential were 0.9 to 2.8 times larger than for [11C]MDL 100907, and the fraction of serotonin 2A receptor in the high-affinity state was estimated as 54% in the neocortex. Conclusions: The serotonin sensitivity of serotonin 2A receptor agonist Radioligand [11C]Cimbi-36 was higher than for antagonist Radioligand [11C]MDL 100907. The serotonin sensitivity of [11C]Cimbi-36 was similar to [11C]AZ10419369, which is one of the most sensitive Radioligands. [11C]Cimbi-36 is a promising Radioligand to examine serotonin release in the primate brain.
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RESEARCH ARTICLE [11C]MADAM Used as a Model for Understanding the Radiometabolism of
2016Co-Authors: Diphenyl Sulfide, Denis Guilloteau, Radioligands Positron, Louisa Barré, Christer HalldinAbstract:In quantitative PET measurements, the analysis of radiometabolites in plasma is essential for determining the exact arterial input function. Diphenyl sulfide compounds are promising PET and SPECT Radioligands for in vivo quantification of the serotonin transporter (SERT) and it is therefore important to investigate their radiometabolism. We have chosen to explore the radiometabolic profile of [11C]MADAM, one of these Radioligands widely used for in vivo PET-SERT studies. The metabolism of [11C]MADAM/MADAM was investigated using rat and human liver microsomes (RLM and HLM) in combination with radio-HPLC or UHPLC/Q-ToF-MS for their identification. The effect of carrier on the radiometabolic rate of the Radioligand [11C]MADAM in vitro and in vivo was examined by radio-HPLC. RLM and HLM incubations were carried out at two different carrier concentrations of 1 and 10 μM. Urine samples after perfusion of [11C]MADAM/MADAM in rats were also analysed by radio-HPLC. Analysis by UHPLC/Q-ToF-MS identified the metabolites produced in vitro to be results of N-demethylation, S-oxidation and benzylic hydroxylation. The presence of carrier greatly affected the radiometabolism rate of [11C]MADAM in both RLM/HLM experiment
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Direct Plasma Metabolite Analysis of Positron Emission Tomography Radioligands by Micellar Liquid Chromatography with Radiometric Detection
2016Co-Authors: Ryuji Nakao, Magnus Schou, Christer HalldinAbstract:Determination of radio-metabolites in plasma samples taken during a positron emission tomography (PET) study is an important component in the pharmacokinetic evaluation of PET Radioligands. We have developed and validated a new analytical procedure for the plasma metabolite analysis of PET Radioligands based on micellar liquid chromatography using an anionic surfactant mobile phase. Chromatographic separation was performed on an octadecyl semipreparative column (10 mm I.D. × 160 mm, 10 μm) using 100 mM sodium dodecyl sulfate (SDS) and 1-butanol in 10 mM sodium-phosphate (pH 7.2) at a flow rate of 5 mL/min. The samples taken from monkey or human plasma during PET measurements were directly injected into a liquid chromatographic (LC) system coupled to an online radiometric detector under micellar conditions using 1–2% (v/v) 1-butanol mobile phase to remove plasma proteins and concentrate the analytes at the column head. At 2 min, mobile phase was changed to elute and separate PET Radioligand and its radiometabolites with high peak capacity under high submicellar conditions (10–25% 1-butanol). This procedure allowed direct plasma injection (up to 2 mL) into the LC column without any pretreatment with a short analysis-time of 8–10 min. Satisfactory reproducibility, linearity, sensitivity, accuracy and recovery were obtained in the validation study. The developed method was successfully applied to study the metabolism for diverse groups of PET Radioligands and provided reliable determination of PET Radioligands in human and monkey plasma. This method is advantageous in terms of simplifying and shortening the processes required to analyze short-lived Radioligands as well as in providing a more accurate estimation of the metabolite corrected input function, especially for the Radioligands with lower recoveries or degradation potential during the deproteination process in a conventional procedure
Robert B Innis - One of the best experts on this subject based on the ideXlab platform.
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measuring specific receptor binding of a pet Radioligand in human brain without pharmacological blockade the genomic plot
NeuroImage, 2016Co-Authors: Mattia Veronese, Robert B Innis, Paolo Zanottifregonara, Gaia Rizzo, Alessandra Bertoldo, Federico E TurkheimerAbstract:PET studies allow in vivo imaging of the density of brain receptor species. The PET signal, however, is the sum of the fraction of Radioligand that is specifically bound to the target receptor and the non-displaceable fraction (i.e. the non-specifically bound Radioligand plus the free ligand in tissue). Therefore, measuring the non-displaceable fraction, which is generally assumed to be constant across the brain, is a necessary step to obtain regional estimates of the specific fractions. The nondisplaceable binding can be directly measured if a reference region, i.e. a region devoid of any specific binding, is available. Many receptors are however widely expressed across the brain, and a true reference region is rarely available. In these cases, the nonspecific binding can be obtained after competitive pharmacological blockade, which is often contraindicated in humans. In this work we introduce the genomic plot for estimating the nondisplaceable fraction using baseline scans only. The genomic plot is a transformation of the Lassen graphical method in which the brain maps of mRNA transcripts of the target receptor obtained from the Allen brain atlas are used as a surrogate measure of the specific binding. Thus, the genomic plot allows the calculation of the specific and nondisplaceable components of Radioligand uptake without the need of pharmacological blockade. We first assessed the statistical properties of the method with computer simulations. Then we sought ground-truth validation using human PET datasets of seven different neuroreceptor Radioligands, where nonspecific fractions were either obtained separately using drug displacement or available from a true reference region. The population nondisplaceable fractions estimated by the genomic plot were very close to those measured by actual human blocking studies (mean relative difference between 2% and 7%). However, these estimates were valid only when mRNA expressions were predictive of protein levels (i.e. there were no significant post-transcriptional changes). This condition can be readily established a priori by assessing the correlation between PET and mRNA expression.
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11c cumi 101 a pet Radioligand behaves as a serotonin 1a receptor antagonist and also binds to α1 adrenoceptors in brain
The Journal of Nuclear Medicine, 2014Co-Authors: Stal Saurav Shrestha, Kimberly J Jenko, Victor W. Pike, Per Svenningsson, Shuiyu Lu, Jeih-san Liow, Robert L. Gladding, Cheryl L. Morse, Sami S Zoghbi, Robert B InnisAbstract:The serotonin 1A receptor is a G-protein–coupled receptor (GPCR) bound to heterotrimeric α, β, and γ G-protein subunits (1). 5-HT1A receptors exhibit two affinity states—high (coupled to G protein) and low (uncoupled). Agonists bind to the high-affinity state of the GPCR and activate secondary cascades downstream. In contrast, antagonists bind to both the high- and the low-affinity states of the GPCR but do not activate receptor signaling. Of 5-HT’s 16 distinct receptor subtypes, the 5-HT1A receptor is known to play a crucial role in the pathophysiology and treatment of major depressive disorder and is a potential biomarker candidate. Currently, no suitable biomarker for major depressive disorder exists. 5-HT1A receptor density can be measured in intact, living brains using PET (2). To date, several PET Radioligands have been developed to measure the 5-HT1A receptor; the five most commonly used are [carbonyl-11C]WAY-100635, 11C-RWAY, 18F-FCWAY, 18F-mefWAY, and 18F-MPPF (3). However, all of these Radioligands are antagonists and, as such, do not discriminate between the active (high-affinity) and inactive (low-affinity) state of the receptor. In addition, none of the current 5-HT1A receptor Radioligands is sensitive to endogenous fluctuations in intrasynaptic 5-HT. This is particularly relevant to the search for biomarker candidates because the high-affinity states to which an agonist binds may be primarily affected under disease conditions, and agonists might be more sensitive to fluctuations in endogenous 5-HT levels. As a result, an agonist 5-HT1A receptor PET Radioligand has been much sought. A 2007 study reported the initial synthesis and in vivo evaluation of a potential agonist 5-HT1A receptor Radioligand, 11C-CUMI-101 (4). In baboons, 11C-CUMI-101 was shown to have optimal brain uptake, good washout, and a plasma free fraction of 60% (5). CUMI-101 exhibited agonist-like properties by dose-dependently stimulating 35S-GTPγS (GTP is guanosine triphosphate) binding in recombinant Chinese Hamster Ovary (CHO) cells expressing human 5-HT1A receptor (4). In contrast, a recent study showed that, in native rat brain tissues, CUMI-101 behaved as a potent 5-HT1A receptor antagonist (6). Thus, it is presently unknown whether CUMI-101 acts as an agonist or an antagonist in human and nonhuman primate brains. The issue of α1 adrenoceptor binding further complicates the picture. Initially, the affinity of CUMI-101 for 5-HT1A receptors was determined using bovine hippocampal membranes. Competitive binding studies of CUMI-101 with 3H-8-OH-DPAT—a potent 5-HT1A receptor agonist—showed the affinity to be in the subnanomolar range (inhibition constant [Ki], 0.15 nM) (4). Ki is obtained from heterologous displacement, and KD (dissociation constant) is obtained from homologous displacement assays. However, CUMI-101 also had moderate affinity to α1 adrenoceptors (Ki = 6.75 nM). α1 adrenoceptors consist of three highly homologous subtypes: α1A, α1B, and α1C. Studies show that many adrenergic drugs, especially ones targeting α1 adrenoceptors, have a nanomolar affinity for 5-HT1A receptors (7). Whether CUMI-101’s moderate in vitro affinity would cause in vivo binding to brain α1 adrenoceptors is also unknown. The present study sought to answer two key questions regarding the functional property and selectivity of CUMI-101. First, does CUMI-101 behave as an agonist or antagonist? Second, does CUMI-101 demonstrate cross-reactivity with α1 adrenoceptors? In this paper, cross-reactivity was defined as the nonselective property of CUMI-101 to specifically bind to α1 adrenoceptors in addition to its intended target—5-HT1A receptors. To address the first question, functional assays were performed using 35S-GTPγS in brain homogenates of rat, monkey, and human. To assess whether CUMI-101 binds to α1 adrenoceptors, both in vitro Radioligand binding studies and in vivo PET imaging studies were done in rodent and primate brains.
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brain and whole body imaging of nociceptin orphanin fq peptide receptor in humans using the pet ligand 11c nop 1a
The Journal of Nuclear Medicine, 2012Co-Authors: Talakad G Lohith, Robert B Innis, Victor W. Pike, Cheryl L. Morse, Sami S Zoghbi, Maria Ferraris Araneta, Vanessa N Barth, Nancy Goebl, Johannes Tauscher, Masahiro FujitaAbstract:Nociceptin/orphanin FQ peptide (NOP) receptor is a new class of opioid receptor that may play a pathophysiologic role in anxiety and drug abuse and is a potential therapeutic target in these disorders. We previously developed a high-affinity PET ligand, 11C-NOP-1A, which yielded promising results in monkey brain. Here, we assessed the ability of 11C-NOP-1A to quantify NOP receptors in human brain and estimated its radiation safety profile. Methods: After intravenous injection of 11C-NOP-1A, 7 healthy subjects underwent brain PET for 2 h and serial sampling of radial arterial blood to measure parent Radioligand concentrations. Distribution volume (VT; a measure of receptor density) was determined by compartmental (1- and 2-tissue) and noncompartmental (Logan analysis and Ichise9s bilinear analysis [MA1]) methods. A separate group of 9 healthy subjects underwent whole-body PET to estimate whole-body radiation exposure (effective dose). Results: After 11C-NOP-1A injection, the peak concentration of radioactivity in brain was high (∼5–7 standardized uptake values), occurred early (∼10 min), and then washed out quickly. The unconstrained 2-tissue-compartment model gave excellent VT identifiability (∼1.1% SE) and fitted the data better than a 1-tissue-compartment model. Regional VT values (mL·cm−3) ranged from 10.1 in temporal cortex to 5.6 in cerebellum. VT was well identified in the initial 70 min of imaging and remained stable for the remaining 50 min, suggesting that brain radioactivity was most likely parent Radioligand, as supported by the fact that all plasma radiometabolites of 11C-NOP-1A were less lipophilic than the parent Radioligand. Voxel-based MA1 VT values correlated well with results from the 2-tissue-compartment model, showing that parametric methods can be used to compare populations. Whole-body scans showed radioactivity in brain and in peripheral organs expressing NOP receptors, such as heart, pancreas, and spleen. 11C-NOP-1A was significantly metabolized and excreted via the hepatobiliary route. Gallbladder had the highest radiation exposure (21 μSv/MBq), and the effective dose was 4.3 μSv/MBq. Conclusion:11C-NOP-1A is a promising Radioligand that reliably quantifies NOP receptors in human brain. The effective dose in humans is low and similar to that of other 11C-labeled Radioligands, allowing multiple scans in 1 subject.
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d2 dopamine receptor internalization prolongs the decrease of Radioligand binding after amphetamine a pet study in a receptor internalization deficient mouse model
NeuroImage, 2010Co-Authors: Mette Skinbjerg, Victor W. Pike, Jeih-san Liow, Christer Halldin, Nicholas Seneca, Jinsoo Hong, Annika Thorsell, Markus Heilig, David R Sibley, Robert B InnisAbstract:Dopamine released by amphetamine decreases the in vivo binding of PET Radioligands to the dopamine D(2) receptor. Although concentrations of extracellular dopamine largely return to baseline within 1 to 2 h after amphetamine treatment, Radioligand binding remains decreased for several hours. The purpose of this study was to determine whether the prolonged decrease of Radioligand binding after amphetamine administration is caused by receptor internalization. To distinguish dopamine displacement from receptor internalization, we used wild-type and arrestin3 (arr3) knockout mice, which are incapable of internalizing D(2) receptors. In addition, we used both the D(2) selective agonist [(11)C]MNPA (which is thought to bind to the high affinity state of the receptor) and the D(2) selective antagonist [(18)F]fallypride (which does not differentiate between high and low affinity state). After an initial baseline scan, animals were divided in three groups for a second scan: either 30 min or 4 h after amphetamine administration (3 mg/kg, i.p.) or as retest. At 30 min, [(11)C]MNPA showed greater displacement than [(18)F]fallypride, but each Radioligand gave similar displacement in knockout and wild-type mice. At 4 h, the binding of both Radioligands returned to baseline in arr3 knockout mice, but remained decreased in wild-type mice. Radioligand binding was unaltered on retest scanning. Our results suggest that the prolonged decrease of Radioligand binding after amphetamine is mainly due to internalization of the D(2) receptor rather than dopamine displacement. In addition, this study demonstrates the utility of small animal PET to study receptor trafficking in vivo in genetically modified mice.
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whole body biodistribution and radiation dosimetry in monkeys and humans of the phosphodiesterase 4 Radioligand 11c r rolipram comparison of two dimensional planar bisected and quadrisected image analyses
Nuclear Medicine and Biology, 2008Co-Authors: David R Sprague, Jeih-san Liow, Victor W. Pike, Masahiro Fujita, Robert B InnisAbstract:Abstract Introduction [ 11 C]( R )-Rolipram is a selective Radioligand for positron emission tomography (PET) imaging of phosphodiesterase 4, an enzyme that metabolizes 3′,5′-cyclic adenosine monophosphate. The aim of this study was to estimate the human radiation absorbed dose of the Radioligand based on its biodistribution in both monkeys and humans. Methods Whole-body PET images were acquired for 2 h after injecting [ 11 C]( R )-rolipram in eight healthy humans and three monkeys. The simple method of using a single two-dimensional (2D) planar image was compared to more time-consuming methods that used two (bisected) or four (quadrisected) tomographic images in the anteroposterior direction. Results Effective dose was 4.8 μGy/MBq based on 2D planar images. The effective dose was only slightly lower by 1% and 5% using the bisected and quadrisected images, respectively. Nevertheless, the two tomographic methods may have more accurately estimated the exposure of some organs (e.g., kidneys) that are asymmetrically located in the body or have radioactivity that appears to overlap on 2D planar images. Monkeys had a different biodistribution pattern compared to humans (e.g., greater urinary excretion) such that their data overestimated the effective dose in humans by 40%. Conclusions The effective dose of [ 11 C]( R )-rolipram was modest and comparable to that of other 11 C-labeled Radioligands. The simple and far less time-consuming 2D planar method provided accurate and somewhat more conservative estimates of effective dose than the two tomographic methods. Although monkeys are commonly used to estimate human radiation exposures, their data gave a considerable overestimation for this Radioligand.
Sjoerd J. Finnema - One of the best experts on this subject based on the ideXlab platform.
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the metabotropic glutamate receptor 5 Radioligand 11c azd9272 identifies unique binding sites in primate brain
Neuropharmacology, 2018Co-Authors: Katarina Varnäs, Sjoerd J. Finnema, Vladimir Stepanov, Akihiro Takano, Anders Jureus, Peter Johnstrom, Patrick Raboisson, Nahid Amini, Christer HalldinAbstract:Abstract The metabotropic glutamate receptor 5 (mGluR5) is a target for drug development and for imaging studies of the glutamate system in neurological and psychiatric disorders. [ 11 C]AZD9272 is a selective mGluR5 PET Radioligand that is structurally different from hitherto applied mGluR5 Radioligands. In the present investigation we compared the binding patterns of radiolabeled AZD9272 and other mGluR5 Radioligands in the non-human primate (NHP) brain. PET studies were undertaken using [ 11 C]AZD9272 and the commonly applied mGluR5 Radioligand [ 11 C]ABP688. Autoradiography studies were performed in vitro using [ 3 H]AZD9272 and the standard mGluR5 Radioligands [ 3 H]M-MTEP and [ 3 H]ABP688 in NHP tissue. Competition binding studies were undertaken in vivo and in vitro using different mGluR5 selective compounds as inhibitors. In comparison to other mGluR5 Radioligands radiolabeled AZD9272 displayed a distinct regional distribution pattern with high binding in ventral striatum, midbrain, thalamus and cerebellum. While the binding of [ 11 C]AZD9272 was almost completely inhibited by the structurally unique mGluR5 compound fenobam (2.0 mg/kg; 98% occupancy), it was only partially inhibited (46% and 20%, respectively) by the mGluR5 selective compounds ABP688 and MTEP, at a dose (2.0 mg/kg) expected to saturate the mGluR5. Autoradiography studies using [ 3 H]AZD9272 confirmed a distinct pharmacologic profile characterized by preferential sensitivity to fenobam. The distinctive binding in ventral striato-pallido-thalamic circuits and shared pharmacologic profile with the pro-psychotic compound fenobam warrants further examination of [ 11 C]AZD9272 for potential application in psychiatric neuroimaging studies.
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Fenfluramine Reduces [11C]Cimbi-36 Binding to the 5-HT2A Receptor in the Nonhuman Primate Brain.
The International Journal of Neuropsychopharmacology, 2017Co-Authors: Kai-chun Yang, Gitte M Knudsen, Vladimir Stepanov, Stefan Martinsson, Anders Ettrup, Lars Farde, Christer Halldin, Akihiro Takano, Sjoerd J. FinnemaAbstract:Background: [11C]Cimbi-36 is a serotonin 2A receptor agonist positron emission tomography Radioligand that has recently been examined in humans. The binding of agonist Radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist Radioligands. In the current study, we compared the effect of serotonin releaser fenfluramine on the binding of [11C]Cimbi-36, [11C]MDL 100907 (a serotonin 2A receptor antagonist Radioligand), and [11C]AZ10419369 (a serotonin 1B receptor partial agonist Radioligand with established serotonin sensitivity) in the monkey brain. Methods: Eighteen positron emission tomography measurements, 6 for each Radioligand, were performed in 3 rhesus monkeys before or after administration of 5.0 mg/kg fenfluramine. Binding potential values were determined with the simplified reference tissue model using cerebellum as the reference region. Results: Fenfluramine significantly decreased [11C]Cimbi-36 (26-62%) and [11C]AZ10419369 (35-58%) binding potential values in most regions (P < 0.05). Fenfluramine-induced decreases in [11C]MDL 100907 binding potential were 8% to 30% and statistically significant in 3 regions. Decreases in [11C]Cimbi-36 binding potential were larger than for [11C]AZ10419369 in neocortical and limbic regions (~35%) but smaller in striatum and thalamus (~40%). Decreases in [11C]Cimbi-36 binding potential were 0.9 to 2.8 times larger than for [11C]MDL 100907, and the fraction of serotonin 2A receptor in the high-affinity state was estimated as 54% in the neocortex. Conclusions: The serotonin sensitivity of serotonin 2A receptor agonist Radioligand [11C]Cimbi-36 was higher than for antagonist Radioligand [11C]MDL 100907. The serotonin sensitivity of [11C]Cimbi-36 was similar to [11C]AZ10419369, which is one of the most sensitive Radioligands. [11C]Cimbi-36 is a promising Radioligand to examine serotonin release in the primate brain.
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Neurokinin-3 Receptor Binding in Guinea Pig, Monkey, and Human Brain: In Vitro and in Vivo Imaging Using the Novel Radioligand, [18F]Lu AF10628.
International Journal of Neuropsychopharmacology, 2016Co-Authors: Katarina Varnäs, Sjoerd J. Finnema, Vladimir Stepanov, Akihiro Takano, Miklós Tóth, Marie Svedberg, Søren Møller Nielsen, Nikolay Khanzhin, Karsten Juhl, Benny Bang-andersenAbstract:Background: Previous autoradiography studies have suggested a marked interspecies variation in the neuroanatomical localization and expression levels of the neurokinin 3 receptor, with high density in the brain of rat, gerbil, and guinea pig, but at the time offered no conclusive evidence for its presence in the human brain. Hitherto available Radioligands have displayed low affinity for the human neurokinin 3 receptor relative to the rodent homologue and may thus not be optimal for cross-species analyses of the expression of this protein. Methods: A novel neurokinin 3 receptor Radioligand, [18F]Lu AF10628 (( S )- N -(cyclobutyl(3-fluorophenyl)methyl)-8-fluoro-2-((3-[18F]-fluoropropyl)amino)-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxamide), was synthesized and used for autoradiography studies in cryosections from guinea pig, monkey, and human brain as well as for positron emission tomography studies in guinea pig and monkey. Results: The results confirmed previous observations of interspecies variation in the neurokinin 3 receptor brain localization with more extensive distribution in guinea pig than in primate brain. In the human brain, specific binding to the neurokinin 3 receptor was highest in the amygdala and in the hypothalamus and very low in other regions examined. Positron emission tomography imaging showed a pattern consistent with that observed using autoradiography. The radioactivity was, however, found to accumulate in skull bone, which limits the use of this Radioligand for in vivo quantification of neurokinin 3 receptor binding. Conclusion: Species differences in the brain distribution of neurokinin 3 receptors should be considered when using animal models for predicting human neurokinin 3 receptor pharmacology. For positron emission tomography imaging of brain neurokinin 3 receptors, additional work is required to develop a Radioligand with more favorable in vivo properties.
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serotonin transporter occupancy by escitalopram and citalopram in the non human primate brain a 11 c madam pet study
Psychopharmacology, 2015Co-Authors: Sjoerd J. Finnema, Lars Farde, Christer Halldin, Benny Bangandersen, Christoffer BundgaardAbstract:Rationale A number of serotonin receptor positron emission tomography (PET) Radioligands have been shown to be sensitive to changes in extracellular serotonin concentration, in a generalization of the well-known dopamine competition model. High doses of selective serotonin reuptake inhibitors (SSRIs) decrease serotonin receptor availability in monkey brain, consistent with increased serotonin concentrations. However, two recent studies on healthy human subjects, using a single, lower and clinically relevant SSRI dose, showed increased cortical serotonin receptor Radioligand binding, suggesting potential decreases in serotonin concentration in projection regions when initiating treatment.
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18 f mcl 524 an 18 f labeled dopamine d2 and d3 receptor agonist sensitive to dopamine a preliminary pet study
The Journal of Nuclear Medicine, 2014Co-Authors: Sjoerd J. Finnema, Vladimir Stepanov, Ryuji Nakao, Anna W Sromek, Tangzhi Zhang, John L Neumeyer, Susan R George, Philip Seeman, Michael G Stabin, Cathrine JonssonAbstract:Classic receptor-binding assays have demonstrated that dopamine receptors exist in 2 affinity states for agonists (1), similar to other G protein–coupled receptors. The 2 affinity states are considered interconvertible, with the high-affinity state corresponding to the functional, G protein–coupled state of the receptor (2). PET studies of dopamine D2 and D3 receptors (D2/D3) have since long predominantly been conducted using antagonists, such as 11C-raclopride. However, antagonists bind with equal affinity to the 2 affinity states of the receptor and do not provide information on the fraction of receptors in the high-affinity state. To overcome this limitation, agonist Radioligands have more recently been developed (3), including 11C-N-propylnorapomorphine (11C-NPA) (4), 11C-MNPA (5), and 11C-4-propyl-9-hydroxynaphthoxazine (6). A reported advantage of these agonist Radioligands is the enhanced sensitivity to amphetamine-induced changes in dopamine concentration when compared with 11C-raclopride (7,8). A limitation of the currently available agonist Radioligands is the labeling with the relatively short-lived radioisotope 11C (half-life, 20.3 min). Radiolabeling of an agonist with a longer-lived radioisotope, such as 18F (half-life, 109.8 min), may provide several advantages. First, an 18F-labeled ligand may favorably be used with bolus-infusion techniques, which allow quantification of binding potential at baseline and at a series of dopamine concentration–altering conditions in a single PET measurement. This paradigm is particularly attractive for application in the recently developed PET/functional MRI systems that allow for simultaneous measurements of changes in neurotransmitter concentration and blood-oxygen-level–dependent signal (9). Second, the longer half-life of 18F will allow for studies evaluating the acute and prolonged effects of a dopamine-related change in receptor binding, thereby having potential to disentangle return of dopamine levels to baseline from receptor internalization (10). Third, the longer half-life of 18F enhances the feasibility of Radioligands to be used in clinical centers where no cyclotron is available for on-site Radioligand production. An 18F-labeled Radioligand with high sensitivity to the endogenous dopamine concentration may therefore have wide utility. Development of 18F-labeled D2/D3 receptor agonist Radioligands has previously been reported, but with only limited success (11). 18F-analogs of successful 11C-labeled aporphine and naphthoxazine scaffold-based Radioligands have not been promising (12,13), because the introduction of 18F into the N-alkyl chain decreases binding affinity significantly. Perhaps the most promising Radioligand so far is (R,S)-2-(N-propyl-N-5′-18F-fluoropentyl)amino-5-hydroxytetralin, though the reported striatal-to-cerebellum binding ratios were only 2.0 in monkeys (14). Follow-up studies with this Radioligand have so far not been reported. In the current study, we radiolabeled the aporphine (R)-(−)-2-18F-fluoroethoxy-N-n-propylnorapomorphine (18F-MCL-524) (Fig. 1). This compound has nanomolar affinity in vitro to the D2 receptor in a state of high affinity (D2high) (3.7 nM) (15), and the radionuclide can be remotely introduced into the substituent at the 2-position. After radiosynthesis, 18F-MCL-524 was evaluated by PET in cynomolgus monkeys. We compared the binding of 18F-MCL-524 to 11C-MNPA and conducted pretreatment studies with raclopride and D-amphetamine to confirm specific binding to the D2/D3 receptors and dopamine sensitivity. A preliminary kinetic analysis was performed using the radiometabolite-corrected arterial input function. Finally, 2 whole-body PET examinations were conducted to obtain dosimetry estimates in preparation for future human studies. FIGURE 1 Chemical structures of 18F-MCL-524 and 11C-MNPA.
Lars Farde - One of the best experts on this subject based on the ideXlab platform.
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Fenfluramine Reduces [11C]Cimbi-36 Binding to the 5-HT2A Receptor in the Nonhuman Primate Brain.
The International Journal of Neuropsychopharmacology, 2017Co-Authors: Kai-chun Yang, Gitte M Knudsen, Vladimir Stepanov, Stefan Martinsson, Anders Ettrup, Lars Farde, Christer Halldin, Akihiro Takano, Sjoerd J. FinnemaAbstract:Background: [11C]Cimbi-36 is a serotonin 2A receptor agonist positron emission tomography Radioligand that has recently been examined in humans. The binding of agonist Radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist Radioligands. In the current study, we compared the effect of serotonin releaser fenfluramine on the binding of [11C]Cimbi-36, [11C]MDL 100907 (a serotonin 2A receptor antagonist Radioligand), and [11C]AZ10419369 (a serotonin 1B receptor partial agonist Radioligand with established serotonin sensitivity) in the monkey brain. Methods: Eighteen positron emission tomography measurements, 6 for each Radioligand, were performed in 3 rhesus monkeys before or after administration of 5.0 mg/kg fenfluramine. Binding potential values were determined with the simplified reference tissue model using cerebellum as the reference region. Results: Fenfluramine significantly decreased [11C]Cimbi-36 (26-62%) and [11C]AZ10419369 (35-58%) binding potential values in most regions (P < 0.05). Fenfluramine-induced decreases in [11C]MDL 100907 binding potential were 8% to 30% and statistically significant in 3 regions. Decreases in [11C]Cimbi-36 binding potential were larger than for [11C]AZ10419369 in neocortical and limbic regions (~35%) but smaller in striatum and thalamus (~40%). Decreases in [11C]Cimbi-36 binding potential were 0.9 to 2.8 times larger than for [11C]MDL 100907, and the fraction of serotonin 2A receptor in the high-affinity state was estimated as 54% in the neocortex. Conclusions: The serotonin sensitivity of serotonin 2A receptor agonist Radioligand [11C]Cimbi-36 was higher than for antagonist Radioligand [11C]MDL 100907. The serotonin sensitivity of [11C]Cimbi-36 was similar to [11C]AZ10419369, which is one of the most sensitive Radioligands. [11C]Cimbi-36 is a promising Radioligand to examine serotonin release in the primate brain.
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serotonin transporter occupancy by escitalopram and citalopram in the non human primate brain a 11 c madam pet study
Psychopharmacology, 2015Co-Authors: Sjoerd J. Finnema, Lars Farde, Christer Halldin, Benny Bangandersen, Christoffer BundgaardAbstract:Rationale A number of serotonin receptor positron emission tomography (PET) Radioligands have been shown to be sensitive to changes in extracellular serotonin concentration, in a generalization of the well-known dopamine competition model. High doses of selective serotonin reuptake inhibitors (SSRIs) decrease serotonin receptor availability in monkey brain, consistent with increased serotonin concentrations. However, two recent studies on healthy human subjects, using a single, lower and clinically relevant SSRI dose, showed increased cortical serotonin receptor Radioligand binding, suggesting potential decreases in serotonin concentration in projection regions when initiating treatment.
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fenfluramine induced serotonin release decreases 11c az10419369 binding to 5 ht1b receptors in the primate brain
Synapse, 2010Co-Authors: Sjoerd J. Finnema, Lars Farde, Christer Halldin, Andrea Varrone, Tzungjeng Hwang, B Gulyas, M E PiersonAbstract:The need for positron emission tomography (PET)-Radioligands that are sensitive to changes in endogenous serotonin (5-HT) levels in brain is recognized in experimental and clinical psychiatric research. We recently developed the novel PET Radioligand [11C]AZ10419369 that is highly selective for the 5-HT1B receptor. In this PET-study in three cynomolgus monkeys, we examined the sensitivity of [11C]AZ10419369 to altered endogenous 5-HT levels. Fenfluramine-induced 5-HT release decreased Radioligand binding in a dose-dependent fashion with a regional average of 27% after 1 mg/kg and 50% after 5 mg/kg. This preliminary study supports that [11C]AZ10419369 is sensitive to endogenous 5-HT levels in vivo and may serve as a tool to examine the pathophysiology and treatment of major psychiatric disorders. Synapse 64:573–577, 2010. © 2010 Wiley-Liss, Inc.
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effect of amphetamine on dopamine d2 receptor binding in nonhuman primate brain a comparison of the agonist Radioligand 11c mnpa and antagonist 11c raclopride
Synapse, 2006Co-Authors: Sjoerd J. Finnema, Lars Farde, Christer Halldin, Nicholas Seneca, Balazs Gulyas, H V Wikstrom, Robert B InnisAbstract:PET measurements of stimulant-induced dopamine (DA) release are typically performed with antagonist Radioligands that bind to both the high- and low-affinity state of the receptor. In contrast, an agonist Radioligand binds preferentially to the high-affinity state and is expected to have greater sensitivity to DA, which is the endogenous agonist. [C-11]MNPA, (R)-2-CH3O-N-n-propylnorapomorphine (MNPA), is a D-2 agonist Radioligand with subnanomolar affinity to the D-2 receptor. The aim of the present study is to assess and compare the sensitivity of the agonist Radioligand [C-11]MNPA and antagonist Radioligand [C-11]raclopride to synaptic DA levels. Four cynomolgus monkeys were examined with [C-11]MNPA and [C-11]raclopride (16 PET measurements with each tracer) at baseline and after pretreatment with various doses of amphetamine. The effect of amphetamine was calculated by the change in binding potential (BP) analyzed with the multilinear reference tissue model (MRTM2). Amphetamine caused a reduction in [C-11]MNPA BP of 4% at 0.1, 23% at 0.2, 25% at 0.5, and 46% at 1.0 mg/kg. [C-11]Raclopride BP was reduced to a lesser extent by 2% at 0.1, 16% at 0.2, 15% at 0.5, and 23% at 1.0 mg/kg. The data were used to estimate the in vivo percentage of high-affinity state receptors to be similar to 60%. These results demonstrate that [C-11]MNPA is more sensitive than [C-11]raclopride to displacement by endogenous DA, and that it may provide additional information about the functional state of the D-2 receptor in illnesses such as schizophrenia and Parkinson's disease.
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effect of amphetamine on dopamine d2 receptor binding in nonhuman primate brain a comparison of the agonist Radioligand 11c mnpa and antagonist 11c raclopride
Synapse, 2006Co-Authors: Sjoerd J. Finnema, Lars Farde, Christer Halldin, Nicholas Seneca, Balazs Gulyas, Hakan Wikstrom, Robert B InnisAbstract:PET measurements of stimulant-induced dopamine (DA) release are typically performed with antagonist Radioligands that bind to both the high- and low-affinity state of the receptor. In contrast, an agonist Radioligand binds preferentially to the high-affinity state and is expected to have greater sensitivity to DA, which is the endogenous agonist. [(11)C]MNPA, (R)-2-CH(3)O-N-n-propylnorapomorphine (MNPA), is a D(2) agonist Radioligand with subnanomolar affinity to the D(2) receptor. The aim of the present study is to assess and compare the sensitivity of the agonist Radioligand [(11)C]MNPA and antagonist Radioligand [(11)C]raclopride to synaptic DA levels. Four cynomolgus monkeys were examined with [(11)C]MNPA and [(11)C]raclopride (16 PET measurements with each tracer) at baseline and after pretreatment with various doses of amphetamine. The effect of amphetamine was calculated by the change in binding potential (BP) analyzed with the multilinear reference tissue model (MRTM2). Amphetamine caused a reduction in [(11)C]MNPA BP of 4% at 0.1, 23% at 0.2, 25% at 0.5, and 46% at 1.0 mg/kg. [(11)C]Raclopride BP was reduced to a lesser extent by 2% at 0.1, 16% at 0.2, 15% at 0.5, and 23% at 1.0 mg/kg. The data were used to estimate the in vivo percentage of high-affinity state receptors to be approximately 60%. These results demonstrate that [(11)C]MNPA is more sensitive than [(11)C]raclopride to displacement by endogenous DA, and that it may provide additional information about the functional state of the D(2) receptor in illnesses such as schizophrenia and Parkinson's disease.
Thomas J Gardella - One of the best experts on this subject based on the ideXlab platform.
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mechanisms of ligand binding to the parathyroid hormone pth pth related protein receptor selectivity of a modified pth 1 15 Radioligand for gαs coupled receptor conformations
Molecular Endocrinology, 2006Co-Authors: Thomas R Dean, Agnes Linglart, Matthew J Mahon, Murat Bastepe, Harald Juppner, John T Potts, Thomas J GardellaAbstract:Mechanisms of ligand binding to the PTH/PTHrP receptor (PTHR) were explored using PTH fragment analogs as Radioligands in binding assays. In particular, the modified amino-terminal fragment analog, 125I-[Aib1,3,Nle8,Gln 10,homoarginine11,Ala12,Trp14,Tyr15]rPTH(1–15)NH2, 125I-[Aib1,3,M]PTH(1–15), was used as a Radioligand that we hypothesized to bind solely to the juxtamembrane (J) portion of the PTHR containing the extracellular loops and transmembrane helices. We also employed 125I-PTH(1–34) as a Radioligand that binds to both the amino-terminal extracellular (N) and J domains of the PTHR. Binding was examined in membranes derived from cells expressing either wild-type or mutant PTHRs. We found that the binding of 125I-[Aib1,3,M]PTH(1–15) to the wild-type PTHR was strongly (∼90%) inhibited by guanosine 5′-O-(3-thio)triphosphate (GTPγS), whereas the binding of 125I-PTH(1–34) was only mildly (∼25%) inhibited by GTPγS. Of these two Radioligands, only 125I-[Aib1,3,M]PTH(1–15) bound to PTHR-delNt, which lacks...
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mechanisms of ligand binding to the parathyroid hormone pth pth related protein receptor selectivity of a modified pth 1 15 Radioligand for gαs coupled receptor conformations
Molecular Endocrinology, 2006Co-Authors: Thomas R Dean, Agnes Linglart, Matthew J Mahon, Murat Bastepe, Harald Juppner, John T Potts, Thomas J GardellaAbstract:Mechanisms of ligand binding to the PTH/PTHrP receptor (PTHR) were explored using PTH fragment analogs as Radioligands in binding assays. In particular, the modified amino-terminal fragment analog, (125)I-[Aib(1,3),Nle8,Gln10,homoarginine11,Ala12,Trp14,Tyr15]rPTH(1-15)NH2, (125)I-[Aib(1,3),M]PTH(1-15), was used as a Radioligand that we hypothesized to bind solely to the juxtamembrane (J) portion of the PTHR containing the extracellular loops and transmembrane helices. We also employed (125)I-PTH(1-34) as a Radioligand that binds to both the amino-terminal extracellular (N) and J domains of the PTHR. Binding was examined in membranes derived from cells expressing either wild-type or mutant PTHRs. We found that the binding of (125)I-[Aib(1,3),M]PTH(1-15) to the wild-type PTHR was strongly (approximately 90%) inhibited by guanosine 5'-O-(3-thio)triphosphate (GTPgammaS), whereas the binding of (125)I-PTH(1-34) was only mildly (approximately 25%) inhibited by GTPgammaS. Of these two Radioligands, only (125)I-[Aib(1,3),M]PTH(1-15) bound to PTHR-delNt, which lacks most of the receptor's N domain, and again this binding was strongly inhibited by GTPgammaS. Binding of (125)I-[Aib(1,3),M]PTH(1-15) to the constitutively active receptor, PTHR-H223R, was only mildly (approximately 20%) inhibited by GTPgammaS, as was the binding of (125)I-PTH(1-34). In membranes prepared from cells lacking Galpha(S) via knockout mutation of Gnas, no binding of (125)I-[Aib(1,3),M]PTH(1-15) was observed, but binding of (125)I-[Aib(1,3),M]PTH(1-15) was recovered by virally transducing the cells to heterologously express Galpha(S). (125)I-PTH(1-34) bound to the membranes with or without Galpha(S). The overall findings confirm the hypothesis that (125)I-[Aib(1,3),M]PTH(1-15) binds solely to the J domain of the PTHR. They further show that this binding is strongly dependent on coupling of the receptor to Galpha(S)-containing heterotrimeric G proteins, whereas the binding of (125)I-PTH(1-34) can occur in the absence of such coupling. Thus, (125)I-[Aib(1,3),M]PTH(1-15) appears to function as a selective probe of Galpha(S)-coupled, active-state PTHR conformations.
