scholarly journals Synthesis and characterization of 5-(2-fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide as a PET imaging ligand for metabotropic glutamate receptor 2

2021 ◽  
Author(s):  
Gengyang Yuan ◽  
Maeva Dhaynaut ◽  
Yu Lan ◽  
Nicolas J Guehl ◽  
Dalena Huynh ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Pet Imaging ◽  
Metabotropic Glutamate Receptor ◽  
Volume Of Distribution ◽  
Potential Candidate ◽  
Brain Images ◽  
Metabotropic Glutamate ◽  
Molar Activity ◽  
Positron Emission

Metabotropic glutamate receptor 2 (mGluR2) is a therapeutic target for the treatment of several neuropsychiatric disorders and conditions. The role of mGluR2 function in etiology could be unveiled by in vivo imaging using positron emission tomography (PET). In this regard, 5-(2-fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide ([11C]13), a potent negative allosteric modulator (NAM), was developed to support this endeavor. Radioligand [11C]13 was synthesized via the O-[11C]methylation of phenol 24 with a high molar activity of 212 ± 76 GBq/µmol (n = 5) and excellent radiochemical purity (> 99%). PET imaging of [11C]13 in rats demonstrated its superior brain heterogeneity, particularly in the regions of striatum, thalamus, hippocampus, and cortex. Accumulation of [11C]13 in these regions of interest (ROIs) was reduced with pretreatment of mGluR2 NAMs, VU6001966 (9) and MNI-137 (26), the extent of which revealed a time-dependent drug effect of the blocking agents. In a nonhuman primate, [11C]13 selectively accumulated in mGluR2-rich regions, especially in different cortical areas, putamen, thalamus, and hippocampus, and resulted in high-contrast brain images. The regional total volume of distribution (VT) estimates of [11C]13 decreased by 14% after the pretreatment with 9. Therefore, [11C]13 is a potential candidate for translational PET imaging studies of mGluR2 function.

scholarly journals In vivo variation in same-day estimates of metabotropic glutamate receptor subtype 5 binding using [11C]ABP688 and [18F]FPEB

2016 ◽  
Vol 37 (8) ◽  
pp. 2716-2727 ◽  
Author(s):  
Christine DeLorenzo ◽  
Jean-Dominique Gallezot ◽  
John Gardus ◽  
Jie Yang ◽  
Beata Planeta ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Emission Tomography ◽  
Receptor Subtype ◽  
Metabotropic Glutamate ◽  
Positron Emission ◽  
Absolute Test ◽  
Residual Radioactivity

Positron emission tomography tracers [11C]ABP688 and [18F]FPEB target the metabotropic glutamate receptor subtype 5 providing quantification of the brain glutamatergic system in vivo. Previous [11C]ABP688 positron emission tomography human test–retest studies indicate that, when performed on the same day, significant binding increases are observed; however, little deviation is reported when scans are >7 days apart. Due to the small cohorts examined previously (eight and five males, respectively), we aimed to replicate the same-day test–retest studies in a larger cohort including both males and females. Results confirmed large within-subject binding differences (ranging from −23% to 108%), suggesting that measurements are greatly affected by study design. We further investigated whether this phenomenon was specific to [11C]ABP688. Using [18F]FPEB and methodology that accounts for residual radioactivity from the test scan, four subjects were scanned twice on the same day. In these subjects, binding estimates increased between 5% and 39% between scans. Consistent with [11C]ABP688, mean absolute test–retest variability was previously reported as <12% when scans were >21 days apart. This replication study and pilot extension to [18F]FPEB suggest that observed within-day binding variation may be due to characteristics of mGluR5; for example, diurnal variation in mGluR5 may affect measurement of this receptor.

scholarly journals in vivo Variation in Metabotropic Glutamate Receptor Subtype 5 Binding Using Positron Emission Tomography and [11C]ABP688

2011 ◽  
Vol 31 (11) ◽  
pp. 2169-2180 ◽  
Author(s):  
Christine DeLorenzo ◽  
J S Dileep Kumar ◽  
J John Mann ◽  
Ramin V Parsey
Keyword(s):  
Positron Emission Tomography ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Preliminary Evidence ◽  
Emission Tomography ◽  
Receptor Subtype ◽  
Metabotropic Glutamate ◽  
Pet Tracer ◽  
Positron Emission

The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in the pathophysiology of mood and anxiety disorders. Recently, a positron emission tomography (PET) tracer exhibiting high selectivity and specificity for mGluR5, 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11C-methyl-oxime ([11C]ABP688), was developed. In this work, eight healthy adult male humans were imaged twice to assess within-subject [11C]ABP688 binding variability using PET. In seven of the eight subjects, significantly higher binding was observed during the second (retest) scan. This binding increase could not be definitively explained by differences in ligand injected mass or dose, or changes in metabolism between scans. In addition, this type of systematic binding increase was not observed in a [11C]ABP688 test–retest study performed by our group on anaesthetized baboons. It is therefore possible that the increased binding was because of physiological changes occurring between scans, such as changes in endogenous glutamate levels. If PET imaging with [11C]ABP688 could detect such differences, as preliminary evidence suggests, it could be used to help uncover the role of glutamate in the pathophysiology of brain disorders. However, regardless of its ability to detect endogenous glutamate differences, [11C]ABP688 binding variability could make accurate assessments of drug occupancy or group differences using this ligand difficult.

scholarly journals Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence

2017 ◽  
Vol 114 (31) ◽  
pp. 8390-8395 ◽  
Author(s):  
Sophie E. Holmes ◽  
Matthew J. Girgenti ◽  
Margaret T. Davis ◽  
Robert H. Pietrzak ◽  
Nicole DellaGioia ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Molecular Mechanisms ◽  
Metabotropic Glutamate Receptor ◽  
Metabotropic Glutamate Receptor 5 ◽  
Metabotropic Glutamate ◽  
Positron Emission ◽  
Positive Correlations ◽  
Human Postmortem Tissue ◽  
Glutamate System

Posttraumatic stress disorder (PTSD) is a prevalent and highly disabling disorder, but there is currently no targeted pharmacological treatment for it. Dysfunction of the glutamate system has been implicated in trauma and stress psychopathology, resulting in a growing interest in modulation of the glutamate system for the treatment of PTSD. Specifically, the metabotropic glutamate receptor 5 (mGluR5) represents a promising treatment target. We used [18F]FPEB, a radioligand that binds to the mGluR5, and positron emission tomography (PET) to quantify in vivo mGluR5 availability in human PTSD vs. healthy control (HCs) subjects. In an independent sample of human postmortem tissue, we investigated expression of proteins that have a functional relationship with mGluR5 and glucocorticoids in PTSD. We observed significantly higher cortical mGluR5 availability in PTSD in vivo and positive correlations between mGluR5 availability and avoidance symptoms. In the postmortem sample, we observed up-regulation of SHANK1, a protein that anchors mGluR5 to the cell surface, as well as decreased expression of FKBP5, implicating aberrant glucocorticoid functioning in PTSD. Results of this study provide insight into molecular mechanisms underlying PTSD and suggest that mGluR5 may be a promising target for mechanism-based treatments aimed at mitigating this disorder.

scholarly journals Design, synthesis, and characterization of [18F]mG2P026 as a high contrast PET imaging ligand for metabotropic glutamate receptor 2

2021 ◽  
Author(s):  
Gengyang Yuan ◽  
Maeva Dhaynaut ◽  
Nicolas J Guehl ◽  
Sepideh Afshar ◽  
Dalena Huynh ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Pet Imaging ◽  
Metabotropic Glutamate Receptor ◽  
Specific Binding ◽  
Tracer Uptake ◽  
Design Synthesis ◽  
Metabotropic Glutamate ◽  
Molar Activity ◽  
Radiochemical Yields

An array of triazolopyridines based on JNJ-46356479 (6) were synthesized as potential PET imaging ligands for metabotropic glutamate receptor 2 (mGluR2) in the brain. The selected candidates 8-11 featured an enhanced positive allosteric modulator (PAM) activity (37-fold max.) and an apparent mGluR2 agonist activity (25-fold max.) compared to compound 6. Radiolabeling of compounds 8 and 9 (also named mG2P026) was achieved via the Cu(I)-mediated radiofluorination in the automated TRACERLabTM FXF-N platform. Both [18F]8 and [18F]9 were obtained with satisfactory radiochemical yields (> 5%, non-decay corrected), high molar activity (> 180 GBq/µmol), and excellent chemical and radiochemical purities (> 98%). Preliminary characterization of [18F]8 and [18F]9 in rats confirmed their excellent brain permeability with [18F]9 showing better brain heterogeneity and favorable binding kinetics. Pretreatment with different classes of PAMs enhanced the radioactivity uptake for both [18F]8 and [18F]9 at the regions of interest by 20.3-40.9% and 16.7-81.6%, respectively, due to their pharmacological effects. Further evaluation of [18F]9 in a nonhuman primate confirmed its superior brain heterogeneity in mapping mGlu2 receptors and its higher specific binding than [18F]6. Pretreatment with 0.5 mg/kg BINA (2) led to an enhanced brain uptake of [18F]9 by 3% in high tracer uptake regions that was consistent with the rat studies. Therefore, [18F]9 has the potential to be translated for human studies.

scholarly journals PET imaging studies to investigate functional expression of mGluR2 using [11C]mG2P001

2021 ◽  
Author(s):  
Gengyang Yuan ◽  
Maeva Dhaynaut ◽  
Nicolas J Guehl ◽  
Neelamegam Ramesh ◽  
Sung-Hyun Moon ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Metabotropic Glutamate Receptor ◽  
Functional Expression ◽  
Imaging Studies ◽  
Positive Allosteric Modulator ◽  
Metabotropic Glutamate ◽  
Glutamate Concentration ◽  
Positron Emission

Metabotropic glutamate receptor 2 (mGluR2) has been extensively studied for the treatment of various neurological and psychiatric disorders. Understanding of the mGluR2 function is pivotal in supporting the drug discovery targeting mGluR2. Herein, the positive allosteric modulation of mGluR2 was investigated via the in vivo positron emission tomography (PET) imaging using 2-((4-(2-[11C]methoxy-4-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)-1-methyl-1H-imidazo[4,5-b]pyridine ([11C]mG2P001).Distinct from the orthosteric compounds, pretreatment with the unlabeled mG2P001, a potent mGluR2 positive allosteric modulator (PAM), resulted in a significant increase instead of decrease of the [11C]mG2P001 accumulation in rat brain detected by PET imaging. Subsequent in vitro studies with [3H]mG2P001 revealed the cooperative binding mechanism of mG2P001 with glutamate and its pharmacological effect that contributed to the enhanced binding of [3H]mG2P001 in transfected CHO cells expressing mGluR2. The in vivo PET imaging and quantitative analysis of [11C]mG2P001 in non-human primates (NHPs) further validated the characteristics of [11C]mG2P001 as an imaging ligand for mGluR2. Self-blocking studies in primates enhanced accumulation of [11C]mG2P001 dose- and delivery-dependently. Altogether, these studies show that [11C]mG2P001 is a sensitive biomarker for mGluR2 expression and the binding is affected by the tissue glutamate concentration.

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