Radiosynthesis and preliminary evaluation of 11C-labeled 4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-benzo[e] [1,2,4] thiadiazine 1,1-dioxide for PET imaging AMPA receptors

Chen, Jiahui; Gan, Jiefeng; Sun, Jiyun; Chen, Zhe; Fu, Hualong; Rong, Jian; Deng, Xiaoyun; Shang, Jingjie; Gong, Jian; Shao, Tuo; Collier, Lee; Wang, Lu; Xu, Hao; Liang, Steven H.

doi:10.1016/j.tetlet.2020.151635

Cited by 6 publications

(3 citation statements)

References 30 publications

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“…These targets, to name a few, prostaglandin EP2 receptor, p38 mitogen-activated protein kinases, tumor necrosis factor, and autotaxin, represent new research directions and an unmet clinical need for PET ligand development for neuroinflammation. Furthermore, the recent development of PET neuroligands for the endocannabinoid pathway, metabotropic/ionotropic glutamate signaling receptors, and phosphodiesterases, for example, mGluR2, TARP γ8, and NMDAR (GluN2B), AMPAR − offers a great opportunity to study the crosstalk and signaling interaction under neuroinflammatory conditions and physiopathology of neurodegenerative diseases. In all, it is of paramount significance to take advantage of modern drug discovery efforts and the establishment of translational preclinical disease models to drive the future development of innovative PET probes.…”

Section: Outlook and Conclusionmentioning

confidence: 99%

The Repertoire of Small-Molecule PET Probes for Neuroinflammation Imaging: Challenges and Opportunities beyond TSPO

et al. 2021

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Neuroinflammation is an adaptive response of the central nervous system to diverse potentially injurious stimuli, which is closely associated with neurodegeneration and typically characterized by activation of microglia and astrocytes. As a noninvasive and translational molecular imaging tool, positron emission tomography (PET) could provide a better understanding of neuroinflammation and its role in neurodegenerative diseases. Ligands to translator protein (TSPO), a putative marker of neuroinflammation, have been the most commonly studied in this context, but they suffer from serious limitations. Herein we present a repertoire of different structural chemotypes and novel PET ligand design for classical and emerging neuroinflammatory targets beyond TSPO. We believe that this Perspective will support multidisciplinary collaborations in academic and industrial institutions working on neuroinflammation and facilitate the progress of neuroinflammation PET probe development for clinical use.

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Section: Outlook and Conclusionmentioning

confidence: 99%

The Repertoire of Small-Molecule PET Probes for Neuroinflammation Imaging: Challenges and Opportunities beyond TSPO

et al. 2021

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“…However, there are no reports on binding properties in vivo for these compounds. Very recently, [ 11 C]-labeled 4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2 H -benzo[ e ][1,2,4]thiadiazine 1,1-dioxide ([ 11 C]AMPA-1905, 60 ) was prepared as non-competitive AMPA antagonist ligand for PET imaging [ 104 ]. [ 11 C]AMPA-1905 (60) was prepared from an N -Boc protected phenolic precursor, applying a one-pot two-step procedure.…”

Section: Glutamate Receptorsmentioning

confidence: 99%

A Review of Molecular Imaging of Glutamate Receptors

et al. 2020

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Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for PET/SPECT studies of dopamine, serotonin, and opiate receptors, but corresponding development of radiotracers for receptors of glutamate, the main excitatory neurotransmitter in mammalian brain, has lagged behind. This state of affairs has persisted despite the central importance of glutamate neurotransmission in brain physiology and in disorders such as stroke, epilepsy, schizophrenia, and neurodegenerative diseases. Recent years have seen extensive efforts to develop useful ligands for molecular imaging of subtypes of the ionotropic (N-methyl-D-aspartate (NMDA), kainate, and AMPA/quisqualate receptors) and metabotropic glutamate receptors (types I, II, and III mGluRs). We now review the state of development of radioligands for glutamate receptor imaging, placing main emphasis on the suitability of available ligands for reliable in vivo applications. We give a brief account of the radiosynthetic approach for selected molecules. In general, with the exception of ligands for the GluN2B subunit of NMDA receptors, there has been little success in developing radiotracers for imaging ionotropic glutamate receptors; failure of ligands for the PCP/MK801 binding site in vivo doubtless relates their dependence on the open, unblocked state of the ion channel. Many AMPA and kainite receptor ligands with good binding properties in vitro have failed to give measurable specific binding in the living brain. This may reflect the challenge of developing brain-penetrating ligands for amino acid receptors, compounded by conformational differences in vivo. The situation is better with respect to mGluR imaging, particularly for the mGluR5 subtype. Several successful PET ligands serve for investigations of mGluRs in conditions such as schizophrenia, depression, substance abuse and aging. Considering the centrality and diversity of glutamatergic signaling in brain function, we have relatively few selective and sensitive tools for molecular imaging of ionotropic and metabotropic glutamate receptors. Further radiopharmaceutical research targeting specific subtypes and subunits of the glutamate receptors may yet open up new investigational vistas with broad applications in basic and clinical research.

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“…Several radiotracers which are designed to bind selectively to AMPA receptors, allowing for the visualization and quantification of receptor distribution and binding affinity, were developed for imaging AMPA receptors using PET [ 23 , 24 , 25 , 26 ]. Despite the initial high brain uptake observed in all these tracers during preliminary evaluation, achieving high specific binding in vivo posed a significant challenge [ 25 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of [11C]BIIB104, an α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic-Acid-Positive Allosteric Modulator, and Evaluation of the Bio-Distribution in Non-Human Primate Brains Using Positron Emission Tomography

Nag,

Jia,

Arakawa

et al. 2024

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The aim of this study was to measure the brain penetrance and kinetics of BIIB104, a first-in-class AMPA receptor potentiator developed for cognitive impairment associated with schizophrenia. It was recently halted in phase 2 clinical development, and there are a lack of tools to directly measure AMPA receptor engagement. To achieve this, the drug candidate was radiolabeled with carbon-11, and its brain penetrance and kinetics were measured in non-human primates via dynamic PET scans. Radiolabeling was achieved through a three-step nucleophilic [11C]cyanation reaction in one pot, resulting in the high radioactivity and radiochemical purity (>99%) of [11C]BIIB104. The study found that [11C]BIIB104 entered the non-human primate brains at 4–5% ID at peak, with a homogeneous distribution. However, a mild regional heterogeneity was observed in the thalamus. The lack of conclusive evidence for a change in regional values after BIIB104 dosing suggests that any specific binding component of BIIB104 is negligible compared to the free and non-specific components in the living brain. Overall, the study demonstrated high brain uptake with minor variability in [11C]BIIB104 distribution across various brain regions, its kinetics were consistent with those of passive diffusion, and the dominating components were the free concentration and non-specific binding. This information is valuable for understanding the potential effects and mechanisms of BIIB104 in the brain.

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Radiosynthesis and preliminary evaluation of 11C-labeled 4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-benzo[e] [1,2,4] thiadiazine 1,1-dioxide for PET imaging AMPA receptors

Cited by 6 publications

References 30 publications

The Repertoire of Small-Molecule PET Probes for Neuroinflammation Imaging: Challenges and Opportunities beyond TSPO

The Repertoire of Small-Molecule PET Probes for Neuroinflammation Imaging: Challenges and Opportunities beyond TSPO

A Review of Molecular Imaging of Glutamate Receptors

Synthesis of [11C]BIIB104, an α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic-Acid-Positive Allosteric Modulator, and Evaluation of the Bio-Distribution in Non-Human Primate Brains Using Positron Emission Tomography

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