Selected PET Radioligands for Ion Channel Linked Neuroreceptor Imaging: Focus on GABA, NMDA and nACh Receptors

Kassenbrock, Alina; Vasdev, Neil; Liang, Steven H.

doi:10.2174/1568026616666160315142457

Cited by 22 publications

(15 citation statements)

References 109 publications

(98 reference statements)

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“…We and others have previously reported selected PET radioligands developed for these targets. [265][266][267][268] Development of receptor subtype-specific radiotracers while maintaining or improving brain uptake remains a major challenge for PET radioligand development for these targets. Nevertheless, recent human PET imaging studies measuring a 7 269 and a 4 b 2 270 nicotinic acetylcholine receptor distribution in healthy volunteers using newly developed radioligands with superior in vivo characteristics support the translational potential of these targets for PET imaging of neurodegenerative diseases.…”

Section: Resultsmentioning

confidence: 99%

Emerging PET Radiotracers and Targets for Imaging of Neuroinflammation in Neurodegenerative Diseases: Outlook Beyond TSPO

et al. 2018

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The dynamic and multicellular processes of neuroinflammation are mediated by the nonneuronal cells of the central nervous system, which include astrocytes and the brain’s resident macrophages, microglia. Although initiation of an inflammatory response may be beneficial in response to injury of the nervous system, chronic or maladaptive neuroinflammation can have harmful outcomes in many neurological diseases. An acute neuroinflammatory response is protective when activated neuroglia facilitate tissue repair by releasing anti-inflammatory cytokines and neurotrophic factors. On the other hand, chronic neuroglial activation is a major pathological mechanism in neurodegenerative diseases, likely contributing to neuronal dysfunction, injury, and disease progression. Therefore, the development of specific and sensitive probes for positron emission tomography (PET) studies of neuroinflammation is attracting immense scientific and clinical interest. An early phase of this research emphasized PET studies of the prototypical imaging biomarker of glial activation, translocator protein-18 kDa (TSPO), which presents difficulties for quantitation and lacks absolute cellular specificity. Many alternate molecular targets present themselves for PET imaging of neuroinflammation in vivo, including enzymes, intracellular signaling molecules as well as ionotropic, G-protein coupled, and immunoglobulin receptors. We now review the lead structures in radiotracer development for PET studies of neuroinflammation targets for neurodegenerative diseases extending beyond TSPO, including glycogen synthase kinase 3, monoamine oxidase-B, reactive oxygen species, imidazoline-2 binding sites, cyclooxygenase, the phospholipase A2/arachidonic acid pathway, sphingosine-1-phosphate receptor-1, cannabinoid-2 receptor, the chemokine receptor CX3CR1, purinergic receptors: P2X7 and P2Y12, the receptor for advanced glycation end products, Mer tyrosine kinase, and triggering receptor expressed on myeloid cells-1. We provide a brief overview of the cellular expression and function of these targets, noting their selectivity for astrocytes and/or microglia, and highlight the classes of PET radiotracers that have been investigated in early-stage preclinical or clinical research studies of neuroinflammation.

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Section: Resultsmentioning

confidence: 99%

Emerging PET Radiotracers and Targets for Imaging of Neuroinflammation in Neurodegenerative Diseases: Outlook Beyond TSPO

et al. 2018

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“…Researchers in the UK have studied [ 11 C]Ro15-4513 in human subjects to explore increases in GABA release following tiagabine administration as well as changes in the GABA system related to alcohol dependence, cigarette smoking, and autism. 1,3 Given the prevalence of therapeutic GABA A PAMs, we anticipate that the development of subtype-specific GABA A PET radioligands will continue in tandem with relevant advances in molecular neurobiology and medicinal chemistry.…”

Section: ■ Pet Radioligands Of the Gaba A Receptormentioning

confidence: 99%

Classics in Neuroimaging: Development of Positron Emission Tomography Tracers for Imaging the GABAergic Pathway

Murrell

Pham

Sowa

et al. 2020

ACS Chem. Neurosci.

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Advances in drug discovery and diverse radiochemical methodologies have led to the discovery of novel positron emission tomography (PET) radiotracers used to image the GABAergic system, shaping our fundamental understanding of a variety of brain health illnesses, including epilepsy, stroke, cerebral palsy, schizophrenia, autism, Alzheimer’s disease, and addictions. In this Viewpoint, we review the state-of-the art of PET imaging with radiotracers that target the GABAA–benzodiazepine receptor complex, challenges and opportunities for imaging GABAB receptors and GABA transporters, and highlight an ongoing need to develop more sensitive radiotracers for imaging GABA release in the central nervous system.

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“…Among the subtypes, the α7nAChRs are composed of five identical α7 subunits, which appear to be involved in the occurrence and development of atherosclerosis and are becoming one of important targets for early identification of vulnerable atherosclerotic plaque (Sine, 2002;Wilund et al, 2009;Hashimoto et al, 2014;Johansson et al, 2014;Chen et al, 2016). Previously published reviews have described the development of radiotracers suitable for the in vivo imaging of α7nAChR (Toyohara et al, 2010;Brust et al, 2012;Bauwens et al, 2015;Kassenbrock et al, 2016). In the past decade, many researchers have been working on the development of a clinically available imaging agent for an ideal target to non-target ratio through safe and efficient drug delivery (Chen et al, 2017;Feng et al, 2017;Ding et al, 2019;Qiu et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

The Availability of the α7-Nicotinic Acetylcholine Receptor in Early Identification of Vulnerable Atherosclerotic Plaques: A Study Using a Novel 18F-Label Radioligand PET

Wang

Yao

Wang

et al. 2021

Front. Bioeng. Biotechnol.

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Background: It has been confirmed that the α7-nicotinic acetylcholine receptor (α7nAChR) is an important target for identifying vulnerable atherosclerotic plaques. Previously, we successfully designed and synthesized a series of 18F-labeled PET molecular probes targeting α7nAChR, which are mainly used in the diagnosis of Alzheimer's disease. Based on the characteristics of α7nAChR in blood vessels, we have firstly screened for a suitable novel 18F-labeled PET molecular probe ([18F]YLF-DW), with high selectivity for α7nAChR over α4β2nAChR and a good effect for the imaging of atherosclerotic animal models, to effectively identify vulnerable atherosclerotic plaques at an early stage. Meanwhile, we compared it with the “gold standard” pathological examination of atherosclerosis, to verify the reliability of [18F]YLF-DW in early diagnosis of atherosclerosis.Methods: The vulnerable atherosclerotic plaques model of ApoE-/-mice were successfully established. Then based on the methods of 3D-QSAR and molecular docking, we designed oxazolo[4,5-b] pyridines and fluorenone compounds, which are targeted at α7nAChR. Through further screening, a novel alpha7 nicotinic acetylcholine receptor radioligand ([18F]YLF-DW) was synthesized and automatically 18F-labeled using a Stynthra RNplus module. Subsequently, we employed [18F]YLF-DW for the targeting of α7nAChR in atherosclerotic plaques and control group, using a micro-PET/CT respectively. After imaging, the mice were sacrificed by air embolism and the carotid arteries taken out for making circular sections. The paraffin embedded specimens were sectioned with 5 μm thickness and stained with oil red. After staining, immunohistochemistry experiment was carried out to verify the effect of micro-PET/CT imaging.Results: The micro-PET/CT imaging successfully identified the vulnerable atherosclerotic plaques in the carotid arteries of ApoE-/-mice; whereas, no signal was observed in normal control mice. In addition, compared with the traditional imaging agent [18F]FDG, [18F]YLF-DW had a significant effect on the early plaques imaging of carotid atherosclerosis. The results of oil red staining and immunohistochemistry also showed early formations of carotid plaques in ApoE-/-mice and provided pathological bases for the evaluation of imaging effect.Conclusion: We innovated to apply the novel molecular probe ([18F]YLF-DW) to the identification of vulnerable atherosclerotic plaques in carotid arteries, to detect atherosclerosis early inflammatory response and provide powerful input for the early diagnosis of atherosclerotic lesions, which may play an early warning role in cardiovascular acute events.

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Selected PET Radioligands for Ion Channel Linked Neuroreceptor Imaging: Focus on GABA, NMDA and nACh Receptors

Cited by 22 publications

References 109 publications

Emerging PET Radiotracers and Targets for Imaging of Neuroinflammation in Neurodegenerative Diseases: Outlook Beyond TSPO

Emerging PET Radiotracers and Targets for Imaging of Neuroinflammation in Neurodegenerative Diseases: Outlook Beyond TSPO

Classics in Neuroimaging: Development of Positron Emission Tomography Tracers for Imaging the GABAergic Pathway

The Availability of the α7-Nicotinic Acetylcholine Receptor in Early Identification of Vulnerable Atherosclerotic Plaques: A Study Using a Novel 18F-Label Radioligand PET

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