New and Old TSPO PET Radioligands for Imaging Brain Microglial Activation in Neurodegenerative Disease

Best, Laura A.; Ghadery, Christine; Pavese, Nicola; Tai, Yen F.; Strafella, Antonio P.

doi:10.1007/s11910-019-0934-y

Cited by 66 publications

(53 citation statements)

References 84 publications

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“…Considering in vivo studies, TSPO expression mainly assayed by PET tracers' uptake showed differences in the expression patterns in animal versus human microglia [48]. In addition, numerous studies have reported enhanced TSPO PET signals in various brain regions in subjects with different neurodegenerative diseases, such as PD, AD, and HD; as well as neurodevelopmental disorders, such as schizophrenia and autism; psychiatric disorders, such as major depressive disorder; and brain injuries (for example, reviewed in [49][50][51]).…”

Section: Microglia and Tspomentioning

confidence: 99%

Diagnostic and Therapeutic Potential of TSPO Studies Regarding Neurodegenerative Diseases, Psychiatric Disorders, Alcohol Use Disorders, Traumatic Brain Injury, and Stroke: An Update

Dimitrova-Shumkovska

Krstanoski

Veenman

2020

Cells

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Neuroinflammation and cell death are among the common symptoms of many central nervous system diseases and injuries. Neuroinflammation and programmed cell death of the various cell types in the brain appear to be part of these disorders, and characteristic for each cell type, including neurons and glia cells. Concerning the effects of 18-kDa translocator protein (TSPO) on glial activation, as well as being associated with neuronal cell death, as a response mechanism to oxidative stress, the changes of its expression assayed with the aid of TSPO-specific positron emission tomography (PET) tracers’ uptake could also offer evidence for following the pathogenesis of these disorders. This could potentially increase the number of diagnostic tests to accurately establish the stadium and development of the disease in question. Nonetheless, the differences in results regarding TSPO PET signals of first and second generations of tracers measured in patients with neurological disorders versus healthy controls indicate that we still have to understand more regarding TSPO characteristics. Expanding on investigations regarding the neuroprotective and healing effects of TSPO ligands could also contribute to a better understanding of the therapeutic potential of TSPO activity for brain damage due to brain injury and disease. Studies so far have directed attention to the effects on neurons and glia, and processes, such as death, inflammation, and regeneration. It is definitely worthwhile to drive such studies forward. From recent research it also appears that TSPO ligands, such as PK11195, Etifoxine, Emapunil, and 2-Cl-MGV-1, demonstrate the potential of targeting TSPO for treatments of brain diseases and disorders.

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Section: Microglia and Tspomentioning

confidence: 99%

Diagnostic and Therapeutic Potential of TSPO Studies Regarding Neurodegenerative Diseases, Psychiatric Disorders, Alcohol Use Disorders, Traumatic Brain Injury, and Stroke: An Update

Dimitrova-Shumkovska

Krstanoski

Veenman

2020

Cells

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“…Using PK11195, the first positron emission tomography (PET) studies in which microglia were labeled in humans came to light, showing that 'activated' microglia were present in areas of demyelination of two multiple sclerosis patients [30]. Nonetheless, TSPO also labels astrocytes and, thus, novel and more specific markers needed to be developed [31]. In 1998, a novel calcium-binding protein, the ionized calcium-binding adaptor molecule 1 (Iba1), was cloned.…”

Section: Microglial Research Moves Away From Culturementioning

confidence: 99%

“…However, dead microglia are unlikely to vanish from the parenchyma without collateral effects and the field will benefit from the development of novel drugs and nanomaterials that allow targeting specific microglial populations or specific microglial functions. Similarly, the unspecificity and low signal-to-noise ratio of TSPO for PET imaging [31] underscores the need for developing imaging tools for in vivo identification of microglia and neuroinflammation, particularly in the human brain.…”

Section: Box 4 Novel Tools and Approachesmentioning

confidence: 99%

Cien Años de Microglía: Milestones in a Century of Microglial Research

Sierra

Paolicelli

Kettenmann

2019

Trends in Neurosciences

149

127

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The year 2019 marks the 100-year anniversary of the discovery of microglia by Pío del Río-Hortega. We will recount the state of neuroscience research at the beginning of the 20th century and the heated scientific dispute regarding microglial identity. We will then walk through some of the milestones of microglial research in the decades since then. In the last 20 years, the field has grown exponentially. Researchers have shown that microglia are unlike any other resident macrophages: they have a unique origin and distinguishing features. Microglia are extraordinarily motile cells and constantly survey their environment, interacting with neurons, astrocytes, oligodendrocytes, neural stem cells, and infiltrating immune cells. We finally highlight some open questions for future research regarding microglia's identity, population dynamics, and dual (beneficial and detrimental) role in pathology.

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“…The first-generation radioligand [ 11 C](R)-PK11195 has been the most widely studied in clinical studies and different neurodegenerative diseases, including multiple sclerosis (Airas et al, 2018), Creutzfeldt-Jakob disease (Iaccarino et al, 2018), and also in psychiatric disorders such as schizophrenia (Di Biase et al, 2017). Although the findings of an increased uptake of this tracer in these pathologies, limitations including low signalto-noise ratio and high non-specific binding has addressed for the synthesis of second-and third-generation TSPO-specific radiopharmaceuticals, linked to [ 11 C] or [ 18 F] and including (Luo et al, 2018;Singhal et al, 2018;Best et al, 2019). Similarly, different studies have reported selective microglial uptake of these tracers in multiple sclerosis animal models and patients (Hagens et al, 2018;Herranz et al, 2019;Nack et al, 2019), amyotrophic lateral sclerosis (Zürcher et al, 2015;Datta et al, 2017), Alzheimer's disease (Alam et al, 2017;Keller et al, 2018;Focke et al, 2019), and Lyme disease on humans (Coughlin et al, 2018), and stroke experimental models (Miyajima et al, 2018), with more discordant results for psychiatric patients, suffering from schizophrenia (Di Biase et al, 2017;Hafizi et al, 2017;Ottoy et al, 2018;Selvaraj et al, 2018) and major depression (Li et al, 2018), probably due to the different stage of disease.…”

Section: Pet and Mr Imaging Of Microglial Activationmentioning

confidence: 99%

Gliosis and Neurodegenerative Diseases: The Role of PET and MR Imaging

Cavaliere

Tramontano

Fiorenza

et al. 2020

Front. Cell. Neurosci.

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Glial activation characterizes most neurodegenerative and psychiatric diseases, often anticipating clinical manifestations and macroscopical brain alterations. Although imaging techniques have improved diagnostic accuracy in many neurological conditions, often supporting diagnosis, prognosis prediction and treatment outcome, very few molecular imaging probes, specifically focused on microglial and astrocytic activation, have been translated to a clinical setting. In this context, hybrid positron emission tomography (PET)/magnetic resonance (MR) scanners represent the most advanced tool for molecular imaging, combining the functional specificity of PET radiotracers (e.g., targeting metabolism, hypoxia, and inflammation) to both high-resolution and multiparametric information derived by MR in a single imaging acquisition session. This simultaneity of findings achievable by PET/MR, if useful for reciprocal technical adjustments regarding temporal and spatial cross-modal alignment/synchronization, opens still debated issues about its clinical value in neurological patients, possibly incompliant and highly variable from a clinical point of view. While several preclinical and clinical studies have investigated the sensitivity of PET tracers to track microglial (mainly TSPO ligands) and astrocytic (mainly MAOB ligands) activation, less studies have focused on MR specificity to this topic (e.g., through the assessment of diffusion properties and T2 relaxometry), and only few exploiting the integration of simultaneous hybrid acquisition. This review aims at summarizing and critically review the current state about PET and MR imaging for glial targets, as well as the potential added value of hybrid scanners for characterizing microglial and astrocytic activation.

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New and Old TSPO PET Radioligands for Imaging Brain Microglial Activation in Neurodegenerative Disease

Cited by 66 publications

References 84 publications

Diagnostic and Therapeutic Potential of TSPO Studies Regarding Neurodegenerative Diseases, Psychiatric Disorders, Alcohol Use Disorders, Traumatic Brain Injury, and Stroke: An Update

Diagnostic and Therapeutic Potential of TSPO Studies Regarding Neurodegenerative Diseases, Psychiatric Disorders, Alcohol Use Disorders, Traumatic Brain Injury, and Stroke: An Update

Cien Años de Microglía: Milestones in a Century of Microglial Research

Gliosis and Neurodegenerative Diseases: The Role of PET and MR Imaging

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