18F-THK5351 PET Can Identify Astrogliosis in Multiple Sclerosis Plaques

Ishibashi, Kenji; Miura, Yoshiharu; Hirata, Kosei; Toyohara, Jun

doi:10.1097/rlu.0000000000002751

Cited by 27 publications

(26 citation statements)

References 8 publications

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“…Therefore, regional changes in MAO-B concentration can be an index of astrocyte reactivity, known as “astrogliosis”. These findings suggest that 18 F-THK5351 accumulates in lesions where astrogliosis occurs, and that 18 F-THK5351 PET can be a powerful biomarker for visualizing and quantifying astrogliosis, as recently demonstrated in patients with neurological disorders [ 10 – 13 ]. More importantly, longitudinal assessment of the degree of astrogliosis in the living human brain can provide new insights into the pathophysiology of neurological disorders.…”

Section: Introductionsupporting

confidence: 64%

Relationship between the temporal course of astrogliosis and symptom improvement in cerebral infarction: report of a case monitored using 18F-THK5351 positron emission tomography

et al. 2020

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Background 18 F-THK5351 was recently shown to bind to monoamine oxidase B (MAO-B) with high affinity. MAO-B is highly concentrated in astrocytes and increases during astrogliosis. Therefore, 18 F-THK5351 accumulates in lesions undergoing astrogliosis. Cerebral infarction causes astrogliosis, which may be beneficial for repairing and regenerating injured cells and tissues in the lesions. Therefore, monitoring the degree of astrogliosis and stroke symptoms is essential for understanding the roles of astrogliosis in cerebral infarction. Case presentation A 72-year-old man, complaining of total loss of sensation in the left index finger, was diagnosed with acute cerebral infarction, and underwent 18 F-THK5351 positron emission tomography (PET) on two occasions after the stroke. The first PET scan performed on day 27 revealed intense uptake in the infarct lesion located around the right precentral and postcentral gyri. However, the second PET scan on day 391 showed that the uptake had diminished significantly. The sensory deficit in the left index finger had improved by 30 and 70% at the times of the first and second PET scans, respectively. Conclusions 18 F-THK5351 uptake in the infarct lesion evidently changed between days 27 and 391, along with improved sensory deficit in the left index finger. Astrocytes reportedly play a role in restoring neuronal integrity. Therefore, the temporal course of astrogliosis may have been related to improving stroke symptoms in this patient, suggesting that the degree of astrogliosis in the infarct lesion may aid in assessing the prognosis in stroke patients.

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Section: Introductionsupporting

confidence: 64%

Relationship between the temporal course of astrogliosis and symptom improvement in cerebral infarction: report of a case monitored using 18F-THK5351 positron emission tomography

et al. 2020

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“…Clinical 18 F-THK-5351 PET studies demonstrated high tracer retention in sites susceptible to astrogliosis in various neurodegenerative conditions (17)(18)(19)(20)(21)(22)(23)(24)(25)(26). The non-selective binding of THK-5351 to MAO-B and tau limits its clinical utility as a biomarker.…”

Section: Introductionmentioning

confidence: 99%

¹⁸F-SMBT-1: A Selective and Reversible PET Tracer for Monoamine Oxidase-B Imaging

et al. 2020

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Reactive astrocytes play a key role in the pathogenesis of various neurodegenerative diseases. Monoamine oxidase-B (MAO-B) is one of the promising targets for the imaging of astrogliosis in the human brain. A novel selective and reversible MAO-B tracer, (S)-(2-methylpyrid-5-yl)-6-[(3-[ 18 F]fluoro-2hydroxy)propoxy]quinoline, ( 18 F-SMBT-1), was successfully developed via lead optimization from firstgeneration tau positron-emission tomography (PET) tracer 18 F-THK-5351. Methods: SMBT-1 was radiolabeled with fluorine-18 using the corresponding precursor. The binding affinity of radiolabeled compounds to MAO-B was assessed using saturation and competitive binding assays. The binding selectivity of 18 F-SMBT-1 to MAO-B was evaluated by autoradiography of frozen human brain tissues. The pharmacokinetics (PK) and metabolism were assessed in normal mice after intravenous administration of 18 F-SMBT-1. A 14-day toxicity study following the intravenous administration of SMBT-1 was performed using rats and mice. Results: In vitro binding assays demonstrated a high binding affinity of SMBT-1 to MAO-B (K D = 3.7 nM). In contrast, it showed low binding affinity to MAO-A and protein aggregates such as amyloid-β and tau fibrils. Autoradiographic analysis showed higher amounts of 18 F-SMBT-1 binding in the Alzheimer's disease (AD) brain sections than in the control brain sections. 18 F-SMBT-1 binding was completely displaced with reversible MAO-B inhibitor lazabemide, demonstrating the high selectivity of 18 F-SMBT-1 for MAO-B. Furthermore, 18 F-SMBT-1 showed a high uptake by brain, rapid washout, and no 4 radiolabeled metabolites in the brain of normal mice. SMBT-1 showed no significant binding to various receptors, ion channels, and transporters, and no toxic effects related to its administration were observed in mice and rats. Conclusion: 18 F-SMBT-1 is a promising and selective MAO-B PET tracer candidate, which would be useful for quantitative monitoring of astrogliosis in the human brain.

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“…In a longitudinal study on patients affected by corticobasal syndrome, [18F]THK5351 binding have been demonstrated to detect dynamical astrogliosis in specific cortical regions (Ezura et al, 2019). In a case of multiple sclerosis, instead, the authors demonstrated the coregistration of [18F]THK5351 uptake with demyelinating plaques (Ishibashi et al, 2019). Another study compared the spatial uptake patterns of [18F]THK5351 and fMRI network alterations in patients with early AD and healthy controls, showing a similar pattern for the precuneus, a region crucial for Alzheimer progression (Yokoi et al, 2018).…”

Section: Pet and Mr Imaging Of Astrocytic Activationmentioning

confidence: 99%

“…Compared to microglial visualization, PET radiotracers specific for astrocytic function have been only recently applied for clinical purpose, mainly binding the mono-amine oxidase type B (MAOB) enzyme, highly expressed by activated astrocytes (Table 1) (Figure 2) (Ishibashi et al, 2019). PET studies using the MAOB radiotracers 11C-DED or [18F]THK5351 in patients affected by Alzheimer's disease have demonstrated an high correlation between brain tau deposition and astrocytic uptake and between cortical glucose hypometabolism, detected by 18F-fluorodeoxyglucose [18F]-FDG PET, and longitudinal decline in astrocytic function detected by 11C-DED (Carter et al, 2019).…”

Section: Pet and Mr Imaging Of Astrocytic Activationmentioning

confidence: 99%

“…During neuroinflammation, astrocytic increased MAO-B (amine oxidases) activity which leads to an oxidative stress due to the formation of hydrogen peroxides (Gulyás et al, 2011). Among PET ligands MAO-B studied and synthesized over the years, two radiotracers were successfully used in patients, one of which containing carbon-11([ 11 C]-L-deprenyl-D2) (Arakawa et al, 2017), the other containing fluorine-18 ([ 18 F]-THK5351) (Ishibashi et al, 2019). The last one was used in a patient with relapsing-remitting multiple sclerosis (MS), it was seen that [ 18 F]-THK5351 accumulation corresponded to sites identified in MRI where there were MS plaques, in lesions undergoing astrogliosis.…”

Section: Monoamine Oxidase-b Pet Tracersmentioning

confidence: 99%

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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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18F-THK5351 PET Can Identify Astrogliosis in Multiple Sclerosis Plaques

Cited by 27 publications

References 8 publications

Relationship between the temporal course of astrogliosis and symptom improvement in cerebral infarction: report of a case monitored using 18F-THK5351 positron emission tomography

Relationship between the temporal course of astrogliosis and symptom improvement in cerebral infarction: report of a case monitored using 18F-THK5351 positron emission tomography

¹⁸F-SMBT-1: A Selective and Reversible PET Tracer for Monoamine Oxidase-B Imaging

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

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18F-THK5351 PET Can Identify Astrogliosis in Multiple Sclerosis Plaques

Cited by 27 publications

References 8 publications

Relationship between the temporal course of astrogliosis and symptom improvement in cerebral infarction: report of a case monitored using 18F-THK5351 positron emission tomography

Relationship between the temporal course of astrogliosis and symptom improvement in cerebral infarction: report of a case monitored using 18F-THK5351 positron emission tomography

18F-SMBT-1: A Selective and Reversible PET Tracer for Monoamine Oxidase-B Imaging

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

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Product

Resources

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¹⁸F-SMBT-1: A Selective and Reversible PET Tracer for Monoamine Oxidase-B Imaging