Visualization of AMPA receptors in living human brain with positron emission tomography

Miyazaki, Tomoyuki; Nakajima, Waki; Hatano, Mai; Shibata, Yusuke; Kuroki, Y.; Arisawa, Tetsu; Serizawa, Asami; Sano, Akane; Kogami, Sayaka; Yamanoue, Tomomi; Kimura, Kazumasa; Hirata, Yushi; Takada, Yuuki; Ishiwata, Yusuke; Sonoda, Masaki; Takao, Masaki; Seki, Chie; Nagai, Yuji; Minamimoto, Takafumi; Kawamura, Kazunori; Zhang, Ming Rong; Ikegaya, Naoki; Iwasaki, Masaki; Kunii, Naoto; Kimura, Yuichi; Yamashita, Fumio; Taguri, Masataka; Tani, Hideaki; Nagai, Nobuhiro; Koizumi, Teruki; Nakajima, Shinichiro; Mimura, Masaru; Yuzaki, Michisuke; Kato, Hirohisa; Higuchi, Makoto; Uchida, Hiroyuki; Takahashi, Takuya

doi:10.1038/s41591-019-0723-9

Cited by 57 publications

(51 citation statements)

References 36 publications

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“…analysis of [ 11 C]K-2 using healthy subjects revealed that the standardized uptake value ratio (SUVR) using white matter as reference, obtained from a 20-min scan, can be a surrogate marker for the binding potential (BP ND : a quantitative index of receptor density in PET imaging), indicating clinical usefulness of [ 11 C]K-2 15 . Furthermore, we observed increased [ 11 C]K-2 uptake in the clinically identified epileptogenic foci of patients with epilepsy 14 . Thus, [ 11 C]K-2 can be a promising radiotracer to investigate the molecular pathology of neuropsychiatric disorders such as epilepsy, Alzheimer's disease, depression, and schizophrenia [16][17][18] .…”

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confidence: 62%

Biodistribution and radiation dosimetry of the positron emission tomography probe for AMPA receptor, [11C]K-2, in healthy human subjects

Hatano

Miyazaki

Ishiwata

et al. 2021

Sci Rep

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Abstract[11C]K-2, a radiotracer exhibiting high affinity and selectivity for α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), is suitable for the quantification of AMPARs in living human brains and potentially useful in the identification of epileptogenic foci in patients. This study aimed to estimate the radiation doses of [11C]K-2 in various organs and calculate the effective dose after injection of [11C]K-2 in healthy human subjects. Twelve healthy male subjects were registered and divided into two groups (370 or 555 MBq of [11C]K-2), followed by 2 h whole-body scans. We estimated the radiation dose of each organ and then calculated the effective dose for each subject. The highest uptake of [11C]K-2 was observed in the liver, while the brain also showed relatively high uptake. The urinary bladder exhibited the highest radiation dose. The kidneys and liver also showed high radiation doses after [11C]K-2 injections. The effective dose of [11C]K-2 ranged from 5.0 to 5.2 μSv/MBq. Our findings suggest that [11C]K-2 is safe in terms of the radiation dose and adverse effects. The injection of 370–555 MBq (10 to 15 mCi) for PET studies using this radiotracer is applicable in healthy human subjects and enables serial PET scans in a single subject.

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confidence: 62%

Biodistribution and radiation dosimetry of the positron emission tomography probe for AMPA receptor, [11C]K-2, in healthy human subjects

Hatano

Miyazaki

Ishiwata

et al. 2021

Sci Rep

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“…An elevation of hippocampal AMPAR levels has been reported in both temporal lobe epilepsy (TLE) patients and several animal epilepsy models (Mathern et al, 1998 ; Lopes et al, 2013 ). This is supported by a positron emission tomography (PET) tracer study of AMPARs ([11C]K-2), showing that [11C]K-2 uptake is increased in the epileptogenic focus of patients with mesial TLE (Miyazaki et al, 2020 ). Therapeutic strategies inhibiting AMPA-mediated currents, e.g., AMPAR antagonists, have been developed to treat epilepsy.…”

Section: Introductionmentioning

confidence: 88%

Bidirectional Dysregulation of AMPA Receptor-Mediated Synaptic Transmission and Plasticity in Brain Disorders

Zhang

Bramham

2020

Front. Synaptic Neurosci.

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AMPA receptors (AMPARs) are glutamate-gated ion channels that mediate the majority of fast excitatory synaptic transmission throughout the brain. Changes in the properties and postsynaptic abundance of AMPARs are pivotal mechanisms in synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission. A wide range of neurodegenerative, neurodevelopmental and neuropsychiatric disorders, despite their extremely diverse etiology, pathogenesis and symptoms, exhibit brain region-specific and AMPAR subunit-specific aberrations in synaptic transmission or plasticity. These include abnormally enhanced or reduced AMPAR-mediated synaptic transmission or plasticity. Bidirectional reversal of these changes by targeting AMPAR subunits or trafficking ameliorates drug-seeking behavior, chronic pain, epileptic seizures, or cognitive deficits. This indicates that bidirectional dysregulation of AMPAR-mediated synaptic transmission or plasticity may contribute to the expression of many brain disorders and therefore serve as a therapeutic target. Here, we provide a synopsis of bidirectional AMPAR dysregulation in animal models of brain disorders and review the preclinical evidence on the therapeutic targeting of AMPARs.

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“…Blocking studies with talampanel (55), an orally active AMPA antagonist, resulted in globally increased cerebral uptake, a finding that often indicates confounding effects of ligand displacement from peripheral binding sites. Very recently, Miyazaki et al [ 105 ] developed a novel radioligand: 2-(2,6-difluoro-4-(2-( N -[ 11 C]methylsulfonamido)ethylthio)-phenoxy)acetamide ([ 11 C]K-2) for the PET imaging of AMPA receptors in the living human brain. The new radiotracer was prepared from a secondary amine type precursor (PEPA, K-1) with [ 11 C]iodomethane in DMF (0.5 M NaOH, 80 °C, 5 min) in a simple radiosynthesis in high yield.…”

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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Visualization of AMPA receptors in living human brain with positron emission tomography

Cited by 57 publications

References 36 publications

Biodistribution and radiation dosimetry of the positron emission tomography probe for AMPA receptor, [11C]K-2, in healthy human subjects

Biodistribution and radiation dosimetry of the positron emission tomography probe for AMPA receptor, [11C]K-2, in healthy human subjects

Bidirectional Dysregulation of AMPA Receptor-Mediated Synaptic Transmission and Plasticity in Brain Disorders

A Review of Molecular Imaging of Glutamate Receptors

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