المؤلفون: Hiroshi Ikenuma, Aya Ogata, Hiroko Koyama, Bin Ji, Hideki Ishii, Takashi Yamada, Junichiro Abe, Chie Seki, Yuji Nagai, Masanori Ichise, Takafumi Minamimoto, Makoto Higuchi, Ming-Rong Zhang, Takashi Kato, Kengo Ito, Masaaki Suzuki, Yasuyuki Kimura

المصدر: EJNMMI Radiopharmacy and Chemistry, Vol 8, Iss 1, Pp 1-16 (2023)

مصطلحات موضوعية: Receptor interacting protein kinase 1, Alzheimer’s disease, Positron emission tomography, Medical physics. Medical radiology. Nuclear medicine, R895-920, Therapeutics. Pharmacology, RM1-950

الوصف: Abstract Background Receptor interacting protein kinase 1 (RIPK1) is a serine/threonine kinase, which regulates programmed cell death and inflammation. Recently, the involvement of RIPK1 in the pathophysiology of Alzheimer’s disease (AD) has been reported; RIPK1 is involved in microglia’s phenotypic transition to their dysfunctional states, and it is highly expressed in the neurons and microglia in the postmortem brains in AD patients. They prompt neurodegeneration leading to accumulations of pathological proteins in AD. Therefore, regulation of RIPK1 could be a potential therapeutic target for the treatment of AD, and in vivo imaging of RIPK1 may become a useful modality in studies of drug discovery and pathophysiology of AD. The purpose of this study was to develop a suitable radioligand for positron emission tomography (PET) imaging of RIPK1. Results (S)-2,2-dimethyl-1-(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)propan-1-one (GSK’963) has a high affinity, selectivity for RIPK1, and favorable physiochemical properties based on its chemical structure. In this study, since 11C-labeling (half-life: 20.4 min) GSK’963 retaining its structure requiring the Grignard reaction of tert-butylmagnesium halides and [11C]carbon dioxide was anticipated to give a low yield, we decided instead to 11C-label a GSK’963 analog ((S)-2,2-dimethyl-1-(5-(m-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)propan-1-one, GG502), which has a high RIPK1 inhibitory activity equivalent to that of the original compound GSK’963. Thus, we successfully 11C-labeled GG502 using a Pd-mediated cross-coupling reaction in favorable yields (3.6 ± 1.9%) and radiochemical purities (> 96%), and molar activity (47–115 GBq/μmol). On autoradiography, radioactivity accumulation was observed for [11C]GG502 and decreased by non-radioactive GG502 in the mouse spleen and human brain, indicating the possibility of specific binding of this ligand to RIPK1. On brain PET imaging in a rhesus monkey, [11C]GG502 showed a good brain permeability (peak standardized uptake value (SUV) ~3.0), although there was no clear evidence of specific binding of [11C]GG502. On brain PET imaging in acute inflammation model rats, [11C]GG502 also showed a good brain permeability, and no significant increased uptake was observed in the lipopolysaccharide-treated side of striatum. On metabolite analysis in rats at 30 min after administration of [11C]GG502, ~55% and ~10% of radioactivity was from unmetabolized [11C]GG502 in the brain and the plasma, respectively. Conclusions We synthesized and evaluated a 11C-labeled PET ligand based on the methylated analog of GSK’963 for imaging of RIPK1 in the brain. Although in autoradiography of the resulting [11C]GG502 indicated the possibility of specific binding, the actual PET imaging failed to detect any evidence of specific binding to RIPK1 despite its good brain permeability. Further development of radioligands with a higher binding affinity for RIPK1 in vivo and more stable metabolite profiles compared with the current compound may be required.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2365-421XTest

الوصول الحر: https://doaj.org/article/cfeab7411ca541868cfb1ec34b86e244Test

المؤلفون: Kiwamu Matsuoka, Kosei Hirata, Naomi Kokubo, Takamasa Maeda, Kenji Tagai, Hironobu Endo, Keisuke Takahata, Hitoshi Shinotoh, Maiko Ono, Chie Seki, Harutsugu Tatebe, Kazunori Kawamura, Ming-Rong Zhang, Hitoshi Shimada, Takahiko Tokuda, Makoto Higuchi, Yuhei Takado

المصدر: NeuroImage: Clinical, Vol 41, Iss , Pp 103560- (2024)

مصطلحات موضوعية: Alzheimer’s disease, Glutamate, Magnetic resonance spectroscopy, Positron emission tomography, Neurofilament light chain plasma levels, Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429

الوصف: In Alzheimer’s disease (AD), aggregated abnormal proteins induce neuronal dysfunction. Despite the evidence supporting the association between tau proteins and brain atrophy, further studies are needed to explore their link to neuronal dysfunction in the human brain. To clarify the relationship between neuronal dysfunction and abnormal proteins in AD-affected brains, we conducted magnetic resonance spectroscopic imaging (MRSI) and assessed the neurofilament light chain plasma levels (NfL). We evaluated tau and amyloid-β depositions using standardized uptake value ratios (SUVRs) of florzolotau (18F) for tau and 11C-PiB for amyloid-β positron emission tomography in the same patients. Heatmaps were generated to visualize Z scores of glutamate to creatine (Glu/Cr) and N-acetylaspartate to creatine (NAA/Cr) ratios using data from healthy controls. In AD brains, Z score maps revealed reduced Glu/Cr and NAA/Cr ratios in the gray matter, particularly in the right dorsolateral prefrontal cortex (rDLPFC) and posterior cingulate cortex (PCC). Glu/Cr ratios were negatively correlated with florzolotau (18F) SUVRs in the PCC, and plasma NfL levels were elevated and negatively correlated with Glu/Cr (P = 0.040, r = −0.50) and NAA/Cr ratios (P = 0.003, r = −0.68) in the rDLPFC. This suggests that the abnormal tau proteins in AD-affected brains play a role in diminishing glutamate levels. Furthermore, neuronal dysfunction markers including Glu/tCr and NAA/tCr could potentially indicate favorable clinical outcomes. Using MRSI provided spatial information about neural dysfunction in AD, enabling the identification of vulnerabilities in the rDLPFC and PCC within the AD’s pathological context.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2213158223002516Test; https://doaj.org/toc/2213-1582Test

الوصول الحر: https://doaj.org/article/e8deeb2471ab4de6915f76e8acd8bb04Test

المؤلفون: Masaki Oya, Kiwamu Matsuoka, Manabu Kubota, Junya Fujino, Shisei Tei, Keisuke Takahata, Kenji Tagai, Yasuharu Yamamoto, Hitoshi Shimada, Chie Seki, Takashi Itahashi, Yuta Y. Aoki, Haruhisa Ohta, Ryu-ichiro Hashimoto, Genichi Sugihara, Takayuki Obata, Ming-Rong Zhang, Tetsuya Suhara, Motoaki Nakamura, Nobumasa Kato, Yuhei Takado, Hidehiko Takahashi, Makoto Higuchi

المصدر: Scientific Reports, Vol 13, Iss 1, Pp 1-10 (2023)

مصطلحات موضوعية: Medicine, Science

الوصف: Abstract Increased excitatory neuronal tones have been implicated in autism, but its mechanism remains elusive. The amplified glutamate signals may arise from enhanced glutamatergic circuits, which can be affected by astrocyte activation and suppressive signaling of dopamine neurotransmission. We tested this hypothesis using magnetic resonance spectroscopy and positron emission tomography scan with 11C-SCH23390 for dopamine D1 receptors in the anterior cingulate cortex (ACC). We enrolled 18 male adults with high-functioning autism and 20 typically developed (TD) male subjects. The autism group showed elevated glutamate, glutamine, and myo-inositol (mI) levels compared with the TD group (p = 0.045, p = 0.044, p = 0.030, respectively) and a positive correlation between glutamine and mI levels in the ACC (r = 0.54, p = 0.020). In autism and TD groups, ACC D1 receptor radioligand binding was negatively correlated with ACC glutamine levels (r = − 0.55, p = 0.022; r = − 0.58, p = 0.008, respectively). The enhanced glutamate-glutamine metabolism might be due to astroglial activation and the consequent reinforcement of glutamine synthesis in autistic brains. Glutamine synthesis could underly the physiological inhibitory control of dopaminergic D1 receptor signals. Our findings suggest a high neuron excitation-inhibition ratio with astrocytic activation in the etiology of autism.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-2322Test

الوصول الحر: https://doaj.org/article/135d6c00a6674ea9842a1e359c92982cTest

المؤلفون: Kenji Tagai, Yoko Ikoma, Hironobu Endo, Oiendrila Bhowmik Debnath, Chie Seki, Kiwamu Matsuoka, Hideki Matsumoto, Masaki Oya, Kosei Hirata, Hitoshi Shinotoh, Keisuke Takahata, Shin Kurose, Yasunori Sano, Maiko Ono, Hitoshi Shimada, Kazunori Kawamura, Ming-Rong Zhang, Yuhei Takado, Makoto Higuchi

المصدر: NeuroImage, Vol 264, Iss , Pp 119763- (2022)

مصطلحات موضوعية: Tau PET, Reference tissues, Alzheimer's disease, Progressive supranuclear palsy, Frontotemporal lobar degeneration, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: Positron emission tomography (PET) with 18F-PM-PBB3 (18F-APN-1607, 18F-Florzolotau) enables high-contrast detection of tau depositions in various neurodegenerative dementias, including Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). A simplified method for quantifying radioligand binding in target regions is to employ the cerebellum as a reference (CB-ref) on the assumption that the cerebellum has minimal tau pathologies. This procedure is typically valid in AD, while FTLD disorders exemplified by progressive supranuclear palsy (PSP) are characterized by occasional tau accumulations in the cerebellum, hampering the application of CB-ref. The present study aimed to establish an optimal method for defining reference tissues on 18F-PM-PBB3-PET images of AD and non-AD tauopathy brains. We developed a new algorithm to extract reference voxels with a low likelihood of containing tau deposits from gray matter (GM-ref) or white matter (WM-ref) by a bimodal fit to an individual, voxel-wise histogram of the radioligand retentions and applied it to 18F-PM-PBB3-PET data obtained from age-matched 40 healthy controls (HCs) and 23 CE, 40 PSP, and five other tau-positive FTLD patients. PET images acquired at 90–110 min after injection were averaged and co-registered to corresponding magnetic resonance imaging space. Subsequently, we generated standardized uptake value ratio (SUVR) images estimated by CB-ref, GM-ref and WM-ref, respectively, and then compared the diagnostic performances. GM-ref and WM-ref covered a broad area in HCs and were free of voxels located in regions known to bear high tau burdens in AD and PSP patients. However, radioligand retentions in WM-ref exhibited age-related declines. GM-ref was unaffected by aging and provided SUVR images with higher contrast than CB-ref in FTLD patients with suspected and confirmed corticobasal degeneration. The methodology for determining reference tissues as optimized here improves the accuracy of 18F-PM-PBB3-PET measurements of tau burdens in a wide range of neurodegenerative illnesses.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S1053811922008849Test; https://doaj.org/toc/1095-9572Test

الوصول الحر: https://doaj.org/article/35a5b66d8dcc4f59a4b9f23e33fa7ea0Test

المؤلفون: Arata Oh-Nishi, Yuji Nagai, Chie Seki, Tetsuya Suhara, Takafumi Minamimoto, Makoto Higuchi

المصدر: Brain, Behavior, & Immunity - Health, Vol 22, Iss , Pp 100446- (2022)

مصطلحات موضوعية: Maternal immune activation, Schizophrenia, Dopamine D2 receptors, Dopamine, Anterior cingulate cortex, Poly I:C, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: Maternal immune activation (MIA) is a risk factor for schizophrenia in the offspring. MIA in pregnant rodents can be induced by injection of synthetic polyriboinosinic-polyribocytidilic acid (Poly I:C), which causes decreased striatal dopamine D2 receptor (D2R) expression and behavioral dysfunction mediated by the dopaminergic system in the offspring. However, previous studies did not determine whether Poly I:C induced cortical dopamine D2R abnormality in an MIA rat model. In this study, we performed micro-positron emission tomography (micro-PET) in vivo imaging and ex vivo neurochemical analyses of cortical D2Rs in MIA. In the micro-PET analyses, the anterior cingulate cortex (ACC) region in the offspring showed significantly reduced binding potential for [11C]FLB457, a high affinity radio-ligand toward D2Rs. Neurochemical analysis showed reduction of D2Rs and augmentation of dopamine turnover in the ACC of the rat offspring. Thus, MIA induces dopaminergic dysfunction in the ACC of offspring, similar to the neuronal pathology reported in patients with schizophrenia.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2666354622000369Test; https://doaj.org/toc/2666-3546Test

الوصول الحر: https://doaj.org/article/296e3bf993cc4e2fa09a2c9bd1817497Test

المؤلفون: Takehito Ito, Yasuyuki Kimura, Chie Seki, Masanori Ichise, Keita Yokokawa, Kazunori Kawamura, Hidehiko Takahashi, Makoto Higuchi, Ming-Rong Zhang, Tetsuya Suhara, Makiko Yamada

المصدر: EJNMMI Research, Vol 8, Iss 1, Pp 1-4 (2018)

مصطلحات موضوعية: Histamine H3 receptor, Working memory, PET, fMRI, Medical physics. Medical radiology. Nuclear medicine, R895-920

الوصف: Abstract Background The histamine H3 receptor is regarded as a drug target for cognitive impairments in psychiatric disorders. H3 receptors are expressed in neocortical areas, including the prefrontal cortex, the key region of cognitive functions such as working memory. However, the role of prefrontal H3 receptors in working memory has not yet been clarified. Therefore, using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) techniques, we aimed to investigate the association between the neural activity of working memory and the density of H3 receptors in the prefrontal cortex. Findings Ten healthy volunteers underwent both fMRI and PET scans. The N-back task was used to assess the neural activities related to working memory. H3 receptor density was measured with the selective PET radioligand [11C] TASP457. The neural activity of the right dorsolateral prefrontal cortex during the performance of the N-back task was negatively correlated with the density of H3 receptors in this region. Conclusions Higher neural activity of working memory was associated with lower H3 receptor density in the right dorsolateral prefrontal cortex. This finding elucidates the role of H3 receptors in working memory and indicates the potential of H3 receptors as a therapeutic target for the cognitive impairments associated with neuropsychiatric disorders.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s13550-018-0406-4Test; https://doaj.org/toc/2191-219XTest

الوصول الحر: https://doaj.org/article/c2cb963f0ae84c61975edfcfff3c4460Test

المؤلفون: Keisuke Takahata, Yasuyuki Kimura, Chie Seki, Masaki Tokunaga, Masanori Ichise, Kazunori Kawamura, Maiko Ono, Soichiro Kitamura, Manabu Kubota, Sho Moriguchi, Tatsuya Ishii, Yuhei Takado, Fumitoshi Niwa, Hironobu Endo, Tomohisa Nagashima, Yoko Ikoma, Ming-Rong Zhang, Tetsuya Suhara, Makoto Higuchi

المصدر: EJNMMI Research, Vol 7, Iss 1, Pp 1-10 (2017)

مصطلحات موضوعية: PET, Perampanel, AMPA, [11C]HMS011, Interspecies differences, Medical physics. Medical radiology. Nuclear medicine, R895-920

الوصف: Abstract Background α-Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor is a primary mediator of fast glutamatergic excitatory signaling in the brain and has been implicated in diverse neuropsychiatric diseases. We recently developed a novel positron emission tomography (PET) ligand, 2-(1-(3-([11C]methylamino)phenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl) benzonitrile ([11C]HMS011). This compound is a radiolabelled derivative of perampanel, an antiepileptic drug acting on AMPA receptors, and was demonstrated to have promising in vivo properties in the rat and monkey brains. In the current study, we performed a human PET study using [11C]HMS011 to evaluate its safety and kinetics. Four healthy male subjects underwent a 120-min PET scan after injection of [11C]HMS011. Arterial blood sampling and metabolite analysis were performed to obtain parent input functions for three of the subjects using high-performance liquid chromatography. Regional distribution volumes (V Ts) were calculated based on kinetic models with and without considering radiometabolite in the brain. The binding was also quantified using a reference tissue model with white matter as reference. Results Brain uptake of [11C]HMS011 was observed quickly after the injection, followed by a rapid clearance. Three hydrophilic and one lipophilic radiometabolites appeared in the plasma, with notable individual variability. The kinetics in the brain with apparent radioactivity retention suggested that the lipophilic radiometabolite could enter the brain. A dual-input graphical model, an analytical model designed in consideration of a radiometabolite entering the brain, well described the kinetics of [11C]HMS011. A reference tissue model showed small radioligand binding potential (BP*ND) values in the cortical regions (BP*ND = 0–0.15). These data suggested specific binding component of [11C]HMS011 in the brain. Conclusions Kinetic analyses support some specific binding of [11C]HMS011 in the human cortex. However, this ligand may not be suitable for practical AMPA receptor PET imaging due to the small dynamic range and metabolite in the brain.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s13550-017-0313-0Test; https://doaj.org/toc/2191-219XTest

الوصول الحر: https://doaj.org/article/ccda0efb0af84ee5ab13c5318aab6d87Test

المؤلفون: Chie Seki, Eiji Yoshida, Hideaki Tashima, Hidekatsu Wakizaka, Makoto Higuchi, Taichi Yamashita, Taiga Yamaya, Takamasa Maeda, Tetsuya Suhara, Yuhei Takado, Yuma Iwao, 前田 貴雅, 吉田 英治, 山下 大地, 山谷 泰賀, 岩男 悠真, 樋口 真人, 田島 英朗, 脇坂 秀克, 関 千江, 須原 哲也, 高堂 裕平

المصدر: JSAP Annual Meetings Extended Abstracts. 2017, :475

المؤلفون: Chie Seki, Hiroshi Ito, Hiroyuki Takuwa, Ichio Aoki, Jeff Kershaw, Makoto Higuchi, Manami Takahashi, Takayuki Obata, Takuya Urushihata, Yasuhiko Tachibana, Yuhei Takado

المصدر: Magnetic Resonance in Medical Sciences. 2018, 17(4):318

المؤلفون: Chie SEKI, Hideaki FUJITA, Iwao KANNO, Kenichi KASHIKURA, Tetsuya MATSUURA, 松浦 哲也, 柏倉 健一, 菅野 巖, 藤田 英明, 関 千江

المصدر: 比較生理生化学 / Hikaku seiri seikagaku(Comparative Physiology and Biochemistry). 1997, 14(2):110