Language：English   Publishing type：Research paper (scientific journal)  

Although the alteration of glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) distribution is believed to underlie physiologic and pathologic neuronal function, there has been no modality to evaluate AMPARs in a living human. [11C]K-2, the PET tracer we previously developed, is the first and only technology, to the best of our knowledge, to visualize AMPAR densities in the living human brain. Despite its favorable kinetics as a PET tracer, the short half-life of 11C limits the potential of [11C]K-2. We recently developed an 18F-labeled PET tracer, [18F]K-40, which demonstrated AMPAR-specific binding properties and brain distribution similar to that of [11C]K-2 in preclinical studies. The purpose of this first-in-human study is to evaluate the properties of [18F]K-40 in humans and to compare the kinetics and PET images of [18F]K-40 with those of [11C]K-2. Methods: Five healthy volunteers were enrolled and underwent dynamic PET imaging using [18F]K-40 and [11C]K-2. The nondisplaceable binding potential (BPND) with white matter as the reference was calculated by Logan graphical analysis using tissue time-activity curves (TACs), and the total distribution volume of [18F]K-40 was calculated using plasma TACs. The intraindividual correlation between BPND values obtained for [18F]K-40 and [11C]K-2 was examined. To optimize the time window for PET scanning, BPND and SUV ratio were evaluated. Results: The tissue TACs of [18F]K-40 showed curves similar to those of [11C]K-2. Logan graphical analysis using plasma TACs revealed reversible binding of [18F]K-40. The BPND obtained with [18F]K-40 and [11C]K-2 significantly correlated in each corresponding region and showed very good correlation, which indicated that K-40, as observed with K-2, can provide PET images that reflect the amount of AMPARs. A good linear relationship was observed between BPND and the summation image of SUV ratios between 40 and 50 min after radiotracer injection. Conclusion: [18F]K-40, as with [11C]K-2, has favorable binding properties as an AMPAR PET tracer. Thus, [18F]K-40 could characterize AMPAR distribution in pathophysiologic conditions of the brain and facilitate the development of novel diagnostics of neuropsychiatric disorders.

DOI： 10.2967/jnumed.124.269405

PubMed

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/braincomms/fcaf036

Web of Science

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Local and global functional connectivity densities (lFCD and gFCD, respectively), derived from functional magnetic resonance imaging (fMRI) data, represent the degree of functional centrality within local and global brain networks. While these methods are well-established for mapping brain connectivity, the molecular and synaptic foundations of these connectivity patterns remain unclear. Glutamate, the principal excitatory neurotransmitter in the brain, plays a key role in these processes. Among its receptors, the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is crucial for neurotransmission, particularly in cognitive functions such as learning and memory. This study aimed to examine the association of the AMPAR density and FCD metrics of intraregional and interregional functional centrality. Using [¹¹C]K-2, a positron emission tomography (PET) tracer specific for AMPARs, we measured AMPAR density in the brains of 35 healthy participants. Our findings revealed a strong positive correlation between AMPAR density and both lFCD and gFCD-lFCD across the entire brain. This correlation was especially notable in key regions such as the anterior cingulate cortex, posterior cingulate cortex, pre-subgenual frontal cortex, Default Mode Network, and Visual Network. These results highlight that postsynaptic AMPARs significantly contribute to both local and global functional connectivity in the brain, particularly in network hub regions. This study provides valuable insights into the molecular and synaptic underpinnings of brain functional connectomes.

DOI： 10.3389/fncir.2024.1497897

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Synaptic phenotypes in living patients with psychiatric disorders are poorly characterized. Excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is a fundamental component for neurotransmission. We recently developed a positron emission tomography (PET) tracer for AMPAR, [¹¹C]K-2, the first technology to visualize and quantify AMPARs density in living human brain. In this study, we characterized patients with major psychiatric disorders with [¹¹C]K-2. One hundred forty-nine patients with psychiatric disorders (schizophrenia, n = 42; bipolar disorder, n = 37; depression, n = 35; and autism spectrum disorder, n = 35) and 70 healthy participants underwent a PET scan with [¹¹C]K-2 for measurement of AMPAR density. We detected brain regions that showed correlation between AMPAR density and symptomatology scores in each of four disorders. We also found brain areas with significant differences in AMPAR density between patients with each psychiatric disorder and healthy participants. Some of these areas were observed across diseases, indicating that these are commonly affected areas throughout psychiatric disorders. Schizophrenia, bipolar disorder, depression, and autism spectrum disorder are uniquely characterized by AMPAR distribution patterns. Our approach to psychiatric disorders using [¹¹C]K-2 can elucidate the biological mechanisms across diseases and pave the way to develop novel diagnostics and therapeutics based on the synapse physiology.

DOI： 10.1038/s41380-024-02785-1

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Other Link： https://www.nature.com/articles/s41380-024-02785-1

Language：English   Publishing type：Research paper (scientific journal)  

The renin-angiotensin system in the brain plays a pivotal role in modulating sympathetic nerve activity and contributes to the pathogenesis of hypertension. Angiotensin II (Ang II) type 1 receptor (AT1R)-associated protein (ATRAP) promotes internalization of AT1R while suppressing pathological overactivation of AT1R signaling. However, the pathophysiological function of ATRAP in the brain remains unknown. Therefore, this study aims to investigate whether ATRAP in the paraventricular nucleus (PVN) is involved in neurogenic hypertension pathogenesis in Ang II-infused rats. The ATRAP/AT1R ratio, which serves as an indicator of tissue AT1R hyperactivity, tended to decrease within the PVN in the Ang II group than in the vehicle group. This suggests an Ang II-induced hyperactivation of the AT1R signaling pathway in the PVN. Lentiviral vectors were generated to stimulate ATRAP expression. At 6 weeks of age, rats were microinjected with LV-Venus (Venus-expressing lentivirus) or LV-ATRAP (Venus-ATRAP-expressing lentivirus). The rats were then randomly divided into four groups: (1) Vehicle/LV-Venus, (2) Vehicle/LV-ATRAP, (3) Ang II/LV-Venus, and (4) Ang II/LV-ATRAP. Two weeks after microinjection, vehicle or Ang II was administered systemically for 2 weeks. In the Ang II/LV-ATRAP group, systolic blood pressure at 1 and 2 weeks following administration was significantly lower than that in the Ang II/LV-Venus group. Furthermore, urinary adrenaline levels tended to decrease in the Ang II/LV-ATRAP group than in the Ang II/LV-Venus group. These findings suggest that enhanced ATRAP expression in the PVN suppresses Ang II-induced hypertension, potentially by suppressing hyperactivation of the tissue AT1R signaling pathway and, subsequently, sympathetic nerve activity.

DOI： 10.1038/s41440-023-01480-y

PubMed

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Authorship：Lead author   Language：Japanese   Publisher：(株)ニュー・サイエンス社  

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Authorship：Lead author   Language：Japanese   Publisher：(一社)日本基礎理学療法学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J05805&link_issn=&doc_id=20210319280006&doc_link_id=10.24780%2Fjptf.23.1_37&url=https%3A%2F%2Fdoi.org%2F10.24780%2Fjptf.23.1_37&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(一社)日本核医学会  

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Language：Japanese   Publisher：(公社)日本理学療法士協会  

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Language：Japanese   Publisher：公益社団法人 日本理学療法士協会  

DOI： 10.14900/cjpt.2012.0.48100735.0

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