{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1360290617793807488.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1038/s41401-020-0456-9"}},{"identifier":{"@type":"URI","@value":"http://www.nature.com/articles/s41401-020-0456-9.pdf"}},{"identifier":{"@type":"URI","@value":"http://www.nature.com/articles/s41401-020-0456-9"}}],"resourceType":"学術雑誌論文(journal article)","dc:title":[{"@value":"Synthesis and preliminary evaluation of novel 11C-labeled GluN2B-selective NMDA receptor negative allosteric modulators"}],"description":[{"notation":[{"@value":"N-methyl-D-aspartate receptors (NMDARs) play critical roles in the physiological function of the mammalian central nervous system (CNS), including learning, memory, and synaptic plasticity, through modulating excitatory neurotransmission. Attributed to etiopathology of various CNS disorders and neurodegenerative diseases, GluN2B is one of the most well-studied subtypes in preclinical and clinical studies on NMDARs. Herein, we report the synthesis and preclinical evaluation of two 11C-labeled GluN2B-selective negative allosteric modulators (NAMs) containing N,N-dimethyl-2-(1H-pyrrolo[3,2-b]pyridin-1-yl)acetamides for positron emission tomography (PET) imaging. Two PET ligands, namely [11C]31 and [11C]37 (also called N2B-1810 and N2B-1903, respectively) were labeled with [11C]CH3I in good radiochemical yields (decay-corrected 28% and 32% relative to starting [11C]CO2, respectively), high radiochemical purity (>99%) and high molar activity (>74 GBq/μmol). In particular, PET ligand [11C]31 demonstrated moderate specific binding to GluN2B subtype by in vitro autoradiography studies. However, because in vivo PET imaging studies showed limited brain uptake of [11C]31 (up to 0.5 SUV), further medicinal chemistry and ADME optimization are necessary for this chemotype attributed to low binding specificity and rapid metabolism in vivo."}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1380290617793807366","@type":"Researcher","foaf:name":[{"@value":"Ji-yun Sun"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807105","@type":"Researcher","foaf:name":[{"@value":"Katsushi Kumata"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807364","@type":"Researcher","foaf:name":[{"@value":"Zhen Chen"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807108","@type":"Researcher","foaf:name":[{"@value":"Yi-ding Zhang"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807112","@type":"Researcher","foaf:name":[{"@value":"Jia-hui Chen"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807489","@type":"Researcher","foaf:name":[{"@value":"Akiko Hatori"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807236","@type":"Researcher","foaf:name":[{"@value":"Hua-long Fu"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807488","@type":"Researcher","foaf:name":[{"@value":"Jian Rong"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807376","@type":"Researcher","foaf:name":[{"@value":"Xiao-yun Deng"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807370","@type":"Researcher","foaf:name":[{"@value":"Tomoteru Yamasaki"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807233","@type":"Researcher","foaf:name":[{"@value":"Lin Xie"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807491","@type":"Researcher","foaf:name":[{"@value":"Kuan Hu"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807362","@type":"Researcher","foaf:name":[{"@value":"Masayuki Fujinaga"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807360","@type":"Researcher","foaf:name":[{"@value":"Qing-zhen Yu"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807363","@type":"Researcher","foaf:name":[{"@value":"Tuo Shao"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807111","@type":"Researcher","foaf:name":[{"@value":"Thomas Lee Collier"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807113","@type":"Researcher","foaf:name":[{"@value":"Lee Josephson"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793806979","@type":"Researcher","foaf:name":[{"@value":"Yi-han Shao"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807238","@type":"Researcher","foaf:name":[{"@value":"Yun-fei Du"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807372","@type":"Researcher","foaf:name":[{"@value":"Lu Wang"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793807235","@type":"Researcher","foaf:name":[{"@value":"Hao Xu"}]},{"@id":"https://cir.nii.ac.jp/crid/1420845751166311552","@type":"Researcher","personIdentifier":[{"@type":"KAKEN_RESEARCHERS","@value":"80443076"},{"@type":"NRID","@value":"1000080443076"},{"@type":"NRID","@value":"9000254235657"},{"@type":"NRID","@value":"9000000967458"},{"@type":"NRID","@value":"9000399539601"},{"@type":"NRID","@value":"9000409791212"},{"@type":"NRID","@value":"9000005146923"},{"@type":"NRID","@value":"9000021179783"},{"@type":"NRID","@value":"9000005185690"},{"@type":"NRID","@value":"9000397426893"},{"@type":"NRID","@value":"9000339142212"},{"@type":"NRID","@value":"9000254701370"},{"@type":"NRID","@value":"9000347046897"},{"@type":"NRID","@value":"9000316216730"},{"@type":"NRID","@value":"9000309573844"},{"@type":"NRID","@value":"9000254704518"},{"@type":"NRID","@value":"9000254236406"},{"@type":"RESEARCHMAP","@value":"https://researchmap.jp/mingtaojun"}],"foaf:name":[{"@value":"Ming-rong Zhang"}]},{"@id":"https://cir.nii.ac.jp/crid/1380290617793806976","@type":"Researcher","foaf:name":[{"@value":"Steven H Liang"}]}],"publication":{"publicationIdentifier":[{"@type":"PISSN","@value":"16714083"},{"@type":"EISSN","@value":"17457254"}],"prism:publicationName":[{"@value":"Acta Pharmacologica Sinica"}],"dc:publisher":[{"@value":"Springer Science and Business Media LLC"}],"prism:publicationDate":"2020-07-13","prism:volume":"42","prism:number":"3","prism:startingPage":"491","prism:endingPage":"498"},"reviewed":"false","dc:rights":["https://www.springer.com/tdm","https://www.springer.com/tdm"],"url":[{"@id":"http://www.nature.com/articles/s41401-020-0456-9.pdf"},{"@id":"http://www.nature.com/articles/s41401-020-0456-9"}],"createdAt":"2020-07-13","modifiedAt":"2023-05-20","project":[{"@id":"https://cir.nii.ac.jp/crid/1040000782023191424","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"19K17156"},{"@type":"JGN","@value":"JP19K17156"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-19K17156/"}],"notation":[{"@language":"en","@value":"Chemoselective methionine 18F-fluorination on unprotected peptides for positron-emission tomography imaging"}]},{"@id":"https://cir.nii.ac.jp/crid/1040566775672868224","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"20H03635"},{"@type":"JGN","@value":"JP20H03635"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20H03635/"}],"notation":[{"@language":"ja","@value":"膜貫通AMPA受容体調節性タンパク質-γ8を標的とするPETプローブの開発"},{"@language":"en","@value":"Development of PET probes for gama 8-dependent transmembrane AMPA receptor regulatory protein"}]}],"relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1050005822275480832","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Development of PET and SPECT Probes for Glutamate Receptors"}]},{"@id":"https://cir.nii.ac.jp/crid/1360004233150170752","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Synthesis and Preliminary Studies of a Novel Negative Allosteric Modulator, 7-((2,5-Dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[<sup>11</sup>C]methoxyphenyl) quinoline-2-carboxamide, for Imaging of Metabotropic Glutamate Receptor 2"}]},{"@id":"https://cir.nii.ac.jp/crid/1360011144287965696","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"1<i>H</i>-Pyrrolo[3,2-<i>b</i>]pyridine GluN2B-Selective Negative Allosteric Modulators"}]},{"@id":"https://cir.nii.ac.jp/crid/1360011144641199488","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"PET and SPECT tracers for glutamate receptors"}]},{"@id":"https://cir.nii.ac.jp/crid/1360011146495517952","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Synthesis and Preliminary Evaluations of a Triazole-Cored Antagonist as a PET Imaging Probe ([<sup>18</sup>F]N2B-0518) for GluN2B Subunit in the Brain"}]},{"@id":"https://cir.nii.ac.jp/crid/1360285705159945216","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Synthesis and characterization of <sup>11</sup>C‐labeled benzyl amidine derivatives as PET radioligands for GluN2B subunit of the NMDA receptors"}]},{"@id":"https://cir.nii.ac.jp/crid/1360292619615380736","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Preclinical pharmacology and pharmacokinetics of CERC‐301, a GluN2B‐selective<i>N</i>‐methyl‐D‐aspartate receptor antagonist"}]},{"@id":"https://cir.nii.ac.jp/crid/1360292620709296000","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"The Effect of the Selective NMDA Receptor Antagonist Traxoprodil in the Treatment of Traumatic Brain Injury"}]},{"@id":"https://cir.nii.ac.jp/crid/1360574095063514624","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Metabotropic Glutamate Receptors: Physiology, Pharmacology, and Disease"}]},{"@id":"https://cir.nii.ac.jp/crid/1360574095155590144","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Allosteric modulators of NMDA receptors: multiple sites and mechanisms"}]},{"@id":"https://cir.nii.ac.jp/crid/1360574095967523200","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Developmental changes in distribution of NMDA receptor channel subunit mRNAs"}]},{"@id":"https://cir.nii.ac.jp/crid/1360848658059668736","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"In Vitro and in Vivo Evaluation of <sup>11</sup>C-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies"}]},{"@id":"https://cir.nii.ac.jp/crid/1360855568622487680","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Preclinical Evaluation of Benzazepine-Based PET Radioligands (<i>R</i>)- and (<i>S</i>)-<sup>11</sup>C-Me-NB1 Reveals Distinct Enantiomeric Binding Patterns and a Tightrope Walk Between GluN2B- and σ<sub>1</sub>-Receptor–Targeted PET Imaging"}]},{"@id":"https://cir.nii.ac.jp/crid/1360855568784742784","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Structure of the zinc‐bound amino‐terminal domain of the NMDA receptor NR2B subunit"}]},{"@id":"https://cir.nii.ac.jp/crid/1361137044755871744","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Working against Time:  Rapid Radiotracer Synthesis and Imaging the Human Brain"}]},{"@id":"https://cir.nii.ac.jp/crid/1361418519745887232","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Using positron emission tomography to facilitate CNS drug development"}]},{"@id":"https://cir.nii.ac.jp/crid/1361418520510696064","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Rapid one-step 18F-radiolabeling of biomolecules in aqueous media by organophosphine fluoride acceptors"}]},{"@id":"https://cir.nii.ac.jp/crid/1361699994156827136","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Chemistry for Positron Emission Tomography: Recent Advances in <sup>11</sup>C‐, <sup>18</sup>F‐, <sup>13</sup>N‐, and <sup>15</sup>O‐Labeling Reactions"}]},{"@id":"https://cir.nii.ac.jp/crid/1361699994471034368","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Fluorinated GluN2B Receptor Antagonists with a 3‐Benzazepine Scaffold Designed for PET Studies"}]},{"@id":"https://cir.nii.ac.jp/crid/1361699994598854912","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Mapping the Binding of GluN2B-Selective N-Methyl-d-aspartate Receptor Negative Allosteric Modulators"}]},{"@id":"https://cir.nii.ac.jp/crid/1361699995526088704","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Highly specific noninvasive photoacoustic and positron emission tomography of brain plaque with functionalized croconium dye labeled by a radiotracer"}]},{"@id":"https://cir.nii.ac.jp/crid/1361981468738347904","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Test No. 107: Partition Coefficient (n-octanol/water): Shake Flask Method"}]},{"@id":"https://cir.nii.ac.jp/crid/1362262945649602944","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Determination of lipophilicity and its use as a predictor of blood–brain barrier penetration of molecular imaging agents"}]},{"@id":"https://cir.nii.ac.jp/crid/1362262946325007360","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors"}]},{"@id":"https://cir.nii.ac.jp/crid/1362544418816993664","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Evaluation of the Novel PET Tracer [11C]HACH242 for Imaging the GluN2B NMDA Receptor in Non-Human Primates"}]},{"@id":"https://cir.nii.ac.jp/crid/1362544419308984064","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Differential expression of five N‐methyl‐D‐aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats"}]},{"@id":"https://cir.nii.ac.jp/crid/1362544419807074944","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Glutamate Receptor Ion Channels: Structure, Regulation, and Function"}]},{"@id":"https://cir.nii.ac.jp/crid/1362544421303846400","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"A novel mechanism of activity‐dependent NMDA receptor antagonism describes the effect of ifenprodil in rat cultured cortical neurones."}]},{"@id":"https://cir.nii.ac.jp/crid/1362825893582973056","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Molecular imaging in drug development"}]},{"@id":"https://cir.nii.ac.jp/crid/1362825894473890432","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Molecular basis of positive allosteric modulation of GluN2B NMDA receptors by polyamines"}]},{"@id":"https://cir.nii.ac.jp/crid/1362825894488032384","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Label-Free Visualization of Early Cancer Hepatic Micrometastasis and Intraoperative Image-Guided Surgery by Photoacoustic Imaging"}]},{"@id":"https://cir.nii.ac.jp/crid/1362825894945789696","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Identification and Preclinical Evaluation of a Radiofluorinated Benzazepine Derivative for Imaging the GluN2B Subunit of the Ionotropic NMDA Receptor"}]},{"@id":"https://cir.nii.ac.jp/crid/1362825895380590976","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"NMDARs in neurological diseases: a potential therapeutic target"}]},{"@id":"https://cir.nii.ac.jp/crid/1362825895826519296","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"A Novel Binding Mode Reveals Two Distinct Classes of NMDA Receptor GluN2B-selective Antagonists"}]},{"@id":"https://cir.nii.ac.jp/crid/1362825896360628608","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Synthesis and Characterization in Rodent Brain of the Subtype-Selective NR2B NMDA Receptor Ligand [<sup>11</sup>C]Ro04-5595 as a Potential Radiotracer for Positron Emission Tomography"}]},{"@id":"https://cir.nii.ac.jp/crid/1363107368751837184","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Allosteric modulators of NR2B‐containing NMDA receptors: molecular mechanisms and therapeutic potential"}]},{"@id":"https://cir.nii.ac.jp/crid/1363388843283160576","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Changing subunit composition of heteromeric NMDA receptors during development of rat cortex"}]},{"@id":"https://cir.nii.ac.jp/crid/1363388844950917120","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Evaluation of <sup>11</sup>C-NR2B-SMe and Its Enantiomers as PET Radioligands for Imaging the NR2B Subunit Within the NMDA Receptor Complex in Rats"}]},{"@id":"https://cir.nii.ac.jp/crid/1363388846262336384","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Developmental and regional expression in the rat brain and functional properties of four NMDA receptors"}]},{"@id":"https://cir.nii.ac.jp/crid/1363670318598874624","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Structure–Affinity Relationships of 2,3,4,5-Tetrahydro-1<i>H</i>-3-benzazepine and 6,7,8,9-Tetrahydro-5<i>H</i>-benzo[7]annulen-7-amine Analogues and the Discovery of a Radiofluorinated 2,3,4,5-Tetrahydro-1<i>H</i>-3-benzazepine Congener for Imaging GluN2B Subunit-Containing <i>N</i>-Methyl-<scp>d</scp>-aspartate Receptors"}]},{"@id":"https://cir.nii.ac.jp/crid/1363670319530926976","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"A Randomized, Placebo-Controlled, Crossover Pilot Trial of the Oral Selective NR2B Antagonist MK-0657 in Patients With Treatment-Resistant Major Depressive Disorder"}]},{"@id":"https://cir.nii.ac.jp/crid/1363670319827796096","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"New advances in NMDA receptor pharmacology"}]},{"@id":"https://cir.nii.ac.jp/crid/1363951795114527232","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"NMDA receptor pathways as drug targets"}]},{"@id":"https://cir.nii.ac.jp/crid/1363951795162370176","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Positron Emission Tomography (PET) Ligand Development for Ionotropic Glutamate Receptors: Challenges and Opportunities for Radiotracer Targeting <i>N</i>-Methyl-<scp>d</scp>-aspartate (NMDA), α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA), and Kainate Receptors"}]},{"@id":"https://cir.nii.ac.jp/crid/1364233269619579520","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Evaluation of<sup>11</sup>C-Me-NB1 as a Potential PET Radioligand for Measuring GluN2B-Containing NMDA Receptors, Drug Occupancy, and Receptor Cross Talk"}]},{"@id":"https://cir.nii.ac.jp/crid/1364233270381500160","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"The NMDA Receptor NR2B Subunit: A Valid Therapeutic Target for Multiple CNS Pathologies"}]}],"dataSourceIdentifier":[{"@type":"CROSSREF","@value":"10.1038/s41401-020-0456-9"},{"@type":"KAKEN","@value":"PRODUCT-23795582"},{"@type":"KAKEN","@value":"PRODUCT-23553299"},{"@type":"OPENAIRE","@value":"doi_dedup___::0d7d60b7398704d35f2a589d04498846"}]}