Structure-Affinity Relationships of 2,3,4,5-Tetrahydro-1H-3-benzazepine and 6,7,8,9-Tetrahydro-5H-benzo[7]annulen-7-amine Analogues and the Discovery of a Radiofluorinated 2,3,4,5-Tetrahydro-1H-3-benzazepine Congener for Imaging GluN2B Subunit-Containing N-Methyl-D-aspartate Receptors

Ahmed Hazem; Haider Ahmed; Varisco Jasmine; Stankovic Maja; Wallimann Rahel; Gruber Stefan; Iten Irina; Hane Surya; Herde Adrienne Mueller; Keller Claudia; Schibli Roger; Schepmann Dirk; Mu Linjing; Wuensch Bernhard; Ametamey Simon M.

首页> 外文期刊>Journal of Medicinal Chemistry >Structure-Affinity Relationships of 2,3,4,5-Tetrahydro-1H-3-benzazepine and 6,7,8,9-Tetrahydro-5H-benzo[7]annulen-7-amine Analogues and the Discovery of a Radiofluorinated 2,3,4,5-Tetrahydro-1H-3-benzazepine Congener for Imaging GluN2B Subunit-Containing N-Methyl-D-aspartate Receptors

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Structure-Affinity Relationships of 2,3,4,5-Tetrahydro-1H-3-benzazepine and 6,7,8,9-Tetrahydro-5H-benzo[7]annulen-7-amine Analogues and the Discovery of a Radiofluorinated 2,3,4,5-Tetrahydro-1H-3-benzazepine Congener for Imaging GluN2B Subunit-Containing N-Methyl-D-aspartate Receptors

机译：2,3,4,5-四氢-1H-3-苯并嗪和6,7,8,9-四羟基-5H-苯并[7] Annulen-7-胺类似物的结构 - 亲和力关系和6,7,8,9-四氢-5H-苯并[7] ，用于成像GLUN2B亚甲基-D-天冬氨酸受体的3,4,5-四氢-1H-3-苯并Z-Benzazepine Congener

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Aspiring to develop a positron emission tomography (PET) imaging agent for the GluN2B subunits of the N-methyl-D-aspartate receptor (NMDAR), a key therapeutic target for drug development toward several neurological disorders, we synthesized a series of 2,3,4,5-tetrahydro-1H-3-benzazepine and 6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amine analogues. After in vitro testing via competition binding assay and autoradiography, [F-18]PF-NB1 emerged as the best performing tracer with respect to specificity and selectivity over sigma 1 and sigma 2 receptors and was thus selected for further in vivo evaluation. Copper-mediated radiofluorination was accomplished in good radiochemical yields and high molar activities. Extensive in vivo characterization was performed in Wistar rats comprising PET imaging, biodistribution, receptor occupancy, and metabolites studies. [F-18]PF-NB1 binding was selective to GluN2B-rich forebrain regions and was specifically blocked by the GluN2B antagonist, CP-101,606, in a dose-dependent manner with no brain radiometabolites. [F-18]PF-NB1 is a promising fluorine-18 PET tracer for imaging the GluN2B subunits of the NMDAR and has utility for receptor occupancy studies.

机译：为N-甲基d天冬氨酸受体（NMDAR），用于药物开发的朝向几个神经病症的关键治疗靶的GluN2B亚基渴望开发一种正电子发射断层摄影（PET）成像剂，我们合成了一系列的2,3 ，4,5-四氢-1H-3-苯并氮杂和6,7,8,9-四氢-5H-苯并[7]轮烯-7-胺的类似物。通过竞争结合测定和放射自显影在体外测试后，[F-18] PF-NB1成为表现最佳的示踪剂超过西格玛1和sigma 2受体对于特异性和选择性从而被选择用于进一步的体内评价。铜介导的放射性氟化在良好的放射化学的产量和高摩尔活动来完成。广泛的体内表征在Wistar大鼠中包含PET成像，生物分布，受体占有率和代谢物的研究进行的。 [F-18] PF-NB1结合是选择性的GluN2B富前脑区域，并具体由GluN2B拮抗剂阻断，CP-101,606，在与无脑radiometabolites以剂量依赖性的方式。 [F-18] PF-NB1是一种很有前途氟-18 PET示踪剂用于成像NMDAR的GluN2B亚基，并且具有用于受体占据研究效用。

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《Journal of Medicinal Chemistry》 |2019年第21期|共21页
作者
Ahmed Hazem; Haider Ahmed; Varisco Jasmine; Stankovic Maja; Wallimann Rahel; Gruber Stefan; Iten Irina; Hane Surya; Herde Adrienne Mueller; Keller Claudia; Schibli Roger; Schepmann Dirk; Mu Linjing; Wuensch Bernhard; Ametamey Simon M.;
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Swiss Fed Inst Technol Inst Pharmaceut Sci Vladimir Prelog Weg 4 CH-8093 Zurich Switzerland;

Swiss Fed Inst Technol Inst Pharmaceut Sci Vladimir Prelog Weg 4 CH-8093 Zurich Switzerland;

Swiss Fed Inst Technol Inst Pharmaceut Sci Vladimir Prelog Weg 4 CH-8093 Zurich Switzerland;

Swiss Fed Inst Technol Inst Pharmaceut Sci Vladimir Prelog Weg 4 CH-8093 Zurich Switzerland;

Swiss Fed Inst Technol Inst Pharmaceut Sci Vladimir Prelog Weg 4 CH-8093 Zurich Switzerland;

Swiss Fed Inst Technol Inst Pharmaceut Sci Vladimir Prelog Weg 4 CH-8093 Zurich Switzerland;

Swiss Fed Inst Technol Inst Pharmaceut Sci Vladimir Prelog Weg 4 CH-8093 Zurich Switzerland;

Swiss Fed Inst Technol Inst Pharmaceut Sci Vladimir Prelog Weg 4 CH-8093 Zurich Switzerland;

Swiss Fed Inst Technol Inst Pharmaceut Sci Vladimir Prelog Weg 4 CH-8093 Zurich Switzerland;

Swiss Fed Inst Technol Inst Pharmaceut Sci Vladimir Prelog Weg 4 CH-8093 Zurich Switzerland;

Swiss Fed Inst Technol Inst Pharmaceut Sci Vladimir Prelog Weg 4 CH-8093 Zurich Switzerland;

Univ Munster Inst Pharmaceut &

Med Chem Corrensstr 48 D-48149 Munster Germany;

Swiss Fed Inst Technol Inst Pharmaceut Sci Vladimir Prelog Weg 4 CH-8093 Zurich Switzerland;

Univ Munster Inst Pharmaceut &

Med Chem Corrensstr 48 D-48149 Munster Germany;

Swiss Fed Inst Technol Inst Pharmaceut Sci Vladimir Prelog Weg 4 CH-8093 Zurich Switzerland;

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1. Structure-Affinity Relationships of 2,3,4,5-Tetrahydro-1H-3-benzazepine and 6,7,8,9-Tetrahydro-5H-benzo[7]annulen-7-amine Analogues and the Discovery of a Radiofluorinated 2,3,4,5-Tetrahydro-1H-3-benzazepine Congener for Imaging GluN2B Subunit-Containing N-Methyl-D-aspartate Receptors [J] . Ahmed Hazem, Haider Ahmed, Varisco Jasmine, Journal of Medicinal Chemistry . 2019,第21期

机译：2,3,4,5-四氢-1H-3-苯并嗪和6,7,8,9-四羟基-5H-苯并[7] Annulen-7-胺类似物的结构 - 亲和力关系和6,7,8,9-四氢-5H-苯并[7] ，用于成像GLUN2B亚甲基-D-天冬氨酸受体的3,4,5-四氢-1H-3-苯并Z-Benzazepine Congener
2. Down-regulation of synaptic GluN2B subunit-containing N-methyl-D-aspartate receptors: a physiological brake on CA1 neuron alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hyperexcitability during benzodiazepine withdrawal. [J] . Shen G, Tietz EI The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics . 2011,第1期

机译：下调突触包含GluN2B亚基的N-甲基-D-天冬氨酸受体：苯二氮卓戒断期间对CA1神经元α-氨基-3-羟基-5-甲基-4-异恶唑丙酸过度兴奋的生理制动。
3. Melanin-concentrating hormone receptor 1 antagonists: synthesis, structure-activity relationship, docking studies, and biological evaluation of 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives. [J] . Kasai S, Kamaura M, Kamata M, Bioorganic and medicinal chemistry . 2011,第21期

机译：黑色素浓缩激素受体1拮抗剂：2,3,4,5-四氢-1H-3-苯并ze庚因衍生物的合成，构效关系，对接研究和生物学评估。
4. A common mechanism allows selective targeting of GluN2B subunit-containing N-methyl-D-aspartate receptors [O] . Julian A. Schreiber, Dirk Schepmann, Bastian Frehland, 2019

机译：通用机制允许选择性靶向含有GluN2B亚基的N-甲基-D-天冬氨酸受体
5. Down-Regulation of Synaptic GluN2B Subunit-Containing N-methyl-d-aspartate Receptors: A Physiological Brake on CA1 Neuron α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Hyperexcitability during Benzodiazepine Withdrawal [O] . Shen, Guofu, Tietz, Elizabeth I. 2010

机译：下调含有突触的GluN2B亚基的N-甲基-d-天冬氨酸受体：苯二氮卓撤药期间对CA1神经元α-氨基-3-羟基-3-羟基-5-甲基-4-异恶唑丙酸的过度兴奋的生理制动。

Structure-Affinity Relationships of 2,3,4,5-Tetrahydro-1H-3-benzazepine and 6,7,8,9-Tetrahydro-5H-benzo[7]annulen-7-amine Analogues and the Discovery of a Radiofluorinated 2,3,4,5-Tetrahydro-1H-3-benzazepine Congener for Imaging GluN2B Subunit-Containing N-Methyl-D-aspartate Receptors

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