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.,Journal of Medicinal Chemistry

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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.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-10-28 , DOI: 10.1021/acs.jmedchem.9b00812
Hazem Ahmed ₁ , Ahmed Haider ₁ , Jasmine Varisco ₁ , Maja Stanković ₁ , Rahel Wallimann ₁ , Stefan Gruber ₁ , Irina Iten ₁ , Surya Häne ₁ , Adrienne Müller Herde ₁ , Claudia Keller ₁ , Roger Schibli _{1,

2} , Dirk Schepmann ₃ , Linjing Mu _{1,

2} , Bernhard Wünsch ₃ , Simon M Ametamey ₁

Affiliation

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, [¹⁸F]PF-NB1 emerged as the best performing tracer with respect to specificity and selectivity over σ1 and σ2 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. [¹⁸F]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. [¹⁸F]PF-NB1 is a promising fluorine-18 PET tracer for imaging the GluN2B subunits of the NMDAR and has utility for receptor occupancy studies.

中文翻译：

2,3,4,5-四氢-1H-3-苯并ze庚因和6,7,8,9-四氢-5H-苯并[7]年青-7-胺类似物的结构亲和关系和放射性氟化2的发现，3,4,5-四氢-1H-3-苯并ze庚因同源物，用于成像包含GluN2B亚基的N-甲基-d-天冬氨酸受体。

渴望开发一种正电子发射断层摄影（PET）成像剂用于的GluN2B亚基Ñ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的治疗靶，我们合成了一系列的2,3 ，4，5-四氢-1 H -3-苯并ze庚因和6,7,8,9-四氢-5 H-苯并[7] Annulen-7-胺类似物。通过竞争结合测定和放射自显影进行体外测试后，[ ¹⁸就对σ1和σ2受体的特异性和选择性而言，F] PF-NB1成为表现最佳的示踪剂，因此被选择用于进一步的体内评估。铜介导的放射性氟化以良好的放射化学收率和较高的摩尔活度完成。在Wistar大鼠中进行了广泛的体内表征，包括PET成像，生物分布，受体占有率和代谢产物研究。[ ¹⁸ F] PF-NB1结合对富含GluN2B的前脑区域具有选择性，并且被GluN2B拮抗剂CP-101606特异性阻断，没有剂量依赖性，且没有脑放射性代谢物。[ ¹⁸ F] PF-NB1是一种很有前途的氟18 PET示踪剂，可用于对NMDAR的GluN2B亚基进行成像，可用于受体占用率研究。

更新日期：2019-10-28

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