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Development of fluorescence imaging probes for nicotinic acetylcholine α4β2∗ receptors.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2017-12-17 , DOI: 10.1016/j.bmcl.2017.12.036 Gurleen K Samra 1 , Irakli Intskirveli 2 , Anitha P Govind 3 , Christopher Liang 1 , Ronit Lazar 2 , William N Green 3 , Raju Metherate 2 , Jogeshwar Mukherjee 4
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2017-12-17 , DOI: 10.1016/j.bmcl.2017.12.036 Gurleen K Samra 1 , Irakli Intskirveli 2 , Anitha P Govind 3 , Christopher Liang 1 , Ronit Lazar 2 , William N Green 3 , Raju Metherate 2 , Jogeshwar Mukherjee 4
Affiliation
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Nicotinic acetylcholine α4β2∗ receptors (nAChRs) are implicated in various neurodegenerative diseases and smoking addiction. Imaging of brain high-affinity α4β2∗ nAChRs at the cellular and subcellular levels would greatly enhance our understanding of their functional role. Since better resolution could be achieved with fluorescent probes, using our previously developed positron emission tomography (PET) imaging agent [18F]nifrolidine, we report here design, synthesis and evaluation of two fluorescent probes, nifrodansyl and nifrofam for imaging α4β2∗ nAChRs. The nifrodansyl and nifrofam exhibited nanomolar affinities for the α4β2∗ nAChRs in [3H]cytisine-radiolabeled rat brain slices. Nifrofam labeling was observed in α4β2∗ nAChR-expressing HEK cells and was upregulated by nicotine exposure. Nifrofam co-labeled cell-surface α4β2∗ nAChRs, labeled with antibodies specific for a β2 subunit extracellular epitope indicating that nifrofam labels α4β2∗ nAChR high-affinity binding sites. Mouse brain slices exhibited discrete binding of nifrofam in the auditory cortex showing promise for examining cellular distribution of α4β2∗ nAChRs in brain regions.
中文翻译：
烟碱乙酰胆碱α4β2*受体荧光成像探针的开发。
烟碱型乙酰胆碱α4β2*受体（nAChRs）与多种神经退行性疾病和吸烟成瘾有关。在细胞和亚细胞水平上对大脑高亲和力α4β2* nAChRs的成像将大大增强我们对其功能作用的了解。由于使用我们以前开发的正电子发射断层扫描（PET）成像剂[18F] nifrolidine可以用荧光探针实现更好的分辨率，因此在此报告了用于对α4β2∗ nAChRs进行成像的两种荧光探针Nifrodansyl和nifrofam的设计，合成和评估。在[3H]胱氨酸放射标记的大鼠脑切片中，nifrodansyl和nifrofam对α4β2* nAChRs具有纳摩尔亲和力。在表达α4β2* nAChR的HEK细胞中观察到了尼福芬标记，并通过尼古丁暴露上调。尼曲磷共标记的细胞表面α4β2* nAChRs，用对β2亚基胞外表位具有特异性的抗体进行标记，表明nifrofam标记了α4β2* nAChR高亲和力结合位点。小鼠脑切片在听觉皮层中显示出了尼福芬的离散结合，表明有望检查脑区域中α4β2* nAChRs的细胞分布。
更新日期：2017-12-17
中文翻译：
烟碱乙酰胆碱α4β2*受体荧光成像探针的开发。
烟碱型乙酰胆碱α4β2*受体（nAChRs）与多种神经退行性疾病和吸烟成瘾有关。在细胞和亚细胞水平上对大脑高亲和力α4β2* nAChRs的成像将大大增强我们对其功能作用的了解。由于使用我们以前开发的正电子发射断层扫描（PET）成像剂[18F] nifrolidine可以用荧光探针实现更好的分辨率，因此在此报告了用于对α4β2∗ nAChRs进行成像的两种荧光探针Nifrodansyl和nifrofam的设计，合成和评估。在[3H]胱氨酸放射标记的大鼠脑切片中，nifrodansyl和nifrofam对α4β2* nAChRs具有纳摩尔亲和力。在表达α4β2* nAChR的HEK细胞中观察到了尼福芬标记，并通过尼古丁暴露上调。尼曲磷共标记的细胞表面α4β2* nAChRs，用对β2亚基胞外表位具有特异性的抗体进行标记，表明nifrofam标记了α4β2* nAChR高亲和力结合位点。小鼠脑切片在听觉皮层中显示出了尼福芬的离散结合，表明有望检查脑区域中α4β2* nAChRs的细胞分布。
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