Discovery of the First Environment-Sensitive Near-Infrared (NIR) Fluorogenic Ligand for α1-Adrenergic Receptors Imaging in Vivo

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• 作者：Zhao Ma ; Yuxing Lin ; Yanna Cheng ; Wenxiao Wu ; Rong Cai ; Shouzhen Chen ; Benkang Shi ; Bo Han ; Xiaodong Shi ; Yubin Zhou ; Lupei Du ; Minyong Li
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：59
• 期：5
• 页码：2151-2162
• 全文大小：640K
• ISSN：1520-4804

文摘

Fluorescent ligands are gaining popularity as tools to aid GPCR research. Nonetheless, in vivo application of such tools is hampered due to their short excitation wavelengths in the visible range and lack of fluorogenic switch. Here we report the discovery of fluorescent ligands (3a–f) for α₁-adrenergic receptors (α₁-ARs) by conjugating the environment-sensitive fluorophore cyane 5 (Cy5) with the quinazoline pharmacophore. Among them, the conjugated compound 3a, with acylated piperazine and the shortest carbon chain spacer, exhibited potent binding and remarkable changes in fluorescence (10-fold) upon binding to α₁-AR. Furthermore, it could be employed to selectively and specifically label α₁-ARs with no washing procedures in single cells, prostate tissue slices, intact tumor xenografts and organs in living mice. Especially, the slice imaging results gave direct and visual evidence that there is a close relationship between α₁-ARs and pathological prostate. It is anticipated that our fluorescent tools will find broad applications in the study of α₁-AR pharmacology and physiology to aid development of novel therapeutics.