title: Discovery of the First Environment-Sensitive Near-Infrared (NIR) Fluorogenic Ligand for α1-Adrenergic Receptors Imaging in Vivo.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University , Jinan, Shandong 250012, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University , Jinan, Shandong 250012, China.
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, School of Pharmacy, Shandong University , Jinan, Shandong 250012, China.
authors.forename: Yanna
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University , Jinan, Shandong 250012, China.
authors.forename: Wenxiao
authors.initials: W
authors.lastname: Wu
authors.affiliation: C. Eugene Bennett Department of Chemistry, West Virginia University , Morgantown, West Virginia 26506, United States.
authors.forename: Rong
authors.initials: R
authors.lastname: Cai
authors.affiliation: Department of Urology, Qilu Hospital of Shandong University , Jinan, Shandong 250012, China.
authors.forename: Shouzhen
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Urology, Qilu Hospital of Shandong University , Jinan, Shandong 250012, China.
authors.forename: Benkang
authors.initials: B
authors.lastname: Shi
authors.affiliation: Department of Pathology, School of Medicine, Shandong University , Jinan, Shandong 250012, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Han
authors.affiliation: C. Eugene Bennett Department of Chemistry, West Virginia University , Morgantown, West Virginia 26506, United States.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Shi
authors.affiliation: Center for Translational Cancer Research, Institute of Biosciences & Technology, Texas A&M University Health Science Center , Houston, Texas 77030, United States.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University , Jinan, Shandong 250012, China.
authors.forename: Lupei
authors.initials: L
authors.lastname: Du
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University , Jinan, Shandong 250012, China.
authors.forename: Minyong
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002232:Carbocyanines / Q000737:chemistry*; D045744:Cell Line, Tumor; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005453:Fluorescence; D005456:Fluorescent Dyes / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000737:chemistry / Q000378:metabolism; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry*; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D002232:Carbocyanines; D005456:Fluorescent Dyes; D008024:Ligands; D010879:Piperazines; D011799:Quinazolines; D018340:Receptors, Adrenergic, alpha-1; C085321:cyanine dye 5; D000077489:Piperazine