title: Identification of a novel indoline derivative for in vivo fluorescent imaging of blood-brain barrier disruption in animal models.
abstract: Disruption of the blood-brain barrier (BBB) can occur in various pathophysiological conditions. Administration of extraneous tracers that can pass the disrupted, but not the intact, BBB and detection of the extravasation have been widely used to assess BBB disruption in animal models. Although several fluorescent tracers have been successfully used, the administration of these tracers basically requires intravascular injection, which can be laborious when using small animals such as zebrafish. To identify fluorescent tracers that could be easily administered into various animal models and visualize the BBB disruption in vivo, we prepared nine structurally related indoline derivatives (IDs) as a minimum set of diverse fluorescent compounds. We found that one ID, ZMB741, had the highest affinity for serum albumin and emitted the strongest fluorescence in the presence of serum albumin of the nine IDs tested. The affinity to serum albumin and the fluorescence intensity was superior to those of Evans blue and indocyanine green that have been conventionally used to assess the BBB disruption. We showed that ZMB741 could be administered into zebrafish by static immersion or mice by intraperitoneal injection and visualizes the active disruption of their BBB. These results suggest that ZMB741 can be a convenient and versatile tool for in vivo fluorescent imaging of BBB disruption in various animal models. The strategy used in this study can also be applied to diversity-oriented libraries to identify novel fluorescent tracers that may be superior to ZMB741.
authors.affiliation: Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yata
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nomoto
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ogiwara
authors.forename: Kohei
authors.initials: K
authors.lastname: Watanabe
authors.forename: Taichi
authors.initials: T
authors.lastname: Shintou
authors.forename: Akira
authors.initials: A
authors.lastname: Tsuboyama
authors.forename: Mie
authors.initials: M
authors.lastname: Okano
authors.forename: Noriko
authors.initials: N
authors.lastname: Umemoto
authors.forename: Zi
authors.initials: Z
authors.lastname: Zhang
authors.forename: Miko
authors.initials: M
authors.lastname: Kawabata
authors.forename: Beibei
authors.initials: B
authors.lastname: Zhang
authors.forename: Junya
authors.initials: J
authors.lastname: Kuroyanagi
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Shimada
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imamura
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tomimoto
authors.forename: Toshio
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D003952:Diagnostic Imaging / Q000379:methods*; D004195:Disease Models, Animal; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051379:Mice; D010539:Permeability; D012709:Serum Albumin / Q000737:chemistry; D015027:Zebrafish
chemical_list: D005456:Fluorescent Dyes; D007211:Indoles; D012709:Serum Albumin; C057812:indoline