Early Diagnosis of Cerebral Ischemia Reperfusion Injury and Revelation of Its Regional Development by a H<sub>3</sub>R Receptor-Directed Probe
Junda Wang, Yuanjun Zhu, Lingfei Yang, Hui Liu, Tongliang Zhou, Fengrong Xu, Ping Xu, Lan Yuan, Lei Liang
Abstract
In vivo imaging of cerebral hydrogen peroxide (H2O2) may facilitate early diagnosis of cerebral ischemia reperfusion injury (CIRI) and a revelation of its pathological progression. In this study, we report our rational design of a brain-targeting fluorescent probe using the basis of a pyridazinone scaffold. A structure–activity relationship study reveals that PCAB is the best candidate (Ki = 15.8 nM) for a histamine H3 receptor (H3R), which is highly expressed in neurons of the central nervous system. As a two-photon fluorescent probe, PCAB exhibits a fast, selective reaction toward both extra- and intracellular H2O2 in SH-SY5Y cells under oxygen glucose deprivation and resupply. In vivo fluorescent imaging of a middle cerebral artery occlusion mouse confirms that PCAB is an ultrasensitive probe with potent blood–brain barrier penetration, precise brain targeting, and fast detection of CIRI.