Bis(arylvinyl)pyrazines, -pyrimidines, and -pyridazines As Imaging Agents for Tau Fibrils and 尾-Amyloid Plaques in Alzheimer鈥檚 Disease Models
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- 作者：Alexander Bol盲nder ; Daniel Kieser ; Constantin Voss ; Silvia Bauer ; Christian Sch枚n ; Steffen Burgold ; Tobias Bittner ; Jana H枚lzer ; Roland Heyny-von Hau脽en ; Gerhard Mall ; Val茅rie Goetschy ; Christian Czech ; Henner Knust ; Robert Berger ; Jochen Herms ; Ingrid Hilger ; Boris Schmidt
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：November 8, 2012
- 年：2012
- 卷：55
- 期：21
- 页码：9170-9180
- 全文大小：525K
- 年卷期：v.55,no.21(November 8, 2012)
- ISSN：1520-4804
文摘
The in vivo diagnosis of Alzheimer鈥檚 disease (AD) is of high socioeconomic interest and remains a demanding field of research. The biopathological hallmarks of the disease are extracellular plaques consisting of aggregated 尾-amyloid peptides (A尾) and tau protein derived intracellular tangles. Here we report the synthesis and evaluation of fluorescent pyrazine, pyrimidine,and pyridazine derivatives in vitro and in vivo aiming at a tau-based diagnosis of AD. The probes were pre-evaluated on human brain tissue by fluorescence microscopy and were found to label all known disease-related alterations at high contrast and specificity. To quantify the binding affinity, a new thiazine red displacement assay was developed and selected candidates were toxicologically profiled. The application in transgenic mouse models demonstrated bioavailability and brain permeability for one compound. In the course of histological testing, we discovered an AD-related deposition of tau aggregates in the Bowman鈥檚 glands of the olfactory epithelium, which holds potential for an endoscopic diagnosis of AD in the olfactory system.