Bis-pyridylethenyl benzene as novel backbone for amyloid-β binding compounds

Rob J A Nabuurs, Varsha V Kapoerchan, Athanasios Metaxas, Sarah Hafith, Maaike de Backer, Mick M Welling, Wim Jiskoot, Adrianus M C H van den Nieuwendijk, Albert D Windhorst, Herman S Overkleeft, Mark A van Buchem, Mark Overhand, Louise van der Weerd

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Detection of cerebral β-amyloid (Aβ) by targeted contrast agents is of great interest for in vivo diagnosis of Alzheimer's disease (AD). Partly because of their planar structure several bis-styrylbenzenes have been previously reported as potential Aβ imaging agents. However, these compounds are relatively hydrophobic, which likely limits their in vivo potential. Based on their structures, we hypothesized that less hydrophobic bis-pyridylethenylbenzenes may also label amyloid. We synthesized several bis-pyridylethenylbenzenes and tested whether these compounds indeed display improved solubility and lower LogP values, and studied their fluorescent properties and Aβ binding characteristics. Bis-pyridylethenylbenzenes showed a clear affinity for Aβ plaques on both human and murine AD brain sections. Competitive binding experiments suggested a different binding site than Chrysamine G, a well-known stain for amyloid. With a LogP value between 3 and 5, most bis-pyridylethenylbenzenes were able to enter the brain and label murine amyloid in vivo with the bis(4-pyridylethenyl)benzenes showing the most favorable characteristics. In conclusion, the presented results suggest that bis-pyridylethenylbenzene may serve as a novel backbone for amyloid imaging agents.

Original languageEnglish
Pages (from-to)6139-6148
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number23
DOIs
Publication statusPublished - 1 Dec 2016

Cite this

Nabuurs, R. J. A., Kapoerchan, V. V., Metaxas, A., Hafith, S., de Backer, M., Welling, M. M., ... van der Weerd, L. (2016). Bis-pyridylethenyl benzene as novel backbone for amyloid-β binding compounds. Bioorganic and Medicinal Chemistry, 24(23), 6139-6148. https://doi.org/10.1016/j.bmc.2016.05.022