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

Autor: Nabuurs RJ; Department of Radiology CS2, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands., Kapoerchan VV; Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands., Metaxas A; Radionucleotide Laboratory, Free University, Amsterdam, Netherlands., Hafith S; Department of Radiology CS2, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands., de Backer M; Department of Radiology CS2, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands., Welling MM; Department of Radiology CS2, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands., Jiskoot W; Division of Drug Delivery Technology, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands., van den Nieuwendijk AM; Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands., Windhorst AD; Radionucleotide Laboratory, Free University, Amsterdam, Netherlands., Overkleeft HS; Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands., van Buchem MA; Department of Radiology CS2, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands., Overhand M; Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands., van der Weerd L; Department of Radiology CS2, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands. Electronic address: l.van_der_weerd@lumc.nl.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2016 Dec 01; Vol. 24 (23), pp. 6139-6148. Date of Electronic Publication: 2016 May 18.
DOI: 10.1016/j.bmc.2016.05.022
Abstrakt: 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.
(Copyright © 2016. Published by Elsevier Ltd.)
Databáze: MEDLINE
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