title: Bis-pyridylethenyl benzene as novel backbone for amyloid-β binding compounds.
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.
authors.affiliation: Department of Radiology CS2, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands.
authors.forename: Rob J A
authors.initials: RJ
authors.lastname: Nabuurs
authors.affiliation: Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands.
authors.forename: Varsha V
authors.initials: VV
authors.lastname: Kapoerchan
authors.affiliation: Radionucleotide Laboratory, Free University, Amsterdam, Netherlands.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Metaxas
authors.affiliation: Department of Radiology CS2, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hafith
authors.affiliation: Department of Radiology CS2, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: de Backer
authors.affiliation: Department of Radiology CS2, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands.
authors.forename: Mick M
authors.initials: MM
authors.lastname: Welling
authors.affiliation: Division of Drug Delivery Technology, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Jiskoot
authors.affiliation: Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands.
authors.forename: Adrianus M C H
authors.initials: AM
authors.lastname: van den Nieuwendijk
authors.affiliation: Radionucleotide Laboratory, Free University, Amsterdam, Netherlands.
authors.forename: Albert D
authors.initials: AD
authors.lastname: Windhorst
authors.affiliation: Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands.
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.affiliation: Department of Radiology CS2, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands.
authors.forename: Mark A
authors.initials: MA
authors.lastname: van Buchem
authors.affiliation: Department of Bioorganic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Overhand
authors.affiliation: 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.
authors.forename: Louise
authors.initials: L
authors.lastname: van der Weerd
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D003287:Contrast Media / Q000138:chemical synthesis / Q000737:chemistry*; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D057054:Molecular Imaging; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging*; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry*; D012995:Solubility; D013267:Stilbenes / Q000737:chemistry; D013343:Styrenes / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: C465418:1,4-bis(4'-hydroxystyryl)-2-methoxybenzene; D016229:Amyloid beta-Peptides; D003287:Contrast Media; D005456:Fluorescent Dyes; D011725:Pyridines; D013267:Stilbenes; D013343:Styrenes
keywords: Alzheimer’s disease; Amyloid-β; Contrast agent; Molecular imaging