TY - JOUR
T1 - Bis-pyridylethenyl benzene as novel backbone for amyloid-β binding compounds
AU - Nabuurs, Rob J A
AU - Kapoerchan, Varsha V
AU - Metaxas, Athanasios
AU - Hafith, Sarah
AU - de Backer, Maaike
AU - Welling, Mick M
AU - Jiskoot, Wim
AU - van den Nieuwendijk, Adrianus M C H
AU - Windhorst, Albert D
AU - Overkleeft, Herman S
AU - van Buchem, Mark A
AU - Overhand, Mark
AU - van der Weerd, Louise
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
U2 - https://doi.org/10.1016/j.bmc.2016.05.022
DO - https://doi.org/10.1016/j.bmc.2016.05.022
M3 - Article
C2 - 27838168
SN - 0968-0896
VL - 24
SP - 6139
EP - 6148
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 23
ER -