Phenolic Bis-styrylbenzenes as β-Amyloid Binding Ligands and Free Radical Scavengers

Abstract

Starting from bisphenolic bis-styrylbenzene DF-9 (4), β-amyloid (Aβ) binding affinity and specificity for phenolic bis-styrylbenzenes, mono-styrylbenzenes and alkyne controls were determined by fluorescence titration with β-amyloid peptide Aβ 1-40 and a fluorescence assay using APP/PS1 transgenic mouse brain sections. Bis-styrylbenzene SAR is derived largely from work on symmetrical compounds; this study is the first to describe Aβ binding data for bis-styrylbenzenes unsymmetrical in the outer rings. With one exception, binding affinity and specificity were decreased by adding and/or changing the substitution pattern of phenol functional groups, changes to the orientation about the central phenyl ring, replacing the alkene with alkyne bonds, or elimination of the central phenyl ring. The only compound with an Aβ binding affinity and specificity comparable to 4 was its 3-hydroxy regioisomer 8. Like 4, 8 crossed the blood-brainbarrier and bound to Aβ plaques in vivo. Using a DPPH assay, phenol functional groups with para orientations seem to be a necessary, but insufficient, criterion for good free radical scavenging properties in these compounds.Alzheimer's disease (AD) 1 is a common neurodegenerative disorder in the elderly 2 characterized by an accumulation of β-amyloid (Aβ) plaques in the brain parenchyma and neurofibrillary tangles (NFTs) in the neuron. 3,4 Although Aβ and NFTs are commonly observed in nondemented elderly, 80 years and older, the molecular pathogenesis of AD is believed to be effected by Aβ production and its clearance. 5,6 The amyloid cascade hypothesis 7 for AD pathogenesis proposes that accumulation and aggregation of Aβ triggers a cascade that leads to the characteristic pathologies of AD. Evidence in support of this hypothesis is obtained from studies of familial AD, which reveal that Aβ accumulation and aggregation are elevated by mutations of the APP, PS1 and PS2 genes. 8 The discovery of the diazo dye Congo red as an Aβ binding ligand 9 provided a starting point in the search for potential in vivo imaging agents using positron emission tomography (PET), single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Investigation of Congo red led to the discovery of bis-styrylbenzenes as a class of compounds with strong Aβ plaque binding properties. These compounds are exemplified by the salicylate bis-styrylbenzenes X-34 (1) 10 shown to penetrate the blood -brain barrier (BBB) and bind to Aβ plaques deposited in APP or APP/PS1 mice. 11 As shown by K114 (3) and DF-9 (4), acidic functional groups are not necessary for good Aβ binding. 12,13 Several stilbene-based compounds, such as SB-13 and BAY94-9172, have been studied for early detection in AD. 14,15 While the structure-activity relationship (SAR) of bis-styrylbenzene compounds has been extensively investigated, the common thread in these studies is that Aβ-binding SAR has been elucidated based largely on symmetrical bis-styrylbenzenes. DesignPreviously, we showed that the bis-styrylbenzene, (E,E)-1...

Quantification of [11C]PIB PET for Imaging Myelin in the Human Brain: A Test—Retest Reproducibility Study in High-Resolution Research Tomography

“…For this purpose, PET tracers such as [ 11 C]BMB, 14 a Congo red derivative, [ 11 C]PIB, 15 a Thioflavin derivative, [ 11 C]CIC, 16 and [ 11 C] MeDAS, 17 two stilbene derivatives, have been explored as myelin imaging biomarkers. Note that Congo-red and Thioflavins have been originally used as histochemical dyes to bind amyloid fibrils rich in β-sheet structures, hallmark of Alzheimer's disease, [18][19][20][21][22] but have also shown significant binding to intact myelin sheaths. This suggests that [ 11 C]PIB, in analogy to its interaction to amyloid fibrils, might have multiple interactions with the myelin structure: on one side, it might get trapped into β-sheet structures of myelin proteins such as MBP, [23][24][25] and on the other side be highly soluble in the myelin-associated lipid bilayer.…”

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

“…Besides the possible influence of the nitrogen atom, this might be due to their planar structure, which was previously suggested to be advantageous for a similar (bis)styrylbenzene with no further substituents. [20] The methoxy group on the inner ring structure seemed to result in a decrease in amyloid binding, particularly for human amyloid. However, in contrast to several known bis-styrylbenzenes, A direct application of bis-pyridylethenylbenzenes for amyloid targeting would be their use in preclinical optical imaging.…”

“…This was already shown for a similar bis-styrylbenzene lacking additional groups, suggesting that planarity indeed plays an important role. [20] Although compounds 12 and 15 showed the highest fluorescent intensity after synthetic amyloid binding of all tested bispyridylethenylbenzenes, on brain sections these compounds were not performing as well as e.g. compounds 11 and 13.…”

Light-triggered vesicle formation: important factors for generation of vesicles and possible applications

“…1) and 4,4′-(1,4-phenylenebis(ethyne-2,1-diyl))diphenol (BPEBOH, Fig. 1) was synthesized following the reported procedure [25,28].…”