| 2. |
- Zhang, Jun, et al.
(author)
-
Detection and Imaging of A beta 1-42 and Tau Fibrils by Redesigned Fluorescent X-34 Analogues
- 2018
-
In: Chemistry - A European Journal. - : WILEY-V C H VERLAG GMBH. - 0947-6539 .- 1521-3765. ; 24:28, s. 7210-7216
-
Journal article (peer-reviewed)abstract
- We revisited the Congo red analogue 2,5-bis(4-hydroxy-3-carboxy-styryl)benzene (X-34) to develop this highly fluorescent amyloid dye for imaging Alzheimers disease (AD) pathology comprising A beta and Tau fibrils. A selection of ligands with distinct optical properties were synthesized by replacing the central benzene unit of X-34, with other heterocyclic moieties. Full photophysical characterization was performed, including recording absorbance and fluorescence spectra, Stokes shift, quantum yield and fluorescence lifetimes. All ligands displayed high affinity towards recombinant amyloid fibrils of A beta 1-42 (13-300nmK(d)) and Tau (16-200nmK(d)) as well as selectivity towards the corresponding disease-associated protein aggregates in AD tissue. We observed that these ligands efficiently displaced X-34, but not Pittsburgh compound B (PiB) from recombinant A beta 1-42 amyloid fibrils, arguing for retained targeting of the Congo red type binding site. We foresee that the X-34 scaffold offers the possibility to develop novel high-affinity ligands for A pathology found in human AD brain in a different mode compared with PiB, potentially recognizing different polymorphs of A fibrils.
|
|
| 3. |
- Zhang, Jun, et al.
(author)
-
Phenolic Bis-styrylbenzo[c]-1,2,5-thiadiazoles as Probes for Fluorescence Microscopy Mapping of A beta Plaque Heterogeneity
- 2019
-
In: Journal of Medicinal Chemistry. - : AMER CHEMICAL SOC. - 0022-2623 .- 1520-4804. ; 62:4, s. 2038-2048
-
Journal article (peer-reviewed)abstract
- A fluorescent bis-styryl-benzothiadiazole (BTD) with carboxylic acid functional groups (X-34/Congo red analogue) showed lower binding affinity toward A beta 1-42 and A beta 1-40 fibrils than its neutral analogue. Hence, variable patterns of neutral OH-substituted bis-styryl-BTDs were generated. All bis-styryl-BTDs showed higher binding affinity to A beta 1-42 fibrils than to A beta 1-40 fibrils. The para-OH on the phenyl rings was beneficial for binding affinity while a meta-OH decreased the affinity. Differential staining of transgenic mouse A beta amyloid plaque cores compared to peripheral coronas using neutral compared to anionic bis-styryl ligands indicate differential recognition of amyloid polymorphs. Hyperspectral imaging of transgenic mouse A beta plaque stained with uncharged para-hydroxyl substituted bis-styryl-BTD implicated differences in binding site polarity of polymorphic amyloid plaque. Most properties of the corresponding bis-styryl-BTD were retained with a rigid alkyne linker rendering a probe insensitive to cis trans isomerization. These new BTDbased ligands are promising probes for spectral imaging of different A beta fibril polymorphs.
|
|
