Anionic Oligothiophenes Compete for Binding of X‐34 but not PIB to Recombinant Aβ Amyloid Fibrils and Alzheimer's Disease Brain‐Derived Aβ

Abstract

Deposits comprised of amyloid‐β (Aβ) are one of the pathological hallmarks of Alzheimer's disease (AD) and small hydrophobic ligands targeting these aggregated species are used clinically for the diagnosis of AD. Herein, we observed that anionic oligothiophenes efficiently displaced X‐34, a Congo Red analogue, but not Pittsburgh compound B (PIB) from recombinant Aβ amyloid fibrils and Alzheimer's disease brain‐derived Aβ. Overall, we foresee that the oligothiophene scaffold offers the possibility to develop novel high‐affinity ligands for Aβ pathology only found in human AD brain, targeting a different site than PIB.

Synthesis of Thiophene‐Based Optical Ligands That Selectively Detect Tau Pathology in Alzheimer's Disease

“…In contrast, the negatively charged tTBT2, displayed staining of both Aβ and tau aggregates (Figure , Supporting Information Figures S1 and S2). Thus, similar to what has been reported earlier for oligothiophenes, anionic carboxyl groups along the tTBT backbone might be an essential chemical determinant for achieving high‐affinity optical ligands towards protein aggregates. However, none of the tTBTs displayed selective staining towards tau pathology, signifying that the bTVBT molecular scaffold was superior for achieving optical ligands that selectively detect tau deposits in brain sections with AD pathology.…”

“…Hence, q‐FTAA‐CN and bTVBT3 most likely have alternative modes of binding to tau aggregates. Previous studies have suggested that anionic oligothiophenes, including q‐FTAA‐CN, have a similar mode of binding to protein aggregates as Congo red and related analogues ,. Anionic oligothiophenes efficiently displaced X‐34, a Congo Red analogue, but not Pittsburgh compound B (PIB) from recombinant Aβ amyloid fibrils and Alzheimer's disease brain‐derived Aβ .…”

“…In addition, LCOs having distinct chemical compositions can also be utilized for spectral assessment of different protein aggregates, such as Aβ or tau deposits in AD . Lately, a thiophene‐based tetrameric ligand, q‐FTAA‐CN (Figure A) with a striking higher affinity for Aβ deposits than aggregated species composed of tau was also identified …”

Amyloid fibril polymorphism: a challenge for molecular imaging and therapy

“…Luminescent‐conjugated oligo‐ and polythiophenes (LCOs and LCPs) represent a promising class of amyloid imaging agents, recognizing and differentiating a broader subset of protein aggregates than conventional amyloid dyes . It was recently shown by combinatorial ssNMR, modelling and fluorescence that the main molecular binding site for the LCO p‐FTAA appears to overlap with that described for Congo red (see more below). LCOs and LCPs contain a twistable thiophene backbone and upon conformational restriction of this backbone, different emission profiles are observed from the oligothiophene derivatives.…”

“…, the pyridinyl‐butadienyl‐motif in PBB3 was replaced by a bi‐thiophene vinyl moiety rendering a set of compounds denoted bi‐thiophene‐vinyl‐benzothiazoles/benzothiazoliums (bTVBTs). When utilizing the bTVBTs in combination with a thiophene‐based ligand, qFTAA‐CN selective towards aggregated Aβ species, the two pathological hallmarks in AD could easily be distinguished (Fig. d).…”