Specific chemical determinants are central for achieving ligands for selective detection of amyloid-β deposits in Alzheimer’s disease

Protein deposits are common hallmarks of several neurodegenerative diseases, including Alzheimer’s disease (AD), and ligands that selectively detect specific protein aggregates are crucial. Herein, we investigated the molecular requirements of a thiophene-based ligand, denoted HS-276, for selective detection of Aβ deposits in human brain tissue sections with AD pathology. The staining of Aβ deposits was altered when replacing the terminal thiophene moiety with other heterocyclic moieties. In addition, when changing the central thiophene moiety of the ligand to a phenylene, a quinoxaline, or a benzothiadiazole moiety, the staining of Aβ aggregates was completely abolished, verifying that specific molecular interactions between these ligands and the aggregates were required. The experimental observations were also verified by theoretical calculations of the ligands’ binding mode towards Aβ filaments. Our findings provide chemical insights for developing ligands that selectively target Aβ deposits and highlight the importance of certain chemical requirements for achieving a selective ligand, such as HS-276, for detecting Aβ deposits in sporadic AD. We foresee that these findings might aid in creating novel agents for clinical imaging of Aβ aggregates in AD.

• Publication year

  2025

• Venue

  Australian journal of chemistry (Print)

• Publication date

  2025-11-11

• Fields of study

  Not labeled

• Identifiers
  DOI 10.1071/ch25095
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

• Thiophene-Based Ligands for Specific Assignment of Distinct Aβ Pathologies in Alzheimer's Disease

  2024cited by this paper
• Dual-ligand fluorescence microscopy enables chronological and spatial histological assignment of distinct amyloid-β deposits

  2024cited by this paper
• Distinct Chemical Determinants are Essential for Achieving Ligands for Superior Optical Detection of Specific Amyloid‐β Deposits in Alzheimer's Disease

  2024cited by this paper
• Cryo-EM structures of cotton wool plaques’ amyloid β and of tau filaments in dominantly inherited Alzheimer disease

  2024cited by this paper
• Cryo-EM structures of amyloid-β and tau filaments in Down syndrome

  2024cited by this paper
• Hallmarks of neurodegenerative diseases.

  2023cited by this paper
• Distinct Heterocyclic Moieties Govern the Selectivity of Thiophene-Vinylene-Based Ligands Towards Aβ or Tau Pathology in Alzheime's Disease.

  2023cited by this paper
• Thiophene‐Based Ligands: Design, Synthesis and Their Utilization for Optical Assignment of Polymorphic‐Disease‐Associated Protein Aggregates

  2023cited by this paper
• Thiophene-Based Ligands for Histological Multiplex Spectral Detection of Distinct Protein Aggregates in Alzheimer´s Disease.

  2023cited by this paper
• Cryo-EM analysis of the effect of seeding with brain-derived Aβ amyloid fibrils.

  2023cited by this paper
• Cryo-EM of Aβ fibrils from mouse models find tg-APPArcSwe fibrils resemble those found in patients with sporadic Alzheimer’s disease

  2023cited by this paper
• Cryo-EM structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer’s disease and cerebral amyloid angiopathy

  2023cited by this paper
• Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids

  2023cited by this paper
• Proteophenes – Amino Acid Functionalized Thiophene‐based Fluorescent Ligands for Visualization of Protein Deposits in Tissue Sections with Alzheimer's Disease Pathology

  2022cited by this paper
• Cryo-EM structures of amyloid-β 42 filaments from human brains

  2022cited by this paper
• Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains

  2022cited by this paper
• Thiophene‐Based Optical Ligands That Selectively Detect Aβ Pathology in Alzheimer's Disease

  2021cited by this paper
• OUP accepted manuscript

  2021cited by this paper
• Autoradiography validation of novel tau PET tracer [F-18]-MK-6240 on human postmortem brain tissue

  2019cited by this paper
• Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer’s disease

  2017cited by this paper
• Fibril structure of amyloid-β(1–42) by cryo–electron microscopy

  2017cited by this paper
• Synthesis of Thiophene-Based Optical Ligands That Selectively Detect Tau Pathology in Alzheimer's Disease.

  2017cited by this paper
• Proteopathic Strains and the Heterogeneity of Neurodegenerative Diseases.

  2016cited by this paper
• Structural Variation in Amyloid-β Fibrils from Alzheimer’s Disease Clinical Subtypes

  2016cited by this paper
• Discovery of 6-(Fluoro-(18)F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([(18)F]-MK-6240): A Positron Emission Tomography (PET) Imaging Agent for Quantification of Neurofibrillary Tangles (NFTs).

  2016cited by this paper
• A Palette of Fluorescent Thiophene-Based Ligands for the Identification of Protein Aggregates

  2015cited by this paper
• Distinct Spacing Between Anionic Groups: An Essential Chemical Determinant for Achieving Thiophene-Based Ligands to Distinguish β-Amyloid or Tau Polymorphic Aggregates

  2015cited by this paper
• Smart near-infrared fluorescence probes with donor-acceptor structure for in vivo detection of β-amyloid deposits.

  2014cited by this paper
• Evaluation of molecules based on the electron donor-acceptor architecture as near-infrared β-amyloidal-targeting probes.

  2014cited by this paper
• The Arctic AβPP mutation leads to Alzheimer’s disease pathology with highly variable topographic deposition of differentially truncated Aβ

  2013cited by this paper
• The Structural Basis for Optimal Performance of Oligothiophene-Based Fluorescent Amyloid Ligands: Conformational Flexibility is Essential for Spectral Assignment of a Diversity of Protein Aggregates

  2013cited by this paper
• Molecular structure of β-amyloid fibrils in Alzheimer's disease brain tissue.

  2013cited by this paper
• Self-propagation of pathogenic protein aggregates in neurodegenerative diseases

  2013cited by this paper
• The Arctic amyloid-β precursor protein (AβPP) mutation results in distinct plaques and accumulation of N- and C-truncated Aβ.

  2012cited by this paper
• Low PiB PET retention in presence of pathologic CSF biomarkers in Arctic APP mutation carriers

  2012cited by this paper
• A Highly Selective and Specific PET Tracer for Imaging of Tau Pathologies

  2012cited by this paper
• Clinical Validation of 18F-AZD4694, an Amyloid-β–Specific PET Radioligand

  2012cited by this paper
• Aminonaphthalene 2-cyanoacrylate (ANCA) probes fluorescently discriminate between amyloid-β and prion plaques in brain.

  2012cited by this paper
• ANCA: A Family of Fluorescent Probes that Bind and Stain Amyloid Plaques in Human Tissue.

  2011cited by this paper
• Novel pentameric thiophene derivatives for in vitro and in vivo optical imaging of a plethora of protein aggregates in cerebral amyloidoses.

  2009cited by this paper
• Phase 1 Study of the Pittsburgh Compound B Derivative 18F-Flutemetamol in Healthy Volunteers and Patients with Probable Alzheimer Disease

  2009cited by this paper
• Small organic probes as amyloid specific ligands – Past and recent molecular scaffolds

  2009cited by this paper
• Whole-Body Biodistribution and Radiation Dosimetry of 18F-GE067: A Radioligand for In Vivo Brain Amyloid Imaging

  2009cited by this paper
• Paired β-sheet structure of an Aβ(1-40) amyloid fibril revealed by electron microscopy

  2008cited by this paper
• Self-Propagating, Molecular-Level Polymorphism in Alzheimer's ß-Amyloid Fibrils

  2005cited by this paper
• In vivo optical imaging of amyloid aggregates in brain: design of fluorescent markers.

  2005cited by this paper
• In vivo detection of amyloid-beta deposits by near-infrared imaging using an oxazine-derivative probe.

  2005cited by this paper
• Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound‐B

  2004cited by this paper
• A comparison of amyloid fibrillogenesis using the novel fluorescent compound K114

  2003cited by this paper
• Imaging Aβ Plaques in Living Transgenic Mice with Multiphoton Microscopy and Methoxy‐X04, a Systemically Administered Congo Red Derivative

  2002cited by this paper
• Neurodegenerative tauopathies.

  2001cited by this paper
• Alpha-synuclein and neurodegenerative diseases

  2001cited by this paper
• X-34, A Fluorescent Derivative of Congo Red: A Novel Histochemical Stain for Alzheimer's Disease Pathology

  2000cited by this paper
• Fluorescent stains, with special reference to amyloid and connective tissues.

  1959cited by this paper
• Article Imaging of Tau Pathology in a Tauopathy Mouse Model and in Alzheimer Patients Compared to Normal Controls

  year unknowncited by this paper

• No citing papers are available for this paper.