In several neurodegenerative diseases, the presence of aggregates of specific proteins in the brain is a significant pathological hallmark; thus, developing ligands able to bind to the aggregated proteins is essential for any effort related to imaging and therapeutics. Here we report the synthesis of thiophene‐based ligands containing nitrogen heterocycles. The ligands selectively recognized amyloid‐β (Aβ) aggregates in brain tissue from individuals diagnosed neuropathologically as having Alzheimer's disease (AD). The selectivity for Aβ was dependent on the position of nitrogen in the heterocyclic compounds, and the ability to bind Aβ was shown to be reduced when introducing anionic substituents on the thiophene backbone. Our findings provide the structural and functional basis for the development of ligands that can differentiate between aggregated proteinaceous species comprised of distinct proteins. These ligands might also be powerful tools for studying the pathogenesis of Aβ aggregation and for designing molecules for imaging of Aβ pathology. Molecular matchmaking: Ligands MK‐6240 and b‐TVBT2 are selective for aggregated tau in Alzheimer's disease (AD). When combining the azaindole moiety of MK‐6240 with the methyl‐bithiophene‐carboxylate unit of b‐TVBT2, the resulting ligand, termed HS‐276, does not show binding to tau but instead high selectivity for Aβ aggregates in AD brain tissue. By introducing small structural alterations of the HS‐276 scaffold, the binding properties change.