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Herein, we investigate the molecular requirements of thiophene\u2010vinyl\u2010benzothiazole based ligands to detect a specific type of A\u03b2 deposits found in individuals with dominantly inherited Alzheimer's disease caused by the Arctic <jats:italic>APP E693G<\/jats:italic> mutation. The staining of these A\u03b2 deposits was alternated when switching the terminal heterocyclic moiety attached to the thiophene\u2010vinyl\u2010benzothiazole scaffold. The most prevalent staining was observed for ligands having a terminal 3\u2010methyl\u20101H\u2010indazole moiety or a terminal 1,2\u2010dimethoxybenzene moiety, verifying that specific molecular interactions between these ligands and the aggregates were necessary. The synthesis of additional thiophene\u2010vinyl\u2010benzothiazole ligands aided in pinpointing additional crucial chemical determinants, such as positioning of nitrogen atoms and methyl substituents, for achieving optimal staining of A\u03b2 aggregates. When combining the optimized thiophene\u2010vinyl\u2010benzothiazole based ligands with a conventional ligand, CN\u2010PiB, distinct staining patterns were observed for sporadic Alzheimer's disease versus dominantly inherited Alzheimer's disease caused by the Arctic <jats:italic>APP E693G<\/jats:italic> mutation. Our findings provide chemical insights for developing novel ligands that allow for a more precise assignment of A\u03b2 deposits, and might also aid in creating novel agents for clinical imaging of distinct A\u03b2 aggregates in AD.<\/jats:p>","DOI":"10.1002\/open.202400186","type":"journal-article","created":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T08:44:45Z","timestamp":1730969085000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Distinct Chemical Determinants are Essential for Achieving Ligands for Superior Optical Detection of Specific Amyloid\u2010\u03b2 Deposits in Alzheimer's Disease"],"prefix":"10.1002","volume":"13","author":[{"given":"Xiongyu","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Physics, Chemistry and Biology Link\u00f6ping University  SE-581 83 Link\u00f6ping Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamid","family":"Shirani","sequence":"additional","affiliation":[{"name":"Department of Physics, Chemistry and Biology Link\u00f6ping University  SE-581 83 Link\u00f6ping Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben","family":"Vidal","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Indiana University School of Medicine  46202 Indianapolis, Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernardino","family":"Ghetti","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Indiana University School of Medicine  46202 Indianapolis, Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Ingelsson","sequence":"additional","affiliation":[{"name":"Krembil Brain Institute University Health Network  M5T 1\u2005M8 Toronto, Ontario Canada"},{"name":"Tanz Centre for Research in Neurodegenerative Diseases Departments of Medicine and Laboratory Medicine &amp; Pathobiology University of Toronto  M5T 0S8 Toronto, Ontario Canada"},{"name":"Molecular Geriatrics Department of Public Health and Caring Sciences Uppsala University  SE-751 85 Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ther\u00e9se","family":"Klingstedt","sequence":"additional","affiliation":[{"name":"Department of Physics, Chemistry and Biology Link\u00f6ping University  SE-581 83 Link\u00f6ping Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5582-140X","authenticated-orcid":false,"given":"K. 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