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Herein, the fibril interactions of two candidate positron emission tomography (PET) imaging ligands, M503 and HY\u2010215, being developed for imaging of PD\/DLB and MSA, respectively, are investigated. Photo\u2010crosslinking mass spectrometry is used to determine the sites of their binding to in\u2009vitro fibrils, and F\u00f6rster resonance energy transfer with fluorescently labeled proteins is used to analyze conformational changes in the disordered \u03b1S C\u2010terminus. Taken together, these studies show that the MSA\u2010selective PET lead, HY\u2010215, interacts with the C\u2010terminus, unlike the PD\u2010selective lead M503. This study indicates that interactions with the often\u2010ignored disordered regions of \u03b1S fibrils should be considered in the development of PET probes and other therapeutic small molecules.<\/jats:p>","DOI":"10.1002\/cbic.202500578","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T01:15:03Z","timestamp":1760404503000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Interactions of Neurodegenerative Disease Positron Emission Tomography Imaging Probe Candidates with the C\u2010Terminus of \u03b1\u2010Synuclein Fibrils"],"prefix":"10.1002","volume":"26","author":[{"given":"Kyle D.","family":"Shaffer","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Pennsylvania  231 S. 34th Street Philadelphia PA 19104 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryann M.","family":"Perez","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Pennsylvania  231 S. 34th Street Philadelphia PA 19104 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marshall G.","family":"Lougee","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Pennsylvania  231 S. 34th Street Philadelphia PA 19104 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinayak V.","family":"Pagar","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Pennsylvania  231 S. 34th Street Philadelphia PA 19104 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee Jong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics University of Pennsylvania  3620 Hamilton Walk Philadelphia PA 19104 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ho Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Radiology University of Pennsylvania  3400 Spruce Street Philadelphia PA 19104 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin A.","family":"Garcia","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics University of Pennsylvania  3620 Hamilton Walk Philadelphia PA 19104 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H.","family":"Mach","sequence":"additional","affiliation":[{"name":"Department of Radiology University of Pennsylvania  3400 Spruce Street Philadelphia PA 19104 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3854-9210","authenticated-orcid":false,"given":"E. 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