{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T23:15:47Z","timestamp":1789082147474,"version":"build-2803163510"},"reference-count":22,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation","doi-asserted-by":"publisher","award":["MJFF-024348"],"award-info":[{"award-number":["MJFF-024348"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cells"],"abstract":"<jats:p>The development of positron emission tomography (PET) tracers targeting \u03b1-synuclein (\u03b1-syn) aggregates is critical for the early diagnosis, differential classification, and therapeutic monitoring of synucleinopathies such as Parkinson\u2019s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. Despite recent advances, challenges including the low abundance of \u03b1-syn aggregates (10\u201350\u00d7 lower than amyloid-beta (A\u03b2) or Tau), structural heterogeneity (e.g., flat fibrils in PD vs. cylindrical forms in DLB), co-pathology with A\u03b2\/Tau, and poor metabolic stability have hindered PET tracer development for this target. To optimize our previously reported pyridothiophene-based radiotracer, [18F]asyn-44, we present the synthesis and evaluation of novel S,N-heterocyclic scaffold derivatives for \u03b1-syn. A library of 49 compounds was synthesized, with 8 potent derivatives (LMD-006, LMD-022, LMD-029, LMD-044, LMD-045, LMD-046, LMD-051, and LMD-052) demonstrating equilibrium inhibition constants (Ki) of 6\u201316 nM in PD brain homogenates, all of which are amenable for radiolabeling with fluorine-18. This work advances the molecular toolkit for synucleinopathies and provides a roadmap for overcoming barriers in PET tracer development, with lead compounds that can be considered for biomarker-guided clinical trials and targeted therapies.<\/jats:p>","DOI":"10.3390\/cells14191531","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T14:16:29Z","timestamp":1759241789000},"page":"1531","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Multi-Fused S,N-Heterocyclic Compounds for Targeting \u03b1-Synuclein Aggregates"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2179-8096","authenticated-orcid":false,"given":"Chao","family":"Zheng","sequence":"first","affiliation":[{"name":"MedChem Imaging, Inc., Boston, MA 02210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8871-2544","authenticated-orcid":false,"given":"Jeffrey S.","family":"Stehouwer","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goverdhan Reddy","family":"Ummenthala","sequence":"additional","affiliation":[{"name":"Laxai Life Sciences, Hyderabad, Telangana 500078, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3219-7455","authenticated-orcid":false,"given":"Yogeshkumar S.","family":"Munot","sequence":"additional","affiliation":[{"name":"Laxai Life Sciences, Hyderabad, Telangana 500078, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2087-5125","authenticated-orcid":false,"given":"Neil","family":"Vasdev","sequence":"additional","affiliation":[{"name":"MedChem Imaging, Inc., Boston, MA 02210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/s41419-023-05672-9","article-title":"Alpha-synuclein in Parkinson\u2019s disease and other synucleinopathies: From overt neurodegeneration back to early synaptic dysfunction","volume":"14","author":"Calabresi","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s13024-021-00501-z","article-title":"Neuropathology and molecular diagnosis of Synucleinopathies","volume":"16","author":"Koga","year":"2021","journal-title":"Mol. 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