{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T07:28:57Z","timestamp":1771486137515,"version":"3.50.1"},"reference-count":35,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T00:00:00Z","timestamp":1758499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["NS110456"],"award-info":[{"award-number":["NS110456"]}]},{"name":"National Institutes of Health","award":["NS110436"],"award-info":[{"award-number":["NS110436"]}]},{"name":"PET","award":["NS110456"],"award-info":[{"award-number":["NS110456"]}]},{"name":"PET","award":["NS110436"],"award-info":[{"award-number":["NS110436"]}]},{"name":"Michael J. Fox Foundation for Parkinsons Disease","award":["NS110456"],"award-info":[{"award-number":["NS110456"]}]},{"name":"Michael J. Fox Foundation for Parkinsons Disease","award":["NS110436"],"award-info":[{"award-number":["NS110436"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) and Lewy Body Dementia (LBD) are defined by accumulation of alpha-synuclein (Asyn) fibrils within Lewy bodies (LBs) and Lewy neurites (LNs). The development of a Positron Emission Tomography (PET) tracer for quantifying Asyn fibrils would improve diagnostic accuracy and provide a biomarker for disease progression. We previously described radioligand [3H]Tg-1-90B, which binds to in vitro Asyn fibrils (PDB 2N0A) via interactions with residues Y39, S42 and K44. Here, we performed molecular docking studies with Tg1-90B and PD\/LBD Asyn fibrils (PDB 8A9L), which predicts interactions with residues Y39 and K43 in a structurally distinct binding site. In radioligand binding assays, Tg-1-90B has moderate to high affinity (Kd 17.5 nM) for amplified LBD fibrils (PDB 8FPT), whose protofilament fold is highly similar to PD\/LBD fibrils (PBD 8A9L). Autoradiography confirmed binding of [3H]Tg-1-90B to LBs in PD brain tissue. However, Tg-1-90B also binds to amyloid-beta fibrils in Alzheimer\u2019s disease (AD) tissue, indicating insufficient selectivity for Asyn fibrils. These results indicate that Tg-1-90B binds to Asyn fibrils in PD tissue but needs further structural optimization. Binding assays with amplified LBD fibrils and autoradiography with postmortem PD tissue can guide further development of Asyn fibril PET ligands for PD\/LBD.<\/jats:p>","DOI":"10.3390\/cells14181477","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T11:18:16Z","timestamp":1758539896000},"page":"1477","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Use of Amplified Lewy Body Dementia Fibrils and Autoradiography to Characterize Binding of Radioligand Tg-1-90B to Alpha-Synuclein Fibrils in Postmortem Brain Tissue"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5492-1847","authenticated-orcid":false,"given":"Jennifer Y.","family":"O\u2019Shea","sequence":"first","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0096-1085","authenticated-orcid":false,"given":"Dhruva D.","family":"Dhavale","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zachary","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas J. A.","family":"Graham","sequence":"additional","affiliation":[{"name":"Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7645-2869","authenticated-orcid":false,"given":"Robert H.","family":"Mach","sequence":"additional","affiliation":[{"name":"Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul T.","family":"Kotzbauer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6469","DOI":"10.1073\/pnas.95.11.6469","article-title":"Alpha-Synuclein in Filamentous Inclusions of Lewy Bodies from Parkinson\u2019s Disease and Dementia with Lewy Bodies","volume":"95","author":"Spillantini","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/42166","article-title":"\u03b1-Synuclein in Lewy Bodies","volume":"388","author":"Spillantini","year":"1997","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/mds.10557","article-title":"Neuropathological Spectrum of Synucleinopathies","volume":"18","author":"Jellinger","year":"2003","journal-title":"Mov. Disord."},{"key":"ref_4","first-page":"879","article-title":"Aggregation of Alpha-Synuclein in Lewy Bodies of Sporadic Parkinson\u2019s Disease and Dementia with Lewy Bodies","volume":"152","author":"Baba","year":"1998","journal-title":"Am. J. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/0896-6273(95)90302-X","article-title":"The Precursor Protein of Non-A Beta Component of Alzheimer\u2019s Disease Amyloid Is a Presynaptic Protein of the Central Nervous System","volume":"14","author":"Iwai","year":"1995","journal-title":"Neuron"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.bbrc.2008.02.127","article-title":"Characterization of Fibrillation Process of \u03b1-Synuclein at the Initial Stage","volume":"369","author":"Tashiro","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7619","DOI":"10.1074\/jbc.274.12.7619","article-title":"Mutant and Wild Type Human Alpha-Synucleins Assemble into Elongated Filaments with Distinct Morphologies In Vitro","volume":"274","author":"Giasson","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1097\/00005072-199603000-00001","article-title":"Neuropathology of Parkinson\u2019s Disease","volume":"55","author":"Forno","year":"1996","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/s41531-022-00357-0","article-title":"Opportunities and Challenges of Alpha-Synuclein as a Potential Biomarker for Parkinson\u2019s Disease and Other Synucleinopathies","volume":"8","author":"Lashuel","year":"2022","journal-title":"npj Park. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1212\/WNL.42.6.1142","article-title":"What Features Improve the Accuracy of Clinical Diagnosis in Parkinson\u2019s Disease: A Clinicopathologic Study","volume":"42","author":"Hughes","year":"1992","journal-title":"Neurology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1136\/jnnp.55.3.181","article-title":"Accuracy of Clinical Diagnosis of Idiopathic Parkinson\u2019s Disease: A Clinico-Pathological Study of 100 Cases","volume":"55","author":"Hughes","year":"1992","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3327","DOI":"10.1016\/j.cell.2023.06.018","article-title":"Toward Imaging of Alpha-Synuclein with PET","volume":"186","author":"Kantarci","year":"2023","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Korat, \u0160., Bidesi, N.S.R., Bonanno, F., Di Nanni, A., Ho\u00e0ng, A.N.N., Herfert, K., Maurer, A., Battisti, U.M., Bowden, G.D., and Thonon, D. (2021). Alpha-Synuclein PET Tracer Development-An Overview about Current Efforts. Pharmaceuticals, 14.","DOI":"10.3390\/ph14090847"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3350","DOI":"10.1016\/j.cell.2023.06.004","article-title":"Development of an \u03b1-Synuclein Positron Emission Tomography Tracer for Imaging Synucleinopathies","volume":"186","author":"Xiang","year":"2023","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2521","DOI":"10.1021\/acschemneuro.8b00177","article-title":"Alpha Synuclein Fibrils Contain Multiple Binding Sites for Small Molecules","volume":"9","author":"Hsieh","year":"2018","journal-title":"ACS Chem. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Bagchi, D.P., Yu, L., Perlmutter, J.S., Xu, J., Mach, R.H., Tu, Z., and Kotzbauer, P.T. (2013). Binding of the Radioligand SIL23 to \u03b1-Synuclein Fibrils in Parkinson Disease Brain Tissue Establishes Feasibility and Screening Approaches for Developing a Parkinson Disease Imaging Agent. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0055031"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e48907","DOI":"10.7554\/eLife.48907","article-title":"Two New Polymorphic Structures of Human Full-Length Alpha-Synuclein Fibrils Solved by Cryo-Electron Microscopy","volume":"8","author":"Taylor","year":"2019","journal-title":"eLife"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e36402","DOI":"10.7554\/eLife.36402","article-title":"Cryo-EM Structure of Alpha-Synuclein Fibrils","volume":"7","author":"Taylor","year":"2018","journal-title":"eLife"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.conb.2020.01.014","article-title":"New Insights on the Structure of Alpha-Synuclein Fibrils Using Cryo-Electron Microscopy","volume":"61","author":"Kovacik","year":"2020","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1038\/s41586-022-05319-3","article-title":"Structures of \u03b1-Synuclein Filaments from Human Brains with Lewy Pathology","volume":"610","author":"Yang","year":"2022","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2750","DOI":"10.1038\/s41467-024-46832-5","article-title":"Structure of Alpha-Synuclein Fibrils Derived from Human Lewy Body Dementia Tissue","volume":"15","author":"Dhavale","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/nsmb.3194","article-title":"Solid-State NMR Structure of a Pathogenic Fibril of Full-Length Human \u03b1-Synuclein","volume":"23","author":"Tuttle","year":"2016","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3891","DOI":"10.1021\/acs.jcim.1c00203","article-title":"AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings","volume":"61","author":"Eberhardt","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.jsb.2017.02.003","article-title":"Helical Reconstruction in RELION","volume":"198","author":"He","year":"2017","journal-title":"J. Struct. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1002\/acn3.51482","article-title":"Quantifying Regional \u03b1 -Synuclein, Amyloid \u03b2, and Tau Accumulation in Lewy Body Dementia","volume":"9","author":"Miller","year":"2022","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.ejphar.2009.06.042","article-title":"In Vitro Characterisation of BF227 Binding to \u03b1-Synuclein\/Lewy Bodies","volume":"617","author":"Mulligan","year":"2009","journal-title":"Eur. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1002\/cmdc.201900689","article-title":"(11) C Radiolabeling of Anle253b: A Putative PET Tracer for Parkinson\u2019s Disease That Binds to \u03b1-Synuclein Fibrils in\u2005Vitro and Crosses the Blood-Brain Barrier","volume":"15","author":"Maurer","year":"2020","journal-title":"ChemMedChem"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1007\/s00259-020-05133-x","article-title":"[11C]MODAG-001\u2014Towards a PET Tracer Targeting \u03b1-Synuclein Aggregates","volume":"48","author":"Kuebler","year":"2021","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6750","DOI":"10.1038\/s41467-023-42305-3","article-title":"The \u03b1-Synuclein PET Tracer [18F] ACI-12589 Distinguishes Multiple System Atrophy from Other Neurodegenerative Diseases","volume":"14","author":"Smith","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"147131","DOI":"10.1016\/j.brainres.2020.147131","article-title":"Identification and in Vitro Characterization of C05-01, a PBB3 Derivative with Improved Affinity for Alpha-Synuclein","volume":"1749","author":"Svedberg","year":"2020","journal-title":"Brain Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1039\/D5MD00057B","article-title":"The Development of a PET Radiotracer for Imaging Alpha Synuclein Aggregates in Parkinson\u2019s Disease","volume":"16","author":"Tian","year":"2025","journal-title":"RSC Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-024-00787-9","article-title":"Positron Emission Tomography Tracers for Synucleinopathies","volume":"20","author":"Xiang","year":"2025","journal-title":"Mol. Neurodegener."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7.5.1","DOI":"10.1002\/0471142301.ns0705s52","article-title":"Analyzing Binding Data","volume":"52","author":"Motulsky","year":"2010","journal-title":"Curr. Protoc. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e43584","DOI":"10.7554\/eLife.43584","article-title":"Heparin-Induced Tau Filaments Are Polymorphic and Differ from Those in Alzheimer\u2019s and Pick\u2019s Diseases","volume":"8","author":"Zhang","year":"2019","journal-title":"eLife"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/nature23002","article-title":"Cryo-EM Structures of Tau Filaments from Alzheimer\u2019s Disease","volume":"547","author":"Fitzpatrick","year":"2017","journal-title":"Nature"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/18\/1477\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:46:59Z","timestamp":1760035619000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/18\/1477"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,22]]},"references-count":35,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["cells14181477"],"URL":"https:\/\/doi.org\/10.3390\/cells14181477","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,22]]}}}