{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T18:07:43Z","timestamp":1782497263502,"version":"3.54.5"},"reference-count":23,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T00:00:00Z","timestamp":1749427200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Michael J Fox Foundation for Parkinson Research","award":["10908"],"award-info":[{"award-number":["10908"]}]},{"name":"Michael J Fox Foundation for Parkinson Research","award":["1268\/20"],"award-info":[{"award-number":["1268\/20"]}]},{"name":"Michael J Fox Foundation for Parkinson Research","award":["U19-NS110456"],"award-info":[{"award-number":["U19-NS110456"]}]},{"name":"Swedish Parkinson Foundation (Parkinsonfonden)","award":["10908"],"award-info":[{"award-number":["10908"]}]},{"name":"Swedish Parkinson Foundation (Parkinsonfonden)","award":["1268\/20"],"award-info":[{"award-number":["1268\/20"]}]},{"name":"Swedish Parkinson Foundation (Parkinsonfonden)","award":["U19-NS110456"],"award-info":[{"award-number":["U19-NS110456"]}]},{"name":"NIH","award":["10908"],"award-info":[{"award-number":["10908"]}]},{"name":"NIH","award":["1268\/20"],"award-info":[{"award-number":["1268\/20"]}]},{"name":"NIH","award":["U19-NS110456"],"award-info":[{"award-number":["U19-NS110456"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The molecular imaging of \u03b1-synuclein (\u03b1-syn) pathology in Parkinson\u2019s disease (PD) and related movement disorders is a clinically unmet need. The aim of this study was to discover and characterize in vitro a radioligand for imaging \u03b1-syn pathology. A library of 78 small molecules was developed and screened using recombinant \u03b1-syn fibrils and brain homogenates from Alzheimer\u2019s disease (AD) donors. The selection criteria were as follows: Ki\u03b1-syn &lt; 30 nM, Kitau and KiA-\u03b2 &gt; 200 nM. Three compounds, GMC-073 (Ki\u03b1-syn: 8 nM), GMC-098 (Ki\u03b1-syn: 9.7 nM), and GMC-058 (Ki\u03b1-syn: 22.5 nM), fulfilled the criteria and were radiolabeled with 3H. [3H]GMC-058 was the only compound with negligible binding in controls, and was further evaluated using tissue microarrays, autoradiography on fresh-frozen brain slices, and in vitro saturation binding assay on brain homogenates. [3H]GMC-058 binding co-localized with \u03b1-syn inclusions in Parkinson\u2019s disease (PD) and multiple-system atrophy (MSA), with dense A-\u03b2 plaques in cerebral amyloid angiopathy and AD and with p-tau inclusions in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Specific binding was highest in PSP and CBD. In vitro KD was highest in AD (5.4 nM), followed by PSP (41 nM) and CBD (75 nM). The KD in MSA, PD, and controls was &gt;100 nM. [3H]GMC-058 is a novel radioligand displaying a low affinity for aggregated \u03b1-syn in tissue, with an in vitro profile also suitable for detecting tau pathology in 4R tauopathies.<\/jats:p>","DOI":"10.3390\/cells14120869","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T09:13:01Z","timestamp":1749460381000},"page":"869","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Development and In Vitro Characterization of [3H]GMC-058 as Radioligand for Imaging Parkinsonian-Related Proteinopathies"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8281-4435","authenticated-orcid":false,"given":"Andrea","family":"Varrone","sequence":"first","affiliation":[{"name":"Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm Health Services, BioClinicum, J4-14, Akademiska Str\u00e5ket 1, 17176 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0086-6168","authenticated-orcid":false,"given":"Vasco C.","family":"Sousa","sequence":"additional","affiliation":[{"name":"Department of Clinical Neuroscience, Division of Imaging Core Facilities, Karolinska Institutet, Stockholm, Sweden, BioClinicum, J5, Akademiska Str\u00e5ket 1, 17176 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manolo","family":"Mugnaini","sequence":"additional","affiliation":[{"name":"Translational Sciences, Neuroscience & Ophthalmology Discovery Research, AbbVie Deutschland GmbH & Co. KG, Knollstra\u00dfe 50, 67061 Ludwigshafen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Biesinger","sequence":"additional","affiliation":[{"name":"Advanced Cell Technologies & Screening, Neuroscience & Ophthalmology Discovery Research, AbbVie Deutschland GmbH & Co. KG, Knollstra\u00dfe 50, 67061 Ludwigshafen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1811-2823","authenticated-orcid":false,"given":"Gunnar","family":"Nordvall","sequence":"additional","affiliation":[{"name":"AlzeCure Pharma AB, H\u00e4lsov\u00e4gen 7, 14157 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee","family":"Kingston","sequence":"additional","affiliation":[{"name":"Isotope Chemistry, Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Pepparedsleden 1, 43183 M\u00f6lndal, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ileana","family":"Guzzetti","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, RIA, Biosciences R&D, AstraZeneca, Pepparedsleden 1, 43183 M\u00f6lndal, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7434-8307","authenticated-orcid":false,"given":"Charles S.","family":"Elmore","sequence":"additional","affiliation":[{"name":"Isotope Chemistry, Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Pepparedsleden 1, 43183 M\u00f6lndal, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6084-2678","authenticated-orcid":false,"given":"Dan","family":"Sunnemark","sequence":"additional","affiliation":[{"name":"Offspring Biosciences, Forskargatan 20 J, 15136 S\u00f6dert\u00e4lje, Sweden"},{"name":"Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, 17176 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinahlee","family":"Saturnino Guarino","sequence":"additional","affiliation":[{"name":"Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 1012, 231 S. 34th Street, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4972-3627","authenticated-orcid":false,"given":"Sjoerd J.","family":"Finnema","sequence":"additional","affiliation":[{"name":"Translational Sciences, Neuroscience & Ophthalmology Discovery Research, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magnus","family":"Schou","sequence":"additional","affiliation":[{"name":"Precision Medicine Diagnostic Development and HBS Science, AstraZeneca R&D Oncology, AstraZeneca J4:14, BioClinicum, Akademiska Str\u00e5ket 1, 17176 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S62","DOI":"10.1016\/S1353-8020(13)70017-8","article-title":"\u03b1-Synucleinopathy phenotypes","volume":"20","author":"McCann","year":"2014","journal-title":"Parkinsonism Relat. 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