{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T23:16:48Z","timestamp":1789082208753,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T00:00:00Z","timestamp":1752796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NINDS","award":["NS061025"],"award-info":[{"award-number":["NS061025"]}]},{"name":"NIH\/NINDS","award":["NS134586"],"award-info":[{"award-number":["NS134586"]}]},{"name":"NIH\/NINDS","award":["NS103988"],"award-info":[{"award-number":["NS103988"]}]},{"name":"NIH\/NINDS","award":["NS075527"],"award-info":[{"award-number":["NS075527"]}]},{"name":"NIH\/NINDS","award":["U19NS110456"],"award-info":[{"award-number":["U19NS110456"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The fibrillary aggregation of \u03b1-synuclein is a hallmark of Parkinson\u2019s disease (PD) and a potential target for diagnostics and therapeutics. Although substantial effort has been devoted to the development of positron emission tomography (PET) probes for detecting \u03b1-synuclein aggregates, no clinically suitable tracer has been reported. The design and synthesis of 43 new N-(6-methoxypyridin-3-yl)quinolin-2-amine derivatives and an evaluation of their \u03b1-synuclein binding affinity is reported here. Compounds 7f, 7j, and 8i exhibited high affinity for \u03b1-synuclein and were selected for 11C, 18F, 125I, or 3H radiolabeling. A photoaffinity variant, TZ-CLX, structurally related to 7j and 8i, demonstrated preferential binding to the C-terminal region of \u03b1-synuclein fibrils. PET brain imaging studies using [11C]7f, [18F]7j, and [11C]8i in non-human primates indicated that these three \u03b1-synuclein PET tracers penetrated the blood\u2013brain barrier. Both [11C]7f and [18F]7j showed more favorable brain washout pharmacokinetics than [11C]8i. In vitro binding assays showed that [125I]8i is a very potent \u03b1-synuclein radioligand, with Kd values of 5 nM for both PD brain tissues and LBD-amplified fibrils; it is also selective for PD tissues versus AD or control tissues. These results strongly suggest that the PET probes based on the N-(6-methoxypyridin-3-yl)quinoline-2-amine scaffold have potential utility in detecting \u03b1-synuclein aggregates in vivo.<\/jats:p>","DOI":"10.3390\/cells14141108","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T15:35:51Z","timestamp":1752852951000},"page":"1108","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Discovery of N-(6-Methoxypyridin-3-yl)quinoline-2-amine Derivatives for Imaging Aggregated \u03b1-Synuclein in Parkinson\u2019s Disease with Positron Emission Tomography"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3167-6479","authenticated-orcid":false,"given":"Haiyang","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5607-4901","authenticated-orcid":false,"given":"Tianyu","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhruva D.","family":"Dhavale","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer Y.","family":"O\u2019Shea","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsofia","family":"Lengyel-Zhand","sequence":"additional","affiliation":[{"name":"Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3841-1825","authenticated-orcid":false,"given":"Dinahlee Saturnino","family":"Guarino","sequence":"additional","affiliation":[{"name":"Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4908-7544","authenticated-orcid":false,"given":"Jiwei","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3783-6392","authenticated-orcid":false,"given":"Xuyi","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6634-8785","authenticated-orcid":false,"given":"Ying-Hwey","family":"Nai","sequence":"additional","affiliation":[{"name":"Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marshall G.","family":"Lougee","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinayak V.","family":"Pagar","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee Jong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin A.","family":"Garcia","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3854-9210","authenticated-orcid":false,"given":"E. James","family":"Petersson","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9811-0950","authenticated-orcid":false,"given":"Chester A.","family":"Mathis","sequence":"additional","affiliation":[{"name":"Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul T.","family":"Kotzbauer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel S.","family":"Perlmutter","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhude","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lamptey, R.N.L., Chaulagain, B., Trivedi, R., Gothwal, A., Layek, B., and Singh, J. 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