{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T05:01:35Z","timestamp":1784523695832,"version":"3.55.0"},"reference-count":20,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["U19-NS110456"],"award-info":[{"award-number":["U19-NS110456"]}]},{"name":"NIH","award":["P30AG072979"],"award-info":[{"award-number":["P30AG072979"]}]},{"name":"NIH","award":["P01AG066597"],"award-info":[{"award-number":["P01AG066597"]}]},{"name":"NIH","award":["P01AG084497"],"award-info":[{"award-number":["P01AG084497"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>A previous study identified [11C]M503-1619 as a lead compound for positron emission tomography (PET) radiotracer development. The goal of the current study was to conduct a structure\u2013activity relationship (SAR) study on M503-1619 to improve its in vitro binding affinity for alpha synuclein (aSyn), as well as to identify potential radiotracers that could be labeled with fluorine-18. The results of the SAR study identified strict SARs regarding the introduction of a fluorine into the N-aryl piperazine and benzamide moieties. The most promising compound was the corresponding 2-fluoroethyl analog of M503-1619. This compound was radiolabeled with fluorine-18, followed by in vivo PET imaging studies on non-human primate and in vitro autoradiography study. In vitro autoradiography studies in human postmortem brain sections demonstrated that 18F-labeled radiotracer has higher binding to synucleinopathies versus control brain tissues. This radiotracer displays the high initial brain uptake and rapid washout that is needed for a PET radiotracer for imaging a protein such as aSyn that has a low target density in the brain. However, the formation of brain penetrant radiolabeled metabolites prevented further evaluation of this compound. Insights from this SAR study are guiding the development of novel aSyn radioligands that avoid formation of the undesirable radiolabeled metabolite.<\/jats:p>","DOI":"10.3390\/molecules31142513","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T02:32:08Z","timestamp":1784514728000},"page":"2513","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Structure\u2013Activity Relationship Study of Alpha Synuclein PET Radiotracer M503-1619"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3877-2917","authenticated-orcid":false,"given":"Gui-Long","family":"Tian","sequence":"first","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\/0000-0002-2833-7727","authenticated-orcid":false,"given":"Chia-Ju","family":"Hsieh","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","family":"Saturnino Guarino","sequence":"additional","affiliation":[{"name":"Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, 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"}]},{"given":"Wai Kit","family":"Chia","sequence":"additional","affiliation":[{"name":"Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shihong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8905-8492","authenticated-orcid":false,"given":"Catherine","family":"Hou","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\/0000-0001-9082-8618","authenticated-orcid":false,"given":"Hsiaoju","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"Young","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\/0000-0003-3854-9210","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\/0000-0002-7645-2869","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"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"key":"ref_1","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. 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