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Development of positron emission tomography (PET) radiotracers to image \u03b1\u2010syn aggregates has been a longstanding goal. This work explores the suitability of a pyridothiophene scaffold for \u03b1\u2010syn PET radiotracers, where 47 derivatives of a potent pyridothiophene (asyn\u201044; K<jats:sub>d<\/jats:sub>=1.85\u2005nM) were synthesized and screened against [<jats:sup>3<\/jats:sup>H]asyn\u201044 in competitive binding assays using post\u2010mortem PD brain homogenates. Equilibrium inhibition constant (K<jats:sub>i<\/jats:sub>) values of the most potent compounds were determined, of which three had K<jats:sub>i<\/jats:sub>\u2032s in the lower nanomolar range (12\u201315\u2005nM). An autoradiography study confirmed that [<jats:sup>3<\/jats:sup>H]asyn\u201044 is promising for imaging brain sections from multiple system atrophy and PD donors. Fluorine\u201018 labelled asyn\u201044 was synthesized in 6\u00b12\u2009% radiochemical yield (decay\u2010corrected, n=5) with a molar activity of 263\u00b1121 GBq\/\u03bcmol. Preliminary PET imaging of [<jats:sup>18<\/jats:sup>F]asyn\u201044 in rats showed high initial brain uptake (&gt;1.5 standardized uptake value (SUV)), moderate washout (~0.4 SUV at 60\u2005min), and low variability. Radiometabolite analysis showed 60\u201380\u2009% parent tracer in the brain after 30 and 60\u2005mins. While [<jats:sup>18<\/jats:sup>F]asyn\u201044 displayed good <jats:italic>in\u2005vitro<\/jats:italic> properties and acceptable brain uptake, troublesome radiometabolites precluded further PET imaging studies. The synthesis and <jats:italic>in\u2005vitro<\/jats:italic> evaluation of additional pyridothiophene derivatives are underway, with the goal of attaining improved affinity and metabolic stability.<\/jats:p>","DOI":"10.1002\/chem.202303921","type":"journal-article","created":{"date-parts":[[2024,2,14]],"date-time":"2024-02-14T14:38:54Z","timestamp":1707921534000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Development of Pyridothiophene Compounds for PET Imaging of \u03b1\u2010Synuclein"],"prefix":"10.1002","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8207-3358","authenticated-orcid":false,"given":"Anna","family":"Pees","sequence":"first","affiliation":[{"name":"Azrieli Centre for Neuro-Radiochemistry Brain Health Imaging Centre Campbell Family Mental Health Research Institute Centre for Addiction and Mental Health (CAMH)  Toronto ON M5T 1R8 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junchao","family":"Tong","sequence":"additional","affiliation":[{"name":"Azrieli Centre for Neuro-Radiochemistry Brain Health Imaging Centre Campbell Family Mental Health Research Institute Centre for Addiction and Mental Health (CAMH)  Toronto ON M5T 1R8 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saritha","family":"Birudaraju","sequence":"additional","affiliation":[{"name":"Sai Life Sciences Ltd.  Hyderabad Telangana India- 500078"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yogeshkumar S.","family":"Munot","sequence":"additional","affiliation":[{"name":"Sai Life Sciences Ltd.  Hyderabad Telangana India- 500078"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven H.","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Radiology and Imaging Sciences Emory University  Atlanta Georgia 30322 United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dinahlee","family":"Saturnino Guarino","sequence":"additional","affiliation":[{"name":"Department of Radiology Perelman School of Medicine University of Pennsylvania  1012, 231 S.\u200534th Street Philadelphia Pennsylvania 19104-6323 United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert H.","family":"Mach","sequence":"additional","affiliation":[{"name":"Department of Radiology Perelman School of Medicine University of Pennsylvania  1012, 231 S.\u200534th Street Philadelphia Pennsylvania 19104-6323 United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9811-0950","authenticated-orcid":false,"given":"Chester A.","family":"Mathis","sequence":"additional","affiliation":[{"name":"Department of Radiology University of Pittsburgh  Pittsburgh Pennsylvania 15213 United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2087-5125","authenticated-orcid":false,"given":"Neil","family":"Vasdev","sequence":"additional","affiliation":[{"name":"Azrieli Centre for Neuro-Radiochemistry Brain Health Imaging Centre Campbell Family Mental Health Research Institute Centre for Addiction and Mental Health (CAMH)  Toronto ON M5T 1R8 Canada"},{"name":"Department of Psychiatry University of Toronto  Toronto ON M5T-1R8 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,3,8]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201900689"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2019.134316"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.semnuclmed.2017.06.003"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph14090847"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40336-016-0217-4"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-022-11267-9"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2022.105422"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nucmedbio.2022.04.001"},{"key":"e_1_2_8_9_1","volume":"08","author":"Irwin D. 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