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However, the vast majority of reported TSPO PET tracers display low binding affinity to a common isoform of human TSPO (<jats:italic>rs6971<\/jats:italic>; A147T), making them unsuitable for universal use in the general population. In this study, we have developed and preclinically validated two novel tracers designed to image TSPO in patients of all genotypes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Novel analogues of known TSPO ligands were synthesised, evaluated for TSPO binding affinity in vitro (membranes prepared from transfected HEK-293T cells expressing wild-type (WT) or A147T TSPO) and radiolabelled with carbon-11 or fluorine-18. They were evaluated in situ (autoradiography on genotyped human brain tissue) and in vivo (rat, both WT and clinically relevant experimental autoimmune encephalomyelitis (EAE) neuroinflammation model) as potential polymorphism-insensitive TSPO PET tracers.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Two new TSPO ligands, DPA-813 and DPA-814, displayed equivalent single-digit nanomolar binding affinities in vitro towards both human TSPO isoforms. [<jats:sup>11<\/jats:sup>C]DPA-813 and [<jats:sup>18<\/jats:sup>F]DPA-814 were synthesised in moderate radiochemical yields, high radiochemical purity, and high molar activity. Autoradiography on human MS tissues showed high specific binding for both tracers, irrespective of the TSPO isoform. The tracers demonstrated high plasma stability after 45\u00a0min and no brain metabolism with &gt;\u200999% intact tracer. Biodistribution in WT animals indicated good brain uptake for both tracers (0.28 and 0.41%ID\/g for [<jats:sup>18<\/jats:sup>F]DPA-814 and [<jats:sup>11<\/jats:sup>C]DPA-813, respectively). PET imaging in the clinically relevant EAE neuroinflammation model in rats showed significantly higher uptake of [<jats:sup>11<\/jats:sup>C]DPA-813 and [<jats:sup>18<\/jats:sup>F]DPA-814 in the spinal cord of the EAE rats compared to the controls.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>We have developed two novel PET tracers that display indiscriminately high binding affinity to both common isoforms of human TSPO, show favourable metabolic stability and brain penetration in rats, and significantly higher uptake in the spinal cord of a neuroinflammatory rat model of multiple sclerosis. Going forward, first-in-human clinical validation will mark a critical juncture in the development of these tracers, which could offer substantial improvements over existing imaging tools for detecting neuroinflammation, irrespective of genetic variations.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s00259-025-07109-1","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T10:34:23Z","timestamp":1738751663000},"page":"2658-2670","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Development and evaluation of [11C]DPA-813 and [18F]DPA-814: novel TSPO PET tracers insensitive to human single nucleotide polymorphism rs6971"],"prefix":"10.1007","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2216-4439","authenticated-orcid":false,"given":"Wissam","family":"Beaino","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"JM Kooijman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6224-1286","authenticated-orcid":false,"given":"Eryn L.","family":"Werry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rens J.","family":"Vellinga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Van den Hoek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3065-4983","authenticated-orcid":false,"given":"Greta","family":"Sohler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3723-9114","authenticated-orcid":false,"given":"Grace A.","family":"Cumbers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4381-7268","authenticated-orcid":false,"given":"Elijah","family":"Genetzakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4074-0433","authenticated-orcid":false,"given":"Edward D.","family":"Harvey-Latham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4962-2367","authenticated-orcid":false,"given":"Robert C.","family":"Schuit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6655-0529","authenticated-orcid":false,"given":"Michael","family":"Kassiou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1250-7656","authenticated-orcid":false,"given":"Albert D.","family":"Windhorst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6242-1941","authenticated-orcid":false,"given":"Jonathan J.","family":"Danon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,5]]},"reference":[{"key":"7109_CR1","doi-asserted-by":"publisher","first-page":"20","DOI":"10.5483\/BMBRep.2020.53.1.273","volume":"53","author":"Y Lee","year":"2020","unstructured":"Lee Y, Park Y, Nam H, Lee J-W, Yu S-W. 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