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In this multi-tau tracer study, we focused on the new second-generation tau PET tracers PI2620, MK6240 and RO948 to investigate this tau complexity in AD, CBD, and PSP brains using post-mortem radioligand binding studies and autoradiography of large and small frozen brain sections. Saturation binding studies indicated multiple binding sites for\n                    <jats:sup>3<\/jats:sup>\n                    H-PI2620 in AD, CBD and PSP brains with different binding affinities (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>d<\/jats:sub>\n                    ranging from 0.2 to 0.7\u2009nM) and binding site densities (following the order:\n                    <jats:italic>B<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    AD\u2009&gt;\u2009\n                    <jats:italic>B<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    CBD\u2009&gt;\u2009\n                    <jats:italic>B<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    PSP). Competitive binding studies complemented these findings, demonstrating the presence of two binding sites [super-high affinity (SHA): IC\n                    <jats:sub>50(1)<\/jats:sub>\n                    = 8.1 pM; and high affinity (HA): IC\n                    <jats:sub>50(2)<\/jats:sub>\n                    = 4.9\u2009nM] in AD brains. Regional binding distribution studies showed that\n                    <jats:sup>3<\/jats:sup>\n                    H-PI2620 could discriminate between AD (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20096) and control cases (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20099), especially in frontal cortex and temporal cortex tissue (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001) as well as in the hippocampal region (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.02).\n                    <jats:sup>3<\/jats:sup>\n                    H-PI2620,\n                    <jats:sup>3<\/jats:sup>\n                    H-MK6240 and\n                    <jats:sup>3<\/jats:sup>\n                    H-RO948 displayed similar binding behaviour in AD brains (in both homogenate competitive studies and one large frozen hemispherical brain section autoradiography studies) in terms of binding affinities, number of sites and regional patterns. Our small section autoradiography studies in the frontal cortex of CBD (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20093) and PSP brains (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20092) showed high specificity for\n                    <jats:sup>3<\/jats:sup>\n                    H-PI2620 but not for\n                    <jats:sup>3<\/jats:sup>\n                    H-MK6240 or\n                    <jats:sup>3<\/jats:sup>\n                    H-RO948. Our findings clearly demonstrate different binding properties among the second-generation tau PET tracers, which may assist in further understanding of tau heterogeneity in AD versus non-AD tauopathies and suggests potential for development of pure selective 4R tau PET tracers.\n                  <\/jats:p>","DOI":"10.1038\/s41380-022-01875-2","type":"journal-article","created":{"date-parts":[[2022,11,29]],"date-time":"2022-11-29T09:05:28Z","timestamp":1669712728000},"page":"1272-1283","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["Discriminative binding of tau PET tracers PI2620, MK6240 and RO948 in Alzheimer\u2019s disease, corticobasal degeneration and progressive supranuclear palsy brains"],"prefix":"10.1038","volume":"28","author":[{"given":"Mona-Lisa","family":"Malarte","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per-G\u00f6ran","family":"Gillberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7669-0712","authenticated-orcid":false,"given":"Amit","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6092-2515","authenticated-orcid":false,"given":"Nenad","family":"Bogdanovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"La\u00ebtitia","family":"Lemoine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7345-5151","authenticated-orcid":false,"given":"Agneta","family":"Nordberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,29]]},"reference":[{"key":"1875_CR1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/nrn.2015.1","volume":"17","author":"Y Wang","year":"2016","unstructured":"Wang Y, Mandelkow E. 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All experiments on autopsied human brain tissue were carried out in accordance with ethical permission obtained from the regional human ethics committee in Stockholm (permission numbers 2011\/962\/31-1, 2006\/901-31\/3 and 2017\/2301-32), and the medical ethics committee of the VU Medical Center for the Netherlands Brain Bank tissue (permission number 1998-06\/5), Indiana University Institutional Review Board, USA.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Previous consent to carry out experiments was given at the time of brain donation, and no supplementary consent was needed for this study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participation"}},{"value":"Previous consent to publish the results of experiments was given at the time of brain donation, and no supplementary consent was needed for this study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}}]}}