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This study aimed to develop and compare bispecific anti-TREM2 antibodies featuring different transferrin receptor (TfR) binders to enhance brain delivery, identifying the most suitable format for in vivo PET imaging of TREM2 in transgenic AD mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Three bispecific TREM2-antibody formats were produced and evaluated for their ability to cross the blood-brain barrier (BBB) via TfR-mediated transcytosis and bind TREM2. Blood concentration profiles up to 72\u00a0h post-injection (p.i.), and ex vivo brain uptake of iodine-125-labeled antibody constructs were quantified in App<jats:sup>NL\u2212G\u2212F<\/jats:sup> and age-matched wild type (WT) mice using a \u03b3-counter. The best-performing bispecific TREM2-antibody was radiolabeled with iodine-124 and used for in vivo PET imaging of brain TREM2 levels in App<jats:sup>NL\u2212G\u2212F<\/jats:sup> mice at 72\u00a0h p.i. Brain TREM2 concentrations were subsequently quantified using ELISA.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>The antibody format carrying two scFv8D3 TfR-binders (IgG-scFv<jats:sub>2<\/jats:sub>), demonstrated the highest brain concentrations of all tested bispecific constructs. This antibody also exhibited significantly higher brain concentrations in App<jats:sup>NL\u2212G\u2212F<\/jats:sup> mice compared to WT mice at both 48 and 72\u00a0h p.i. This difference was further visualized and quantified through in vivo PET imaging. Moreover, brain concentrations of the antibody ligand correlated with elevated TREM2 levels in brain homogenates.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>These findings highlight IgG-scFv<jats:sub>2<\/jats:sub> as a promising radioligand for in vivo PET imaging of TREM2, advancing non-invasive neuroinflammation studies and supporting drug development for AD and other neurodegenerative diseases.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s00259-025-07358-0","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T06:15:54Z","timestamp":1748412954000},"page":"4320-4333","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["PET imaging of TREM2 in amyloid-beta induced neuroinflammation"],"prefix":"10.1007","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5765-1002","authenticated-orcid":false,"given":"Amelia D","family":"Dahl\u00e9n","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0339-831X","authenticated-orcid":false,"given":"Sahar","family":"Roshanbin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7601-8862","authenticated-orcid":false,"given":"Ximena","family":"Aguilar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2832-0732","authenticated-orcid":false,"given":"Nadja M","family":"Bucher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3874-6962","authenticated-orcid":false,"given":"Sara","family":"Lopes van den Broek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9430-3859","authenticated-orcid":false,"given":"Dag","family":"Sehlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8196-4041","authenticated-orcid":false,"given":"Stina","family":"Syv\u00e4nen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,28]]},"reference":[{"key":"7358_CR1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2022.2793","author":"S Shcherbinin","year":"2022","unstructured":"Shcherbinin S, Evans CD, Lu M, Andersen SW, Pontecorvo MJ, Willis BA, et al. 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