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Immuno-PET combines the high affinity and exceptional specificity of monoclonal antibodies with the non-invasive imaging technique positron emission tomography (PET). Its application in neurodegenerative disease brain imaging has been limited due to the marginal uptake across the blood\u2013brain barrier (BBB). The emergence of BBB-shuttle antibodies with enhanced uptake across the BBB extended immuno-PET to brain imaging. We recently reported about specific brain uptake of a bispecific aducanumab mTfR antibody in APP\/PS1 TG mice using <jats:sup>89<\/jats:sup>Zr-immuno-PET. However, a sufficient target-to-background ratio was reached at a relatively late scanning time point of 7\u00a0days post-injection. To investigate if a better target-to-background ratio could be achieved earlier, an aducanumab BBB-shuttle with a mutated Fc region for reduced FcRn affinity was evaluated.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Procedures<\/jats:title>\n                <jats:p>Adu<jats:sup>H310A<\/jats:sup>-8D3 and Adu-8D3 were modified with DFO*-NCS and subsequently radiolabeled with <jats:sup>89<\/jats:sup>Zr. The potential influence of the H310A mutation, modification with DFO*-NCS, and subsequent radiolabeling on the in vitro binding to amyloid-beta and mTfR1 was investigated via amyloid-beta peptide ELISA and FACS analysis using mTfR1 transfected CHO-S cells. Blood kinetics, brain uptake, in vivo PET imaging and target engagement of radiolabeled Adu<jats:sup>H310A<\/jats:sup>-8D3 were evaluated and compared to non-mutated Adu-8D3 in APP\/PS1 TG mice and wild-type animals as controls.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Radiolabeling was performed with sufficient radiochemical yields and radiochemical purity. In vitro binding to amyloid-beta and mTfR1 showed no impairment. [<jats:sup>89<\/jats:sup>Zr]Zr-Adu<jats:sup>H310A<\/jats:sup>-8D3 showed faster blood clearance and earlier differentiation of amyloid-beta-related brain uptake compared to [<jats:sup>89<\/jats:sup>Zr]Zr-Adu-8D3. However, only half of the brain uptake was observed for [<jats:sup>89<\/jats:sup>Zr]Zr-Adu<jats:sup>H310A<\/jats:sup>-8D3.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Although a faster blood clearance of Adu<jats:sup>H310A<\/jats:sup>-8D3 was observed, it was concluded that no beneficial effects for <jats:sup>89<\/jats:sup>Zr-immuno-PET imaging of brain uptake were obtained.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical Abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1007\/s11307-024-01931-z","type":"journal-article","created":{"date-parts":[[2024,8,2]],"date-time":"2024-08-02T15:03:31Z","timestamp":1722611011000},"page":"823-834","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Investigation of the Impact of the H310A FcRn Region Mutation on 89Zr-Immuno-PET Brain Imaging with a BBB-Shuttle Anti\u2011Amyloid Beta Antibody"],"prefix":"10.1007","volume":"26","author":[{"given":"Thomas E.","family":"Wuensche","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natascha","family":"Stergiou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Mes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariska","family":"Verlaan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther J. 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