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Background: Recent preclinical and clinical studies in the diagnosis and treatment of Alzheimer Disease (AD) focus on antibody based radioligands and therapeutics by targeting amyloid‐β (Aβ).1 So far, imaging brain targets with bispecific antibodies (using transferrin receptor protein1 as shuttling mechanism) has only been investigated using 124I.2 The disadvantages of 124I limit drastically its clinical potential.3 Therefore, 89Zr is suggested as more suitable positron emitter for labelling of antibodies4, especially in combination with DFO*, the next generation chelator candidate for clinical 89Zr‐immuno‐PET.5 In this study, we evaluated [89Zr]Zr‐DFO*‐NCS labeled bispecific Abeta‐mAb‐scFab8D3 and its mutated analogue Abeta‐mAb‐scFab8D3 T1/2 with faster pharmacokinetics for Aβ imaging and targeting in a preclinical Alzheimer mouse model. Method: Abeta‐mAb‐scFab8D3 ± T1/2 and the nonspecific isotype control B12‐mAb‐scFab8D3 ± T1/2 were modified with DFO*‐NCS, and subsequently radiolabeled with 89Zr.6 The radiolabeled biologicals (1 mg/kg) were intravenously injected in APP/PS1 transgenic mice as well as in littermates which served as controls (n=5 per group). Blood pharmacokinetics were determined up to 3 (T1/2) or 7 days post injection (p.i.). PET/CT and PET/MRI scans were acquired for 1h at different time points. Result: The PET images showed a clear brain uptake for the bispecific Abeta‐mAb‐scFab8D3 ± T1/2 in APP/PS1 mice, while the corresponding B12‐mAb‐scFab8D3 ± T1/2 in APP/PS1 mice, as well as Abeta‐mAb‐scFab8D3 ± T1/2 in the littermates showed no specific uptake. Abeta‐mAb‐scFab8D3 demonstrated 2‐fold higher brain uptake (2% ID/g) than Abeta‐mAb‐scFab8D3 T1/2 (1% ID/g). Conclusion: 89Zr‐DFO*‐immuno‐PET revealed high and specific uptake of the bispecific Abeta‐mAb‐scFab8D3 in the brain. In this context, we demonstrated that slow kinetics of the biologicals contribute to improve Aβ targeting. The new bispecific Abeta‐mAb‐scFab8D3 looks very promising and supports further development toward companion and complementary diagnostics for AD. References: 1. Selkoe, D. J. Nature Reviews Neurology 15, 365–366 (2019). 2. Sehlin, D. et al. Nat. Commun. 7, 10759 (2016). 3. Verel, I. et al. Cancer Biother. Radiopharm. 18, 655–661 (2003). 4. O'Brien, H. A. J. Radioimmunoimaging Radioimmunother. 17, (1983). 5. Chomet, M. et al. Eur. J. Nucl. Med. Mol. Imaging 1–14 (2020). doi:10.1007/s00259‐020‐05002‐7. 6. Vugts, D. J. et al. Eur. J. Nucl. Med. Mol. Imaging 44, 286–295 (2017). [ABSTRACT FROM AUTHOR]