Jens Fissers1,2, Ann-Marie Waldron1,3, Thomas De Vijlder4, Bianca Van Broeck5, Darrel J Pemberton6, Marc Mercken5, Pieter Van Der Veken2, Jurgen Joossens2, Koen Augustyns2, Stefanie Dedeurwaerdere3, Sigrid Stroobants1, Steven Staelens1, Leonie Wyffels7,8. 1. Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium. 2. Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium. 3. Department of Translational Neurosciences, University of Antwerp, Antwerp, Belgium. 4. Pharmaceutical Development & Manufacturing Sciences, Janssen Pharmaceutica NV, Beerse, Belgium. 5. Neuroscience Discovery Department, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Antwerp, Belgium. 6. Department of Experimental Medicine, Janssen Pharmaceutica NV, Beerse, Belgium. 7. Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium. leonie.wyffels@uza.be. 8. Department of Nuclear Medicine, University Hospital Antwerp, Wilrijkstraat 10, 2650, Edegem, Belgium. leonie.wyffels@uza.be.
Abstract
PURPOSE: The aim of this study was to evaluate the in vitro and in vivo characteristics of [(89)Zr]JRF/AβN/25, a radiolabeled monoclonal antibody directed against amyloid-β (Aβ). PROCEDURES: JRF/AβN/25 was labeled with (89)Zr following modification with desferal. The affinity of the tracer for Aβ1-40 was determined in a saturation binding assay. In vitro stability was evaluated, and in vivo plasma stability and biodistribution of [(89)Zr]Df-Bz-JRF/AβN/25 were determined in wild-type mice. To evaluate whether the antibody can cross the blood-brain barrier, brain uptake in wild-type mice was additionally assessed by ex vivo autoradiography. RESULTS: [(89)Zr]Df-Bz-JRF/AβN/25 was obtained in an average radiochemical yield of 50 % and a radiochemical purity of >97 %. A saturation binding assay demonstrated specific binding of [(89)Zr]Df-Bz-JRF/AβN/25 to Aβ1-40 with nanomolar affinity. The tracer was stable in buffer and proved to be stable in vivo with >92 % intact monoclonal antibody (mAb) remaining in the plasma at 48 h post injection. A biodistribution study showed a slow blood clearance with no significant accumulation of activity in any of the organs. Furthermore, [(89)Zr]Df-Bz-JRF/AβN/25 demonstrated modest brain penetration, which slowly decreased in time. This cerebral uptake was confirmed by ex vivo autoradiography. CONCLUSIONS: [(89)Zr]Df-Bz-JRF/AβN/25 binds with high affinity to Aβ1-40. The tracer displays an acceptable in vivo stability and is able to cross the blood-brain barrier. [(89)Zr]Df-Bz-JRF/AβN/25 might therefore be a potential candidate for in vivo imaging of Aβ deposition in the brain.
PURPOSE: The aim of this study was to evaluate the in vitro and in vivo characteristics of [(89)Zr]JRF/AβN/25, a radiolabeled monoclonal antibody directed against amyloid-β (Aβ). PROCEDURES: JRF/AβN/25 was labeled with (89)Zr following modification with desferal. The affinity of the tracer for Aβ1-40 was determined in a saturation binding assay. In vitro stability was evaluated, and in vivo plasma stability and biodistribution of [(89)Zr]Df-Bz-JRF/AβN/25 were determined in wild-type mice. To evaluate whether the antibody can cross the blood-brain barrier, brain uptake in wild-type mice was additionally assessed by ex vivo autoradiography. RESULTS: [(89)Zr]Df-Bz-JRF/AβN/25 was obtained in an average radiochemical yield of 50 % and a radiochemical purity of >97 %. A saturation binding assay demonstrated specific binding of [(89)Zr]Df-Bz-JRF/AβN/25 to Aβ1-40 with nanomolar affinity. The tracer was stable in buffer and proved to be stable in vivo with >92 % intact monoclonal antibody (mAb) remaining in the plasma at 48 h post injection. A biodistribution study showed a slow blood clearance with no significant accumulation of activity in any of the organs. Furthermore, [(89)Zr]Df-Bz-JRF/AβN/25 demonstrated modest brain penetration, which slowly decreased in time. This cerebral uptake was confirmed by ex vivo autoradiography. CONCLUSIONS: [(89)Zr]Df-Bz-JRF/AβN/25 binds with high affinity to Aβ1-40. The tracer displays an acceptable in vivo stability and is able to cross the blood-brain barrier. [(89)Zr]Df-Bz-JRF/AβN/25 might therefore be a potential candidate for in vivo imaging of Aβ deposition in the brain.
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