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Synthesis and Evaluation of a Zr-89-Labeled Monoclonal Antibody for Immuno-PET Imaging of Amyloid-β Deposition in the Brain

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Abstract

Purpose

The aim of this study was to evaluate the in vitro and in vivo characteristics of [89Zr]JRF/AβN/25, a radiolabeled monoclonal antibody directed against amyloid-β (Aβ).

Procedures

JRF/AβN/25 was labeled with 89Zr 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 [89Zr]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

[89Zr]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 [89Zr]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, [89Zr]Df-Bz-JRF/AβN/25 demonstrated modest brain penetration, which slowly decreased in time. This cerebral uptake was confirmed by ex vivo autoradiography.

Conclusions

[89Zr]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. [89Zr]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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Acknowledgments

The authors are thankful to Joana Ramalho (Janssen Pharmaceutica) for her support with the in vitro binding assays and to Philippe Joye and Caroline Berghmans (Molecular Imaging Center Antwerp) for their support with the in vivo experiments. We also want to thank Annemie Van Eetveldt (Translational Neurosciences, University of Antwerp) for her help with the brain autoradiography studies. This work was supported in part by the Agency for Innovation by Science and Technology (IWT) grant 42/FA020000/5970.

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Authors and Affiliations

  1. Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium

    Jens Fissers, Ann-Marie Waldron, Sigrid Stroobants, Steven Staelens & Leonie wyffels

  2. Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium

    Jens Fissers, Pieter Van Der Veken, Jurgen Joossens & Koen Augustyns

  3. Department of Translational Neurosciences, University of Antwerp, Antwerp, Belgium

    Ann-Marie Waldron & Stefanie Dedeurwaerdere

  4. Neuroscience Discovery Department, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Antwerp, Belgium

    Bianca Van Broeck & Marc Mercken

  5. Pharmaceutical Development & Manufacturing Sciences, Janssen Pharmaceutica NV, Beerse, Belgium

    Thomas De Vijlder

  6. Department of Experimental Medicine, Janssen Pharmaceutica NV, Beerse, Belgium

    Darrel J. Pemberton

  7. Department of Nuclear Medicine, University Hospital Antwerp, Wilrijkstraat 10, 2650, Edegem, Belgium

    Leonie wyffels

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  1. Jens Fissers
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Correspondence to Leonie wyffels.

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Conflict of Interest

The authors declare that they have no conflict of interest. All authors contributed to the conception of the study, coordinated the experimental design, and contributed to the writing and proofreading of the final manuscript.

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Fissers, J., Waldron, AM., De Vijlder, T. et al. Synthesis and Evaluation of a Zr-89-Labeled Monoclonal Antibody for Immuno-PET Imaging of Amyloid-β Deposition in the Brain. Mol Imaging Biol 18, 598–605 (2016). https://doi.org/10.1007/s11307-016-0935-z

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  • DOI: https://doi.org/10.1007/s11307-016-0935-z

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