Augustyns, Koen

Dedeurwaerdere, Stefanie

Fissers, Jens

Joossens, Jurgen

Mercken, Marc

Pemberton, Darrel J.

Staelens, Steven

Stroobants, Sigrid

Van Broeck, Bianca

van der Veken, Pieter

Van Eetveldt, Annemie

Waldron, Ann-Marie

Wyffels, Leonie

Abstract: Introduction: The accumulation of amyloid-\u3b2 is a pathological hallmark of Alzheimers disease and is a target for molecular imaging probes to aid in diagnosis and disease monitoring. This study evaluated the feasibility of using a radiolabeled monoclonal anti-amyloid-\u3b2 antibody (JRF/A\u3b2N/25) to non-invasively assess amyloid-\u3b2 burden in aged transgenic mice (APPPS1-21) with \u3bcPET imaging. Methods: We investigated the antibody JRF/A\u3b2N/25 that binds to full-length A\u3b2. JRF/A\u3b2N/25 was radiolabeled with a [89Zr]-desferal chelate and intravenously injected into 12-13 month aged APPPS1-21 mice and their wild-type (WT) controls. Mice underwent in vivo \u3bcPET imaging at 2, 4 and 7 days post injection and were sacrificed at the end of each time point to assess brain penetrance, plaque labeling, biodistribution and tracer stability. To confirm imaging specificity we also evaluated brain uptake of a non-amyloid targeting [89Zr]-labeled antibody (Trastuzumab) as a negative control, additionally we performed a competitive blocking study with non-radiolabeled Df-Bz-JRF/A\u3b2N/25 and finally we assessed the possible confounding effects of blood retention. Results: Voxel-wise analysis of \u3bcPET data demonstrated significant [89Zr]-Df-Bz-JRF/A\u3b2N/25 retention in APPPS1-21 mice at all time points investigated. With ex vivo measures of radioactivity, significantly higher retention of [89Zr]-Df-Bz-JRF/A\u3b2N/25 was found at 4 and 7 day pi in APPPS1-21 mice. Despite the observed genotypic differences, comparisons with immunohistochemistry revealed that in vivo plaque labeling was low. Furthermore, pre-treatment with Df-Bz-JRF/A\u3b2N/25 only partially blocked [89Zr]-Df-Bz-JRF/A\u3b2N/25 uptake indicative of a high contribution of non-specific binding. Conclusion: Amyloid plaques were detected in vivo with a radiolabeled monoclonal anti-amyloid antibody. The low brain penetrance of the antibodies in addition to non-specific binding prevented an accurate estimation of plaque burden. However, it should be noted that [89Zr]-Df-Bz-JRF/A\u3b2N/25 nevertheless demonstrated in vivo binding and strategies to increase brain penetrance would likely achieve better results

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In vivo amyloid-<tex>\beta$</tex> imaging in the APPPS1-21 transgenic mouse model with a 89Zr- labeled monoclonal antibody

In vivo amyloid-<tex>\beta$</tex> imaging in the APPPS1-21 transgenic mouse model with a 89Zr- labeled monoclonal antibody

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