In Vivo Amyloid-β Imaging in the APPPS1-21 Transgenic Mouse Model with a (89)Zr-Labeled Monoclonal Antibody.

Introduction: The accumulation of amyloid-beta is a pathological hallmark of Alzheimer's 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 antiamyloid-beta antibody (JRF/A beta N/25) to non-invasively assess amyloid-beta burden in aged transgenic mice (APPPS1-21) with mu PET imaging. Methods: We investigated the antibody JRF/A beta N/25 that binds to full-length A. JRF/Af,N/25 was radiolabeled with a [Zr-89]-desferal chelate and intravenously injected into 12-13 month aged APPPS1-21 mice and their wild-type (WT) controls. Mice underwent in vivo mu PET 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 [Zr-89]-labeled antibody (trastuzumab) as a negative control, additionally we performed a competitive blocking study with non radiolabeled Df-Bz-JRF/A beta N/25 and finally we assessed the possible confounding effects of blood retention. Results: Voxel-wise analysis of mu PET data demonstrated significant [Zr-89]-Df-Bz-JRF/A beta N/25 retention in APPPS1-21 mice at all time points investigated. With ex vivo measures of radioactivity, significantly higher retention of [Zr-89]-Df-Bz-JRF/A beta N/25 was found at 4 and 7 days 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 beta N/25 only partially blocked [Zr-89]-Df-Bz-JRF/A beta N/25 uptake indicative of a high contribution of nonspecific binding. Conclusion: Amyloid plaques were detected in vivo with a radiolabeled monoclonal anti-amyloid antibody. The low brain penetrance of the antibody in addition to nonspecific binding prevented an accurate estimation of plaque burden. However, it should be noted that [Zr-89]-Df-Bz-JRF/A beta N/25 nevertheless demonstrated in vivo binding and strategies to increase brain penetrance would likely achieve better results.