Lopes van den Broek Sara, Sehlin Dag, Andersen Jens V, Aldana Blanca I, Beschörner Natalie, Nedergaard Maiken, Knudsen Gitte M, Syvänen Stina, Herth Matthias M
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Rudbeck Laboratory, Department of Public Health and Caring Sciences, University of Uppsala, Uppsala, Sweden.
Front Nucl Med. 2022 Sep 23;2:1001722. doi: 10.3389/fnume.2022.1001722. eCollection 2022.
Alzheimer's disease (AD) is the most common neurodegenerative disease, with an increasing prevalence. Currently, there is no ideal diagnostic molecular imaging agent for diagnosing AD. Antibodies (Abs) have been proposed to close this gap as they can bind selectively and with high affinity to amyloid β (Aβ)-one of the molecular hallmarks of AD. Abs can even be designed to selectively bind Aβ oligomers or isoforms, which are difficult to target with small imaging agents. Conventionally, Abs must be labeled with long-lived radionuclides which typically results in in high radiation burden to healthy tissue. Pretargeted imaging could solve this challenge as it allows for the use of short-lived radionuclides. To develop pretargeted imaging tools that can enter the brain, AD mouse models are useful as they allow testing of the imaging approach in a relevant animal model that could predict its clinical applicability. Several mouse models for AD have been developed with different characteristics. Commonly used models are: 5xFAD, APP/PS1 and tg-ArcSwe transgenic mice. In this study, we aimed to identify which of these models were best suited to investigate pretargeted imaging approaches beyond the blood brain barrier. We evaluated this by pretargeted autoradiography using the Aβ-targeting antibody 3D6 and an In-labeled Tz. Evaluation criteria were target-to-background ratios and accessibility. APP/PS1 mice showed Aβ accumulation in high and low binding brain regions and is as such less suitable for pretargeted purposes. 5xFAD and tg-ArcSwe mice showed similar uptake in high binding regions whereas low uptake in low binding regions and are better suited to evaluate pretargeted imaging approaches. 5xFAD mice are advantaged over tg-ArcSwe mice as pathology can be traced early (6 months compared to 18 months of age) and as 5xFAD mice are commercially available.
阿尔茨海默病（AD）是最常见的神经退行性疾病，其患病率呈上升趋势。目前，尚无理想的用于诊断AD的分子影像诊断剂。抗体（Abs）被认为可填补这一空白，因为它们能够选择性且高亲和力地结合淀粉样β蛋白（Aβ）——AD的分子标志物之一。甚至可以设计抗体来选择性结合Aβ寡聚体或异构体，而小分子显像剂难以靶向这些物质。传统上，抗体必须用长寿命放射性核素标记，这通常会给健康组织带来高辐射负担。预靶向成像可以解决这一挑战，因为它允许使用短寿命放射性核素。为了开发能够进入大脑的预靶向成像工具，AD小鼠模型很有用，因为它们可以在相关动物模型中测试成像方法，从而预测其临床适用性。已经开发出了几种具有不同特征的AD小鼠模型。常用的模型有：5xFAD、APP/PS1和tg-ArcSwe转基因小鼠。在本研究中，我们旨在确定这些模型中哪一种最适合研究血脑屏障以外的预靶向成像方法。我们通过使用靶向Aβ的抗体3D6和铟标记的Tz进行预靶向放射自显影来评估这一点。评估标准是靶本底比和可及性。APP/PS1小鼠在高结合和低结合脑区均显示Aβ积累，因此不太适合用于预靶向目的。5xFAD和tg-ArcSwe小鼠在高结合区域显示出相似的摄取，而在低结合区域摄取较低，更适合评估预靶向成像方法。5xFAD小鼠比tg-ArcSwe小鼠更具优势，因为其病理学变化可在早期（6个月，而tg-ArcSwe小鼠为18个月）被追踪到，并且5xFAD小鼠有商业供应。
