Almost 50 million people worldwide are affected by Alzheimer's disease (AD), the most common neurodegenerative disorder. Development of disease-modifying therapies would benefit from reliable, non-invasive positron emission tomography (PET) biomarkers for early diagnosis, monitoring of disease progression, and assessment of therapeutic effects. Traditionally, PET ligands have been based on small molecules that, with the right properties, can penetrate the blood-brain barrier (BBB) and visualize targets in the brain. Recently a new class of PET ligands based on antibodies have emerged, mainly in applications related to cancer. While antibodies have advantages such as high specificity and affinity, their passage across the BBB is limited. Thus, to be used as brain PET ligands, antibodies need to be modified for active transport into the brain. Here, we review the development of radioligands based on antibodies for visualization of intrabrain targets. We focus on antibodies modified into a bispecific format, with the capacity to undergo transferrin receptor 1 (TfR1)-mediated transcytosis to enter the brain and access pathological proteins, e.g. amyloid-beta. A number of such antibody ligands have been developed, displaying differences in brain uptake, pharmacokinetics, and ability to bind and visualize the target in the brain of transgenic mice. Potential pathological changes related to neurodegeneration, e.g. misfolded proteins and neuroinflammation, are suggested as future targets for this novel type of radioligand. Challenges are also discussed, such as the temporal match of radionuclide half-life with the ligand's pharmacokinetic profile and translation to human use. In conclusion, brain PET imaging using bispecific antibodies, modified for receptor-mediated transcytosis across the BBB, is a promising method for specifically visualizing molecules in the brain that are difficult to target with traditional small molecule ligands.

中文翻译：

---

工程抗体：脑PET的新可能性？

全世界有将近5000万人患有阿尔茨海默氏病（AD），这是最常见的神经退行性疾病。疾病改良疗法的发展将受益于可靠的，非侵入性的正电子发射断层扫描（PET）生物标记物，用于早期诊断，疾病进展监测和治疗效果评估。传统上，PET配体基于具有适当特性的小分子，可以穿透血脑屏障（BBB）并可视化大脑中的靶标。最近，出现了一类新的基于抗体的PET配体，主要用于与癌症有关的应用中。尽管抗体具有诸如高特异性和亲和力之类的优势，但它们穿过BBB的通道受到限制。因此，要用作大脑PET配体，需要对抗体进行修饰，以将其主动转运到大脑中。在这里，我们回顾了基于抗体的放射性配体的发展，用于脑内靶标的可视化。我们专注于修饰为双特异性形式的抗体，具有进行转铁蛋白受体1（TfR1）介导的胞吞作用进入大脑和访问病理性蛋白（例如淀粉样蛋白-β）的能力。已经开发了许多这样的抗体配体，其在脑摄取，药代动力学以及结合和显现转基因小鼠脑中靶标的能力方面显示出差异。与神经变性相关的潜在病理变化，例如错误折叠的蛋白质和神经炎症，被建议作为这种新型放射性配体的未来目标。还讨论了挑战，例如放射性核素半衰期与配体的药代动力学特征在时间上的匹配以及向人类使用的转化。