Development of new PET radiopharmaceuticals for imaging specific microglial phenotypes

神经炎症在神经系统疾病的病理过程中起着至关重要的作用。在急性炎症事件中，小胶质细胞被激活，炎症过程被维持，直到体内平衡恢复。然而，在慢性条件下，小胶质细胞可能仍处于激活状态，因此它们的保护特性转变为慢性炎症过程。然后，小胶质细胞根据其微环境的刺激和激活的持续时间而采用改变的表型，从而调节相反的效应并失去其正常的功能。中枢神经系统免疫反应的失调似乎是阿尔茨海默病或额颞痴呆等神经退行性疾病发展的中心因素。然而，不同的小胶质细胞表型的异质性并不能得出关于小胶质细胞激活是促进还是抵消疾病过程的明确结论。正电子发射断层扫描(PET)是一种非侵入性技术，特别适用于研究中枢神经系统代谢机制的改变。PET可以用来纵向检测和量化对体内免疫反应至关重要的神经病理生物标志物，从而确定疾病的进展和治疗策略的效果。目前的标准，TSPO PET，不能区分相反的小胶质细胞极化，因此不能对小胶质细胞的功能做出直接的陈述。因此，本研究项目旨在开发新的放射示踪剂来检测与疾病相关的和内环境平衡的小胶质细胞表型。这些研究将集中在TREM2(在髓样细胞上表达的触发受体2)免疫受体的放射性配基，它在调节小胶质细胞特征方面发挥重要作用，以及嘌呤能P2Y12受体。初步数据表明，TREM2和P2Y12对应相反的小胶质细胞表型。特定的放射性标记的TREM2抗体和P2Y12R配体可能对激活的小胶质细胞在神经炎症过程的不同阶段的功能作用提供关键的见解。

Neuroinflammation plays a crucial role in the pathology of neurological diseases. In an acute inflammatory event, microglia are activated and inflammatory processes are maintained until homeostasis is restored. Under chronic conditions, however, microglia may remain activated, so that their protective properties turn into chronic inflammatory processes. Microglia then adopt an altered phenotype depending on stimuli of their microenvironment and the duration of activation, thereby mediating opposite effects and losing their normal functionality. Dysregulation of the immune response in the CNS appears to be a central factor in the development of neurodegenerative diseases such as Alzheimer's disease or frontotemporal dementia. However, the heterogeneity of different microglial phenotypes does not allow clear conclusions on whether microglial activation promotes or counteracts the disease process. Positron emission tomography (PET) is a non-invasive technique that is particularly suitable for studying altered metabolic mechanisms in the CNS. PET can be used to longitudinally detect and quantify neuropathological biomarkers which are critical to the immune response in vivo, and thus to determine disease progression and effects of therapeutic treatment strategies. The current standard, TSPO PET, is not able to discriminate between opposing microglial polarizations, so that no direct statement on microglia function can be made.This research project therefore aims to develop new radiotracers to detect both disease-associated and homeostatic microglial phenotype. The studies will focus on radioligands of the TREM2 (Triggering Receptor Expressed on Myeloid cells 2) immunoreceptor, which plays an important role in regulating microglial signature, and the purinergic P2Y12 receptor. Preliminary data suggest that TREM2 and P2Y12 map opposite microglia phenotypes. Specific radiolabeled TREM2 antibodies and P2Y12R ligands may provide key insights into the functional role of activated microglia in different stages of neuroinflammatory processes.