The dynamic and multicellular processes of neuroinflammation are mediated by the nonneuronal cells of the central nervous system, which include astrocytes and the brain's resident macrophages, microglia. Although initiation of an inflammatory response may be beneficial in response to injury of the nervous system, chronic or maladaptive neuroinflammation can have harmful outcomes in many neurological diseases. An acute neuroinflammatory response is protective when activated neuroglia facilitate tissue repair by releasing anti-inflammatory cytokines and neurotrophic factors. On the other hand, chronic neuroglial activation is a major pathological mechanism in neurodegenerative diseases, likely contributing to neuronal dysfunction, injury, and disease progression. Therefore, the development of specific and sensitive probes for positron emission tomography (PET) studies of neuroinflammation is attracting immense scientific and clinical interest. An early phase of this research emphasized PET studies of the prototypical imaging biomarker of glial activation, translocator protein-18 kDa (TSPO), which presents difficulties for quantitation and lacks absolute cellular specificity. Many alternate molecular targets present themselves for PET imaging of neuroinflammation in vivo, including enzymes, intracellular signaling molecules as well as ionotropic, G-protein coupled, and immunoglobulin receptors. We now review the lead structures in radiotracer development for PET studies of neuroinflammation targets for neurodegenerative diseases extending beyond TSPO, including glycogen synthase kinase 3, monoamine oxidase-B, reactive oxygen species, imidazoline-2 binding sites, cyclooxygenase, the phospholipase A2/arachidonic acid pathway, sphingosine-1-phosphate receptor-1, cannabinoid-2 receptor, the chemokine receptor CX3CR1, purinergic receptors: P2X7 and P2Y12, the receptor for advanced glycation end products, Mer tyrosine kinase, and triggering receptor expressed on myeloid cells-1. We provide a brief overview of the cellular expression and function of these targets, noting their selectivity for astrocytes and/or microglia, and highlight the classes of PET radiotracers that have been investigated in early-stage preclinical or clinical research studies of neuroinflammation.

中文翻译：

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用于神经退行性疾病神经炎症成像的新兴 PET 放射性示踪剂和靶点：超越 TSPO 的前景。

神经炎症的动态和多细胞过程是由中枢神经系统的非神经元细胞介导的，其中包括星形胶质细胞和大脑常驻的巨噬细胞、小胶质细胞。尽管炎症反应的启动可能有益于神经系统损伤，但慢性或适应不良的神经炎症可能在许多神经系统疾病中产生有害结果。当激活的神经胶质细胞通过释放抗炎细胞因子和神经营养因子促进组织修复时，急性神经炎症反应具有保护作用。另一方面，慢性神经胶质细胞激活是神经退行性疾病的主要病理机制，可能导致神经元功能障碍、损伤和疾病进展。因此，用于神经炎症正电子发射断层扫描（PET）研究的特异性和灵敏探针的开发引起了巨大的科学和临床兴趣。这项研究的早期阶段强调对胶质细胞激活的典型成像生物标志物易位蛋白 18 kDa (TSPO) 进行 PET 研究，该标志物定量困难且缺乏绝对的细胞特异性。许多替代分子靶标可用于体内神经炎症的 PET 成像，包括酶、细胞内信号分子以及离子型受体、G 蛋白偶联受体和免疫球蛋白受体。我们现在回顾了放射性示踪剂开发的主要结构，用于 PET 研究神经退行性疾病的神经炎症靶点，包括糖原合成酶激酶 3、单胺氧化酶-B、活性氧、咪唑啉-2 结合位点、环氧合酶、磷脂酶 A2/花生四烯酸酸途径、1-磷酸鞘氨醇受体-1、大麻素-2 受体、趋化因子受体 CX3CR1、嘌呤能受体：P2X7 和 P2Y12、晚期糖基化终产物受体、Mer 酪氨酸激酶和骨髓细胞表达的触发受体-1 。我们简要概述了这些靶标的细胞表达和功能，指出它们对星形胶质细胞和/或小胶质细胞的选择性，并重点介绍了在神经炎症的早期临床前或临床研究中已研究的 PET 放射性示踪剂的类别。