Molecular probes to image and target the neurovascular unit in health and disease

摘要 内皮细胞（EC）、星形胶质细胞和周细胞是神经血管单位（NVU）的组成部分， 在血脑屏障（BBB）的形成和维持中起关键作用。这些细胞表达摄取， 调节分子、治疗药物和毒素的CNS渗透的外排膜转运蛋白。的 BBB和转运蛋白的功能可能在许多神经系统疾病中被破坏。因此，发展 研究NVU细胞及其在体内BBB选择性转运特性的工具是翻译的关键优先事项。 神经科学研究。我们发现了一组独特的小分子， 以精确的亲和力和特异性运输到EC、周细胞或星形胶质细胞的细胞质中。我们 有证据表明，这些分子通过膜转运蛋白进入细胞，选择性地在每个细胞中表达， 细胞类型。我们假设这些分子可以作为活体动物和人类的探针 成像以及用于药物的细胞特异性递送。在本提案中，我们旨在确定 的探针膜转运在体内;建立使用这些分子作为细胞特异性药物的可行性 载体或作为放射性药物用于正电子发射断层摄影术（PET）的人体成像， 在阿尔茨海默病和中风模型中测试它们的体内特性。该项目将改善我们的 了解跨越BBB的分子转运机制，并可能改变选择性地 在健康和疾病中对NVU的细胞进行成像和生物学调节。

ABSTRACT Endothelial cells (ECs), astrocytes and pericytes are integral components of the neurovascular unit (NVU) and play critical roles in blood brain barrier (BBB) formation and maintenance. These cells express uptake and efflux membrane transporters that regulate CNS penetration of molecules, therapeutic drugs and toxins. The function of the BBB and transporters is likely disrupted in many neurological disorders. Thus, development of tools to study NVU cells and their properties of BBB selective transport in vivo is a key priority in translational neuroscience research. We have discovered a unique set of small molecules that can be selectively transported into the cytoplasm of either ECs, pericytes or astrocytes with exquisite affinity and specificity. We have evidence that these molecules enter cells through membrane transporters, selectively expressed in each cell type. We hypothesize that these molecules could be adapted as probes for intravital animal and human imaging and also for cell-specific delivery of drugs. In this proposal, we aim to identify the precise mechanisms of probe membrane transport in vivo; establish the feasibility of using these molecules as cell-specific drug carriers or as radiopharmaceuticals for human imaging with positron emission tomography (PET) and finally test their in vivo properties in models of Alzheimer's disease and stroke. This project will improve our understanding of molecular transport mechanisms across the BBB and may transform the ability to selectively image and pharmacologically modulate cells of the NVU in health and disease.