LRRK2正电子分子探针的研制及其在神经退行性疾病中的成像研究

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene is the main reason to cause Parkinson’s disease (PD). It also induced α-synuclein and tau neurofibillary tangles, which was considered to associate with the occurrence of neurodegenerative diseases such as Alzheimer's disease (AD). Until now, no specific LRRK2 molecular probe was developed to study the change of LRRK2 expression in neurodegenerative diseases. Many other radiotracers were applied to learn other pathological changes in patients with LRRK2 mutation, such as glucose metabolism, neuroinflammation. In our previous study, we found some LRRK2 molecular probes, which were designed from LRRK2 ligands, could apply for imaging. In this study, a series of 18F labeled LRRK2 molecular probes will be designed, developed and evaluated in vitro and in vivo. Suitable molecular probes will be selected to evaluate the distribution of LRRK2 in LRRK2 transgenic AD, PD mice, control mice, and to study the change of LRRK2 distribution with ages in these mice. It will be used for diagnosis of neurodegenerative diseases with LRRK2 mutation, and to study the occurrence and development of neurodegenerative diseases. The completion of this study will be promising tool for early diagnosis of neurodegenerative diseases, and it will provide data for the intervention time of neurodegenerative diseases as well.

富亮氨酸重复序列激酶2（LRRK2）突变是引起帕金森症（PD）的重要原因之一。它可以诱导α突触核蛋白和tau蛋白的沉积，被认为与阿尔茨海默症（AD）等神经退行性疾病的发生也存在一定的联系。目前尚没有LRRK2特异性分子探针用于研究神经退行性疾病中LRRK2的变化。临床上只能用其他探针判断LRRK2突变病人的其他病理，如糖代谢，神经炎症等的改变。我们前期发现一些LRRK2配体可以改造成LRRK2分子探针，用于显像研究。因此，本研究将研制一系列18F标记的LRRK2分子探针，选择合适的分子探针用于评价LRRK2转基因PD和AD模型鼠与正常鼠中LRRK2的分布，LRRK2随着老鼠年龄增加的变化情况。将其应用到LRRK2诱导的神经退行性疾病的早期诊断，并研究此类神经退行性疾病的发生发展过程。本研究的完成将为临床早期诊断神经退行性疾病提供工具，并为神经退行性疾病的干预时间提供依据。

富亮氨酸重复序列激酶2（LRRK2）分子探针的开发，可以有效的评估相关神经退行性疾病中LRRK2的改变情况。对于我们研究神经退行性疾病的发生和进展有重要的意义。本研究开发了基于嘧啶结构的LRRK2探针。临床前评价显示他们与LRRK2具有较好的亲和力（Kd = 6.9 nM，14.3 nM）。在正常小鼠试验中，这些探针有较高的进脑量和较好的滞留。同时，我们验证的表现出多巴胺转运体的缺失和相关运动障碍的LRRK敲除老鼠和LRRK2 G2019S转基因老鼠中，这些探针与LRRK敲除老鼠和LRRK2 G2019S转基因老鼠脑内的LRRK2均有特异性的结合。以上结果显示，这些探针是具有临床应用前景的LRRK2分子探针。LRRK2分子探针的构建，有利于我们研究神经退行性疾病的发生和进展，为相关疾病的诊断和干预，提供有效的手段。