VMAT2在帕金森病发病机制中的作用及相关microPET显像研究

The accurate mechanism of pathogenesis of Parkinson's disease (PD) is unclear. A variety of factors may play a role in the pathogenesis of PD. Recently, the protective function on dopamine (DA) neurons of the vesicular monoamine transporter (VMAT2) has been implicated a possible role in DA related disorders. We previously prepared a specific VMAT2 tracer, 18F-9-fluoropropyl-(+)-dihydrotetrabenzazine (18F-FP-(+)-DTBZ), in our lab. With the tracer at hand, we found that (1) rotenone, a biological toxicant used for prepare PD model, partly decreased VMAT2 function, (2) under condition of VMAT2 being inhibited, rats were more sensitive to produce PD after treated with rotenone, at a lower dose (0.5 vs 2.5 mg/kg/day). We now put forward our hypothesis that simultaneous inhibition of both VMAT2 and mitochondrial complex I (i.e. caused with rotenone) may be，or at least one of, the main factors of pathogenesis of PD. To prove our hypothesis, in this project, we will track the function of VMAT2 in rats in vivo longitudinally with a small animal PET (microPET) and 18F-FP-(+)-DTBZ during the process of animal rotenone PD model. Rats will be treated with (1) rotenone, (2) VMAT2 inhibitor, as well as (3) a combination of these two substance, and then followed with longitudinally monitoring of behavioral test, in vivo VMAT2 imaging with microPET, and other biomarkers analysis associated with PD. We want to map out law curves of the VMAT2 function during the PD occurrence and progression, and furtherly clarify the role of VMAT2 in pathogenesis of PD. The aim of this project is to confirm whether decrease of VMAT2 function with its inhibitor is a key determinant of PD pathogenesis. We hope our research give a new thinking for investigation of the prevention and therapy of PD.

帕金森病（PD）的发病机制尚不明确，多种因素可能在PD发病过程中起作用。本项目基于囊泡单胺转运体（VMAT2）对多巴胺神经元的保护机制，在前期已研制VMAT2示踪药物的基础上，预实验发现当VMAT2被抑制时，大鼠对鱼藤酮（Rotenone，一种线粒体功能抑制剂）更加敏感，能够在更低的Rotenone剂量下产生PD。据此，我们提出科学假说：VMAT2和线粒体功能的联合抑制作用，可能是PD发病的主要因素之一。在本研究中，我们将利用小动物专用PET（microPET），在活体内、纵向跟踪研究实验动物在VMAT2抑制剂、Rotenone、以及二者联合给药等条件下，动物PD的发生、发展规律，系统研究实验动物的VMAT2功能、行为学以及其它PD相关分子生物学指标的变化趋势，揭示VMAT2在PD发生发展中的变化规律，阐明VMAT2在PD发病机制中的作用，为PD的预防和治疗研究提供新的思路。

帕金森病（PD）是老年人常见疾病之一，其发病机制尚不明确。中枢神经系统的II型囊泡单胺转运体（VMAT2）可能与帕金森病的发生发展密切相关。本研究首先制备了一种特异性靶向VMAT2的正电子药物[18F]FP-(+)-DTBZ，完成了药物合成与关键中间体的质量控制，建立了一步法制备[18F]FP-(+)-DTBZ的18F的标记方案，完成工艺优化，并实现了自动化放射合成。获得的正电子药物产率高，纯度好（放射化学纯度>99%），稳定性佳，为推广应用奠定了基础。然后，我们以[18F]FP-(+)-DTBZ为工具药物，利用小动物正电子发射计算机断层（microPET）活体成像技术，研究了不同程度的6-OHDA 定位损毁的大鼠PD动物模型大脑中VMAT2的变化规律，发现在PD进展过程中，VMAT2的功能持续性降低，其程度与PD严重程度具有相关性。最后我们系统研究了VMAT2抑制剂与PD相关的神经毒素MPTP之间的协同作用，发现VMAT2抑制剂能够增强MPTP对多巴胺神经元的敏感性，促进PD的发生与发展，表明VMAT2的功能降低可能是PD发生与发展的敏感因素之一。本研究为PD的发生发展提供了一种新的机制学说，可能对PD的防治研究具有指导意义。本项目研制的VMAT2示踪药物[18F]FP-(+)-DTBZ在国内获得了临床应用。