多功能囊泡单胺转运体2分子影像探针18F-FP-(+)-DTBZ在DM和PD的相关性研究

Vesicular monoamine transporter 2 (VMAT2) is closely relating to Diabetes Mellitus (DM) and Parkinson's Disease (PD). We develop multi-function VMAT2 probe using 18F labeled VMAT2 specific ligand 18F-FP-(+)-DTBZ. The project is going to complete the synthesis and performance testing of 18F-FP-(+)-DTBZ and its labeling condition optimization to achieve an automatic synthesizing technique. What's more, biological characteristics and specific binding analysis will be extensively studied. The number of VMAT2 in basal ganglia and β cells amount (BCM) in islet on model rat were revealed with small animal positron emission tomography, autoradiography and immunohistochemistry. The pattern of BCM during progression of DM could be explored through quantitative image analysis, especially the relationship of molecular mechanism between DM and PD. In addition, different animal models with different decrease of BCM were developed to explore explore new quantitative methods related to the reduction of BCM during the PD development. VMAT2 based targeting molecular imaging can be dynamically reveal the course of the reduction during the development of DM, providing effective methods of non-invasive in vivo and theoretical basis for the diagnosis and treatment of DM. There is no research on quantitative study on BCM related PD abroad. The subject on reduction of BCM will have broad application prospects, further providing early diagnosis of PD-related scientific theory and a safe and effective method for in vitro quantitative analysis.

囊泡单胺转运体2(VMAT2)与帕金森病(PD)和糖尿病(DM)密切相关。本课题合成VMAT2多功能特异性探针18F-FP-(+)-DTBZ，并完成放化基础研究。研究不同程度BCM减少量可能诱发的PD动物模型，探讨18F-FP-(+)-DTBZ 在BCM减少在PD发病相关性定量分析的新方法，结合放射自显影和免疫组化。进一步将18F-FP-(+)-DTBZ运用于临床，探索BCM减少在诱发PD病情进展中的变化规律。基于VMAT2的靶向分子显像能够动态反映BCM减少相关DM的发展过程，为PD、DM的诊断及治疗相关研究提供有效的活体非侵入性手段及理论基础依据,关于BCM相关的PD定量研究国内外尚处于空白，课题的进一步研究将为BCM减少相关的PD早期诊断提供科学的理论依据和安全有效的体外定量分析方法，必将具有广阔的应用前景。

大量研究证据表明糖尿病和帕金森病这两种与年龄相关的慢性疾病之间关系密切, DM和PD之间有很多相同的病理生理学机制。由于VMAT2在中枢神经系统和胰岛β细胞DA转运中均有重要作用，故应用VMAT2靶点分子探针18F-FP-(+)-DTBZ可深入探究DM和PD相关性。1）本课题按原计划成功制备出放化纯大于99%的 18F-FP-(+)-DTBZ PET 显像剂，并通过优化合成工艺，建立了满足日常临床需求的自动化合成方法。2）在此基础上完成了18F-FP-(+)-DTBZ在正常动物体内的分布、特异性结合分析等临床前期评价，建立了动物模型脑多巴胺能相关显像方法学及分析方法学，基于PMOD软件应用18F-FP-(+)-DTBZ大鼠脑PET图像建立了多巴胺能PET分析脑模版，应用此模版可以对大鼠多巴胺能显像图像进行较准确的分析评价。3）本课题建立了稳定的1型糖尿病大鼠动物模型，证实18F-FP-(+)-DTBZ显像可以有效地评价T1DM动物BCM情况，并且进一步发现纹状体VMAT2表达和胰腺BCM水平呈正相关。4）本课题使用ZDF大鼠作为2型糖尿病动物模型，研究发现T2DM大鼠纹状体VMAT2表达和空腹血糖水平呈负相关，并且发现T2DM导致的多巴胺神经功能异常中，VMAT2表达异常要早于DAT，其程度也要重于DAT。5）本课题研究发现T2DM患者胰腺18F-FP-(+)-DTBZ摄取较正常人减低，说明VMAT2靶点分子探针18F-FP-(+)-DTBZ可用于糖尿病患者BCM的定量评价。此外，发现PD伴T2DM患者尾状核和壳核18F-FP-(+)-DTBZ摄取较PD患者减低，这一结果说明T2DM会加剧脑内尾状核和壳核VMAT2表达的下降。本课题采用VMAT2靶点探针18F-FP-(+)-DTBZ作为显像基础，从分子水平对DM的BCM变化情况作为切入点，联合PD脑多巴胺能进行分子影像研究，明确DM和PD相互之间可能存在的潜在联系，对探究两种疾病的发病机制、早期诊断、治疗评估及改进治疗方法具有重要的临床意义。