含磺胺基肿瘤靶向正电子发射计算机断层扫描显像示踪剂的研究

发布时间：2018-01-09 13:07

本文关键词：含磺胺基肿瘤靶向正电子发射计算机断层扫描显像示踪剂的研究　出处：《武汉工程大学》2015年硕士论文　论文类型：学位论文

【摘要】：正电子发射计算机断层扫描显像技术(Positron Emission Computed Tomography,PET)是目前唯一用解剖形态方式进行功能、代谢和受体等无创伤性显像的技术,也是目前临床上用来诊断和指导治疗肿瘤的最佳手段之一。目前临床上常用的PET示踪剂对肿瘤组织缺乏靶向性或特异选择性,对肿瘤显像效果较差,且易受体内物质代谢的影响,常常造成假阳性、假阴性的误诊,而且合成步骤冗长、反应条件苛刻,对PET成像技术的推广十分不利。本文针对这些不足,设计并合成了一种新型的肿瘤靶向正电子发射计算机断层扫描显像示踪剂。主要研究工作如下:1.综述了正电子发射计算机断层扫描显像技术的工作原理与优势,重点阐述了正电子发射计算机断层扫描显像示踪剂的种类与研究进展,并介绍了磺胺及其衍生物对肿瘤的特异亲和性与靶向性能。2.以对甲苯磺酰氯、乙二胺、二乙醇胺等为原料,采用经典的Richman-Atkins法经过保护、关环、脱保护等步骤合成了1,4,7-三氮杂环壬烷-1,4,7-三乙酸(NOTA),再与磺胺、18F-分别进行缩合、配合反应,从而制备了水溶性肿瘤靶向PET示踪剂18F-Al-NOTA-SN,并对所合成的化合物进行了FT-IR、UV、1H-NMR、质谱等结构表征以及高效液相色谱分析与分离纯化。实验结果表明,采用F-Al法进行放射性18F-离子标记过程需要20分钟,纯化过程需要45分钟。18F-离子标记效率为92.3%,纯化后的18F-Al-NOTA-SN放射性化学纯度达95%以上,放射性活度为24mCi,可以满足细胞实验与动物成像实验对放射性示踪剂纯度、用量的要求。3.对肿瘤靶向PET显像示踪剂18F-Al-NOTA-SN进行了生物体内外稳定性、正常细胞与肿瘤细胞摄取、细胞毒性、正常雌性BALB/c-nu小鼠以及HeLa荷瘤雌性BALB/c-nu小鼠的PET显像和体内生物分布实验等性能研究。实验结果表明,18F-Al-NOTA-SN具有良好的体内外生物稳定性,较低的细胞毒性,较高的肿瘤细胞选择性摄取率,较好的肿瘤靶向性,可获得较好的肿瘤靶向PET显像效果。正常细胞与肿瘤细胞对18F-Al-NOTA-SN摄取性能差异明显,HeLa宫颈癌细胞、HepG-2肝癌细胞、231乳腺癌细胞的摄取率明显高于293T人肾上皮细胞、COS-7非洲绿猴肾细胞。高浓度的示踪剂对HeLa、HepG-2、231乳腺癌细胞具有较高的细胞毒性,而对正常细胞293T、COS-7细胞的毒性较低。18F-Al-NOTA-SN在BALB/c-nu小鼠体内主要通过肝、肾代谢,对HeLa瘤组织PET显像较好,肿瘤边界清晰,与周围非靶向正常组织器官对比度高,显像效果好,并且显像增强效果能被含靶向基团的配体NOTA-SN通过预注射显著抑制。这些实验结果表明,18F-Al-NOTA-SN具有良好的肿瘤靶向性。与临床常用的示踪剂18F标记的2-氟-18-2-脱氧-D-葡萄糖(18F-FDG)对比显像实验表明,在不禁食条件下18F-Al-NOTA-SN具有更好的肿瘤靶向显像增强对比度与分辨率,且受食物中糖类与体内代谢的影响较小,有望成为一种新型肿瘤靶向PET成像示踪剂。
[Abstract]:Positron Emission Computed Tomography. Peat) is the only non-invasive imaging technique using anatomic morphology, such as function, metabolism and receptor. It is also one of the best methods to diagnose and guide the treatment of tumor. At present, the commonly used PET tracer is lack of targeting or specific selectivity to tumor tissue, and the effect of tumor imaging is poor. It is easy to be affected by substance metabolism in vivo, which often leads to false positive and false negative misdiagnosis, and the synthetic steps are lengthy and the reaction conditions are harsh, which is very unfavorable to the popularization of PET imaging technology. A novel tracer for tumor targeting positron emission computed tomography imaging was designed and synthesized. 1. The principle and advantages of positron emission computed tomography (PET) imaging are reviewed. The types and research progress of positron emission computed tomography (PET) tracer were reviewed, and the specific affinity and targeting property of sulfanilamide and its derivatives to tumor were introduced. 2. To p-toluenesulfonyl chloride (p-toluenesulfonyl chloride). Using ethylenediamine and diethanolamine as raw materials, 1 ~ (4) O _ (7) -triazocyclic nonane ~ (-1) was synthesized by classical Richman-Atkins method after protection, ring closing and deprotection. The water-soluble tumor targeting PET tracer 18F-Al-NOTA-SN was prepared by condensation with sulfamethylamine 18F-. The synthesized compounds were characterized by FT-IRX UVX 1H-NMR-MS, and were analyzed and purified by HPLC. The experimental results showed that the synthesized compounds were isolated and purified by high performance liquid chromatography (HPLC). It takes 20 minutes to label radioactive 18F- ions by F-Al method and 45 minutes to purify them. The efficiency of 18F- ion labeling is 92.3%. The purified 18F-Al-NOTA-SN has a radiochemical purity of more than 95% and a radioactivity of 24mCi. it can satisfy the purity of radiotracer in cell and animal imaging experiments. In vivo and in vitro stability, uptake and cytotoxicity of 18F-Al-NOTA-SN, a tracer for tumor targeting PET imaging, were studied. The characteristics of PET imaging and biodistribution in vivo of normal female BALB/c-nu mice and HeLa bearing female BALB/c-nu mice were studied. 18F-Al-NOTA-SN has good biological stability in vivo and in vitro, lower cytotoxicity, higher selective uptake rate of tumor cells and better tumor targeting. The difference of 18F-Al-NOTA-SN uptake between normal cells and tumor cells was significant. The uptake rate of HepG-2 hepatoma cell line was significantly higher than that of 293T human renal epithelial cell line COS-7. High concentration of tracer was used to treat HeLa. The breast cancer cell line HepG-22231has high cytotoxicity and 293T to normal cells. The toxicity of COS-7 cells was lower. 18F-Al-NOTA-SN was mainly metabolized by liver and kidney in BALB/c-nu mice, and PET imaging of HeLa tumor tissue was better. The boundary of tumor is clear, the contrast with non-target normal tissues and organs is high, and the imaging effect is good. Moreover, the enhanced effects of the imaging can be significantly inhibited by pre-injection of ligand NOTA-SN with targeted groups. 18F-Al-NOTA-SN has a good tumor targeting ability, which is compared with the 18F-FDG labeled by 18F as a tracer. Contrast imaging experiments show that. 18F-Al-NOTA-SN has better contrast and resolution enhanced by 18F-Al-NOTA-SN, and is less affected by carbohydrate in food and metabolism in vivo. It is expected to be a new type of tumor targeted PET imaging tracer.
【学位授予单位】：武汉工程大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R730.4;TQ421.7

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