本文關(guān)鍵詞：含磺胺基腫瘤靶向正電子發(fā)射計算機(jī)斷層掃描顯像示蹤劑的研究　出處：《武漢工程大學(xué)》2015年碩士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 正電子發(fā)射計算機(jī)斷層掃描顯像示蹤劑 腫瘤靶向性 磺胺 1 4 7-三氮雜環(huán)壬烷-1 4 7-三乙酸(NOTA) 18F-離子標(biāo)記

【摘要】：正電子發(fā)射計算機(jī)斷層掃描顯像技術(shù)(Positron Emission Computed Tomography,PET)是目前唯一用解剖形態(tài)方式進(jìn)行功能、代謝和受體等無創(chuàng)傷性顯像的技術(shù),也是目前臨床上用來診斷和指導(dǎo)治療腫瘤的最佳手段之一。目前臨床上常用的PET示蹤劑對腫瘤組織缺乏靶向性或特異選擇性,對腫瘤顯像效果較差,且易受體內(nèi)物質(zhì)代謝的影響,常常造成假陽性、假陰性的誤診,而且合成步驟冗長、反應(yīng)條件苛刻,對PET成像技術(shù)的推廣十分不利。本文針對這些不足,設(shè)計并合成了一種新型的腫瘤靶向正電子發(fā)射計算機(jī)斷層掃描顯像示蹤劑。主要研究工作如下:1.綜述了正電子發(fā)射計算機(jī)斷層掃描顯像技術(shù)的工作原理與優(yōu)勢,重點闡述了正電子發(fā)射計算機(jī)斷層掃描顯像示蹤劑的種類與研究進(jìn)展,并介紹了磺胺及其衍生物對腫瘤的特異親和性與靶向性能。2.以對甲苯磺酰氯、乙二胺、二乙醇胺等為原料,采用經(jīng)典的Richman-Atkins法經(jīng)過保護(hù)、關(guān)環(huán)、脫保護(hù)等步驟合成了1,4,7-三氮雜環(huán)壬烷-1,4,7-三乙酸(NOTA),再與磺胺、18F-分別進(jìn)行縮合、配合反應(yīng),從而制備了水溶性腫瘤靶向PET示蹤劑18F-Al-NOTA-SN,并對所合成的化合物進(jìn)行了FT-IR、UV、1H-NMR、質(zhì)譜等結(jié)構(gòu)表征以及高效液相色譜分析與分離純化。實驗結(jié)果表明,采用F-Al法進(jìn)行放射性18F-離子標(biāo)記過程需要20分鐘,純化過程需要45分鐘。18F-離子標(biāo)記效率為92.3%,純化后的18F-Al-NOTA-SN放射性化學(xué)純度達(dá)95%以上,放射性活度為24mCi,可以滿足細(xì)胞實驗與動物成像實驗對放射性示蹤劑純度、用量的要求。3.對腫瘤靶向PET顯像示蹤劑18F-Al-NOTA-SN進(jìn)行了生物體內(nèi)外穩(wěn)定性、正常細(xì)胞與腫瘤細(xì)胞攝取、細(xì)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顯像和體內(nèi)生物分布實驗等性能研究。實驗結(jié)果表明,18F-Al-NOTA-SN具有良好的體內(nèi)外生物穩(wěn)定性,較低的細(xì)胞毒性,較高的腫瘤細(xì)胞選擇性攝取率,較好的腫瘤靶向性,可獲得較好的腫瘤靶向PET顯像效果。正常細(xì)胞與腫瘤細(xì)胞對18F-Al-NOTA-SN攝取性能差異明顯,HeLa宮頸癌細(xì)胞、HepG-2肝癌細(xì)胞、231乳腺癌細(xì)胞的攝取率明顯高于293T人腎上皮細(xì)胞、COS-7非洲綠猴腎細(xì)胞。高濃度的示蹤劑對HeLa、HepG-2、231乳腺癌細(xì)胞具有較高的細(xì)胞毒性,而對正常細(xì)胞293T、COS-7細(xì)胞的毒性較低。18F-Al-NOTA-SN在BALB/c-nu小鼠體內(nèi)主要通過肝、腎代謝,對HeLa瘤組織PET顯像較好,腫瘤邊界清晰,與周圍非靶向正常組織器官對比度高,顯像效果好,并且顯像增強效果能被含靶向基團(tuán)的配體NOTA-SN通過預(yù)注射顯著抑制。這些實驗結(jié)果表明,18F-Al-NOTA-SN具有良好的腫瘤靶向性。與臨床常用的示蹤劑18F標(biāo)記的2-氟-18-2-脫氧-D-葡萄糖(18F-FDG)對比顯像實驗表明,在不禁食條件下18F-Al-NOTA-SN具有更好的腫瘤靶向顯像增強對比度與分辨率,且受食物中糖類與體內(nèi)代謝的影響較小,有望成為一種新型腫瘤靶向PET成像示蹤劑。
[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.
【學(xué)位授予單位】：武漢工程大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：R730.4;TQ421.7

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