正电子发射断层显像（Positron Emission Tomography-PET）能够定量和动态地显示出体内发生的代谢途径和生理过程，PET以及PET和CT的结合应用技术的优势体现在能够及时和准确地诊断疾病。PET和CT的结合应用技术有助于提高病灶定位的准确性，缩短检查时间从而为肿瘤的治疗提供指导。目前，广泛被应用于肿瘤诊断的PET显像药物是一种葡萄糖的类似物：2-18F-氟脱氧葡萄糖（[18F]FDG）。尽管[18F]FDG 对多种肿瘤的诊断很有效，但其也存在许多假阳性诊断：难以区别炎症细胞和肿瘤细胞，在脑内的背景值过高导致不能对脑肿瘤进行有效诊断，以及对于增长较慢的肿瘤也无法进行准确诊断。另一方面，氟-18由于其较长的半衰期（110分钟），类氢原子的大小以及较低的能量而成为理想的正电子发射核素，鉴于此，除了[18F]FDG外，越来越多的新型氟-18标记的肿瘤显像剂被开发，并进一步开展其作为PET肿瘤诊断剂的临床研究。不受控制的细胞增殖是恶性肿瘤的最重要特征，多数恶性肿瘤的发生、发展均与细胞周期调控功能紊乱有关。细胞周期是在细胞周期依赖性蛋白激酶(cyclin dependent kinases, CDKs)的调控下完成的，CDKs在肿瘤细胞中会出现异常表达，因此研发小分子的CDK抑制剂使其成为治疗癌症的潜在药物成为近几年医药开发的热点。鉴于CDK2的结构和生物化学性质已经得到确定，为此CDK2抑制剂的研究成为治疗肿瘤的有效途径。其中2-氨基噻唑衍生物和吡唑并[1,5-a]嘧啶类化合物是两类CDK2抑制剂，是近年来抗肿瘤药物的研究热点之一。我们课题组对18F标记的吡唑并[1,5-a]嘧啶类化合物作为PET肿瘤显像剂进行了初步研究，所得到的放化产物进行了荷S180瘤小鼠的体内分布实验。结果显示用对甲苯磺酸酯基（OTs）作为标记前体所得到的18F标记产物在肿瘤中吸收在30-60分钟出现峰值，但是在非靶组织中清除较慢导致肿瘤和非靶组织的比值不够理想，影响了显像效果。本论文在完善18F标记的吡唑并[1,5-a]嘧啶类化合物的研究工作外，还设计和合成了未见文献报道的新18F标记的吡唑并[1,5-a]嘧啶，2-氨基噻唑和5’-脱氧尿苷类化合物，并对所得到的18F标记的化合物进行了一系列的体内和体外的生物研究从而评价其作为PET肿瘤显像剂的研究价值。本论文进行了以下方面的研究工作：1、对五个18F标记的吡唑并[1,5-a]嘧啶类化合物（三个2-[18F]氟乙基胺类的吡唑并[1,5-a]嘧啶化合物和两个2-[18F]-4-硝基苯酰胺类的吡唑并[1,5-a]嘧啶化合物）以及[18F]FDG、L-[18F]FET进行了体外的S180细胞摄取实验。结果显示五个化合物在S180细胞中的摄取均高于L-[18F]FET，其中2-[18F]氟乙基胺类的吡唑并[1,5-a]嘧啶化合物在S180细胞中的摄取高于[18F]FDG和2-[18F]-4-硝基苯酰胺类的吡唑并[1,5-a]嘧啶化合物。并选取其中一个2-[18F]氟乙基胺类的吡唑并[1,5-a]嘧啶化合物进行了荷S180瘤小鼠的微型PET显像，结果显示肿瘤病灶区有一定的信号，但在代谢器官中信号也较强，这与荷S180瘤小鼠体内生物分布实验结果相符合，有待进一步研究和改进。2、对噻唑环修饰的吡唑并[1,5-a]嘧啶类化合物进行18F标记和对18F标记的目标化合物进行体内体外生物评价：以丙二腈为起始原料，分别和原甲酸三乙酯、水合肼反应得到3-氨基-4-氰基吡唑，接着在乙酰乙酸乙酯的作用下关环生成吡唑并[1,5-a]嘧啶母核，然后用三氯氧磷氯化得到7-氯取代的3-氰基吡唑并[1,5-a]嘧啶活性中间体，再用乙醇胺取代7-氯，羟基与对甲苯磺酰氯反应生成磺酸酯，对甲苯磺酸酯基又在叠氮化钠的作用下转换成叠氮基团，接着与相应的炔丙基磺酸酯发生Click反应，得到噻唑环修饰的吡唑并[1,5-a]嘧啶类18F标记前体化合物，最后成功将19F和18F通过亲核取代反应引入到噻唑环修饰的吡唑并[1,5-a]嘧啶化合物中。合成的目标化合物和重要中间体的结构均通过IR、1HNMR、19FNMR、13CNMR和MS鉴定，18F标记产物通过与19F取代的产物进行radio-HPLC保留时间的对照得到确认。对所得到的18F标记产物进行了酯水分配系数和体外稳定性等理化性质的测定，并在荷S180瘤小鼠体内进行了生物分布的评价研究。结果显示该18F标记产物为亲水性，体外稳定性好，在非靶器官肝和肾中清除较快，在肿瘤中有一定的吸收。3、对2-氨基噻唑衍生物进行18F标记和对18F标记的目标化合物进行体内和体外的生物评价：对CDK2的抑制剂BNS-032进行修饰，在2-氨基噻唑的氨基部位通过与叔丁氧羰基保护的对羟基苯甲酸酰化反应将叔丁氧羰基保护的对羟基苯甲酰胺基团引入到母体化合物中，再通过三氟乙酸将叔丁氧羰基水解掉，之后与1,2-双（甲苯磺酰氧基）乙烷反应将对甲苯磺酸酯基引入得到18F标记前体化合物，最后成功将18F通过亲核反应引入到2-氨基噻唑衍生物中，而相应的19F产物是通过溴乙基氟和酚羟基反应得到。合成的目标化合物和重要中间体的结构均通过IR、1HNMR、19FNMR、13CNMR和MS鉴定，18F标记产物通过与19F取代的产物进行radio-HPLC保留时间的对照得到确认。对所得到的18F标记产物进行了酯水分配系数和体外稳定性等理化性质的测定，并在荷S180瘤小鼠体内进行了生物分布的评价研究。结果显示该18F标记产物为亲酯性，体外稳定性好，在肿瘤中的有一定的摄取和滞留，而在非靶器官中清除较慢。通过体外人体乳腺癌细胞的抑制实验，初步证明该18F标记产物对乳腺癌细胞有特异性吸收。4、对5’-脱氧尿苷类化合物进行18F标记和对18F标记的目标化合物进行体内和体外的生物评价：首先将5’-脱氧尿苷的2’和3’位的羟基与丙酮进行丙叉反应保护起来，再对5’位的羟基进行结构修饰，通过与对甲苯磺酸酐反应得到对甲苯磺酸酯，然后与叠氮化钠反应得到相应的叠氮产物，再与炔丙基磺酸酯发生Click反应，得到对甲苯磺酸酯的标记前体，最后成功将18F通过亲核反应引入到5’-脱氧尿苷中，而相应的19F产物是通过对甲苯磺酸酯的标记前体与三水合四丁基氟化铵反应得到。合成的目标化合物和重要中间体的结构均通过IR、1HNMR、19FNMR、13CNMR和MS鉴定，18F标记产物通过与19F取代的产物进行radio-HPLC保留时间的对照得到确认。考虑到标记率不高，所以就没有再进行丙叉的水解，而将丙叉保护的18F标记产物进行了酯水分配系数和体外稳定性等理化性质的测定，并在荷S180瘤小鼠体内进行了生物分布的评价研究。结果显示该18F标记产物为亲水性，体外稳定性好，在非靶器官肝和血中清除较快，肿瘤中有一定的吸收。

With the increasing availability of PET (positron emission tomography) to provide quantitative kinetic information of metabolic pathways and physiological processes in vivo, PET and in particular integrated PET/CT technique can detect diseases earlier and more accurately than any other imaging technique. 18F-2-fluoro-2-deoxyglucose (18F-FDG), an analogue of glucose, is the most widely used compound for cancer detection. In spite of being a very effective PET tracer for many types of tumors, 18F-FDG is often difficult to differentiate tumor from inflammatory cells, especially for brain tumors because of high background in the brain, and its low uptake in tumors that are growing slowly can cause false-negative results. Considering the drawbacks of using FDG for tumor imaging and the advantages of fluorine-18 as an ideal positron-emitting radionuclide (relatively longer half-life (110min), comparable size to H atom and lower energy) , there are more new agents rather than FDG radiolabeled with 18F that are under investigation or have found clinical use in cancer management.Uncontrolled cellular proliferation is a hallmark of tumorigenesis, and misregulation of cell-cycle occurs with high frequency in many cancers. The regulation of the cell cycle is governed and controlled by cyclin dependent kinases (CDKs). The abnormal expression of CDKs is known to be associated with a wide variety of human cancers, and so considerable effort has been focused on the development of small molecule CDK inhibitors as potential therapeutic anticancer agents. The development of CDK2 inhibitors is an effective way to explore therapeutic anticancer agents because the characteristics of structure and biochemistry of CDK2 has been best confirmed. 2-Aminothiazole and pyrazolo[1,5-a]pyrimidine derivatives are two kinds of CDK2 inhibitors and attracted wide interest in the field of the development of anticancer drugs in recent years. Preliminary biodistribution experiments were performed in S180 tumor bearing mice to evaluate the potential of pyrazolo[1,5-a]pyrimidine derivatives for application in PET tumor imaging. The results showed that the tumor uptake of 18F labeled tracers which employed tosylate as precursors occurred peak value between 30 and 60 minutes post-injection. Unfortunately, the slow clearance rate from non-target organs and tissues resulted in unsatisfactory tumor to non-target ratios which had negative influence on imaging. This paper not only reported additional research on 18F labeled pyrazolo[1,5-a]pyrimidine derivatives which were synthesized previously, but also reported the design, synthesis and evaluation of novel 18F labeled 2-aminothiazole and pyrazolo[1,5-a]pyrimidine derivatives in vivo and vitro as potential use for PET tumor imaging agents. The work of this paper had been summarized as follows:1、The uptake characteristics of the five 18F labeled pyrazolo[1,5-a]pyrimidine derivatives (three tracers were 2-[18F]fluoroethylamino-pyrazolo[1,5-a]pyrimidine derivatives and two tracers were 2-[18F]fluoro-4-nitrobenzamide- pyrazolo[1,5-a] pyrimidine derivatives) with those of [18F]FDG and L-[18F]FET in S180 tumor cells were compared. The results showed that the uptake of the five tracers were higher than that of L-[18F]FET, and 2-[18F]fluoroethylamino- pyrazolo[1,5-a]pyrimidine derivatives displayed higher accumulation than those of [18F]FDG and 2-[18F]fluoro-4-nitrobenzamide- pyrazolo[1,5-a] pyrimidine derivatives. MicroPET image of one of 2-[18F]fluoroethylamino- pyrazolo[1,5-a]pyrimidine derivatives had been acquired in S180 tumor-bearing mouse and illustrated that the uptake in S180 tumor was obvious. On the other hand, the tracer uptake in excretory organs was predominant which data was in accordance with the results of ex vivo biodistribution. Based on the results, much effort and improvement are needed in the future research.2、The synthesis and evaluation of 18F labeled pyrazolo[1,5-a]pyrimidine derivative modified by thiazole ring in vivo and vitro: 3-Amino-1H-pyrazole-4-carbonitrile was obtained by treatment of malononitrile with triethyl orthoformate and hydrazine hydrate, then cyclized with ethyl acetoacetate to obtain pyrazolo[1,5-a]pyrimidine core which was chlorinated by phosphorus oxychloride to afford active intermediate 7-Cl substitution of 3-carbonitrile pyrazolo[1,5-a]pyrimidine core. Substitution of 7-Cl in 3-carbonitrile pyrazolo[1,5-a]pyrimidine core with ethanol amine provided the hydroxyl intermediate which was changed to tosylate intermediate by reaction with toluene sulfonyl chloride. The tosylate group was substituted by azide group provided by NaN3. The click reaction between the azide and the corresponding propargyl tosylate provided the thiazole ring modified precursor of 18F labeled pyrazolo[1,5-a]pyrimidine derivative. Finally, 19F and 18F were successfully introduced into the thiazole ring modified pyrazolo[1,5-a]pyrimidine derivative. The structures of the targeted compounds and important intermediates were confirmed by IR、1H NMR、19F NMR 、13C NMR and Mass spectra. 18F labeled compound was confirmed by comparison the retention time with that of the corresponding 19F substitution compound measured by Radio-HPLC. The physical and chemical properties including lipophilicity and stability of 18F labeled compound were measured. Meanwhile, biodistribution studies were performed in mice bearing S180 tumor cells. The results showed that the 18F labeled compound was hydrophilic, stable in vitro, fast clearance from liver and kidney with certain tumor uptake. 3、The synthesis and evaluation of 18F labeled 2-aminothiazole derivative in vivo and vitro：Direct incorporation of Boc protected 4-hydroxy benzamide group into 2-aminothiazole group in BNS-032 which is a CDK2 inhibitor was obtained through acylation of intermediate amine with Boc protected hydroxybenzoic acid. The cleavage of Boc protection of the benzamide hydroxyl group with trifluoroacetic acid gave the corresponding phenol group. The precursor for making 18F labeled compound was prepared via O-alkylation of phenolic hydroxyl intermediate with ethylene glycol-1,2-bistosylate. Finally, 18F was successfully incorporated into 2-aminothiazole group by nucleophilic substitution. The corresponding 19F substituted compound was achieved by reaction of 1-bromo-2-fluoroethane with phenol group. The structures of the targeted compounds and important intermediates were confirmed by IR、1H NMR、19F NMR 、13C NMR and Mass spectra. 18F labeled compound was confirmed by comparison the retention time with that of the corresponding 19F substitution compound measured by radio-HPLC. The physical and chemical properties including lipophilicity and stability of 18F labeled compound were measured. Meanwhile, biodistribution studies were performed in mice bearing S180 tumor cells. The results showed that the 18F labeled compound was lipophilic, stable in vitro, low clearance from non-target organs with moderate tumor uptake and retention. On the other hand, the results of blocking experiments displayed that the 18F labeled compound had specific uptake in breast cancer cells. 4、The synthesis and evaluation of 18F labeled uridine derivative in vivo and vitro：2’,3’-Dimethoxypropane was obtained by treatment of uridine with acetone, then reacted with toluenesulfonic acid anhydride to produce tosylation. The tosylation was changed to azide, following the click reaction with the corresponding propargyl tosylate to generate the tosylate precursor. Finally, 19F and 18F were successfully introduced into the 5’-deoxy uridine and The structures of the targeted compounds and important intermediates were confirmed by IR、1H NMR、19F NMR 、13C NMR and Mass spectra. 18F labeled compound was confirmed by comparison the retention time with that of the corresponding 19F substitution compound measured by radio-HPLC. The physical and chemical properties including lipophilicity and stability of 18F labeled compound were measured. Meanwhile, biodistribution studies were performed in mice bearing S180 tumor cells. The results showed that the 18F labeled compound was hydrophilic, stable in vitro, fast clearance from liver and blood with modest tumor uptake and retention.