PSMA靶向18F-Glu-urea-R PET/CT分子探针的合成及对前列腺癌诊断的研究

Prostate cancer is the third most common cancer and the second leading cause of cancer-related death for males in western countries. Current methods for detecting prostate cancer are limited, leaving many early malignancies undiagnosed. Therefore, the ability to visualize early prostate cancer is increasingly important for treatment planning and informing therapeutic selection. Current imaging techniques could not provide highly specific and sensitive detection of prostate cancer. A specific and sensitive means of imaging early prostate cancer is the goal of our current effort. Prostate specific membrane antigen (PSMA) is an attractive target for the detection of primary prostate cancer. PSMA is a transmembrane protein that is up-regulated in prostate cancer. Since PSMA is expressed by virtually all prostate cancers and its expression is further increased in metastatic, poorly differentiated and hormone-refractory carcinomas, it is a very attractive target for developing radiopharmaceuticals for the diagnosis, staging and treatment of prostate cancer. Researchers have developed and radiolabeled some monoclonal antibodies that bind to the extracellular domain of PSMA which have entered into clinical trials. Although monoclonal antibodies could offer potential for tumor targeting, poor tumor penetrability and long circulating half-life may limit their effectiveness as diagnostic radiopharmaceuticals. Researchers found that small molecules can offer significant advantages over antibodies for targeting prostate cancer. Small molecules can be designed with affinities similar to the monoclonal antibodies. Small molecules can exhibit enhanced diffusibility to the extravascular space and faster blood clearance than monoclonal antibodies, thus resulting in lower background signal. In addition, the opportunity to synthesize analogues exhibiting various chemical properties offers alteration of binding affinity as well as pharmacokinetics. Thus, radiolabeled small molecule radiotracers that bind PSMA may offer the better approach in the diagnosis of prostate cancer. Small molecule Glu-urea-R can specifically recognize PSMA and has important value in the PET/CT field of prostate cancer. In this topic, Glu-urea-R was testified as the core structure to develop the molecular probe of PET/CT in prostate cancer. We use 18F to label Glu-urea-R and explore the preparation and purification methods of 18F-Glu-urea-R. We will analyse its metabolism and distribution in nude mice and assess its security. Then we will assess the sensitivity and specificity of the probe in diagnosis of prostate cancer by animal experiments and by comparative analysis with traditional tracer 11C-choline. 18F-Glu-urea-R could offer a new strategy in early diagnosis, staging, restaging and the monitoring of therapy of prostate cancer.

前列腺癌的早期诊断，术后复发、转移灶的定位诊断以及术后治疗疗效的监测缺乏有效的影像学措施。谷氨酸尿素小分子及其类似物Glu-urea-R能够靶向识别前列腺癌细胞膜表面的特异性膜抗原PSMA，在前列腺癌PET/CT分子影像学领域具有重要的研究价值。本课题拟以Glu-urea-R为核心结构，研究开发新型前列腺癌PET/CT分子探针，攻关核素18F标记Glu-urea-R前列腺癌PET/CT分子探针的制备、纯化方法，同时使其与PSMA高效特异性的结合，分析其在荷前列腺癌裸鼠体内代谢、分布情况，并评估新型前列腺癌分子探针的安全性；通过动物实验探讨18F-Glu-urea-R的PET/CT对前列腺癌的成像特点，并与传统示踪剂11C-胆碱前列腺癌PET/CT成像进行对比分析，评价新型探针在前列腺癌诊断中的敏感性、特异性；为前列腺癌的早期诊断，术前分期，术后复发灶定位再分期及疗效评估与监测提供新的策略。

前列腺癌世界发病率在恶性肿瘤中位居第二。多数前列腺癌患者死于肿瘤转移，术后复发等因素。因此前列腺癌的早期诊断，靶向治疗及术后复发的早期诊断对预后至关重要。前列腺特异性膜抗原（PSMA）在正常前列腺组织中有表达，但在前列腺癌组织中表达明显增加。因此研制以PSMA为靶点的前列腺癌特异性PET/CT造影剂对前列腺癌的诊断甚至靶向治疗具有良好的研究价值及发展前景。本课题组探索前列腺特异性膜抗原靶向性谷氨酸尿素小分子（Glu-urea-R）的研制。按照标准的无水无氧操作技术进行实验操作；利用磁共振波谱法与质谱法分析确定化合物结构，通过亲和力实验检测各种化合物与PSMA的实际亲和力。将其中1种前期合成的化合物Glu-Urea-Lys与辅基SFB进行合成，通过对制备经验的总结，对18F-Glu-Urea-lys造影剂进行制备，评估其制备条件的经济性与可行性，并利用18F-Glu-urea-lys造影剂进行PET扫描。评估造影剂的显像效果、肿瘤特异性以及排泄速度等。通过研究证实，Glu-Urea-Lys标准品的制备条件要求低，为后续造影剂18F-Glu-Urea-Lys的制备提供了重要的参考依据,这类小分子造影剂具备良好的创新性及可行性。小分子18F-Glu-Urea-lys造影剂易于合成，具有良好的实用性，且对目标肿瘤显像效果良好，排泄快。在前列腺癌的早期诊断、术后监测和复发转移的诊断中可作为一种理想的造影剂，拥有良好的影像学诊断价值和发展前景。

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