Evaluation, optimization and labeling of substituted 1,3,4-oxadiazole derivatives as tracers for imaging of human telomerase reverse transcriptase (hTERT) activity in tumors

评估、优化和标记取代的 1,3,4-恶二唑衍生物作为肿瘤中人端粒酶逆转录酶 (hTERT) 活性成像的示踪剂

• 批准号: 411078056
• 负责人: Dr. Christian Paul Konken
• 金额: --
• 依托单位: Klinik für Nuklearmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/411078056?language=en
• 关键词: Evaluation; optimization; labeling; substituted; oxadiazole

Human telomeres can be referred to as "end-caps" of chromosomes. They are composed of specific repeating nucleotide sequences and associated proteins.[1] The telomerase is consisting mainly of the (human) telomerase reverse transcriptase ((h)TERT) catalytic subunit and a telomeric RNA (TR or TERC) component. The primary function is the maintenance and therefore synthesis of telomere repeating units at the ends of alleles of linear chromosomes.[2,3] Once the telomeres reach a critical length, the corresponding cells enter replicative senescence or apoptosis is induced. Continuously dividing cells such as germ cells, stem cells and, most importantly, a vast majority of cancer cells (85-95%) depend on a high telomerase activity to ensure their survival. In contrast, telomerase activity is barely detectable in most adult somatic cells.[4–6] Given the above features suggests telomerase as a target for imaging of tumors. Despite the ideal properties of hTERT for development of imaging agents and numerous research efforts as well as examples of directed (radio)therapy[7,8] and indirect imaging[9–12], no small molecule inhibitor labeled for the use in diagnostic imaging modalities is known to date. Radiolabeling of these ligands for targeted, non-invasive imaging by positron emission tomography (PET) might be an especially attractive approach for tumors not accumulating or insufficiently accumulating clinically established metabolic tracers such as [18F]fluorodeoxyglucose (FDG) or [18F]fluorethyltyrosin (FET), in particular prostate-[13], breast-[14] and renal[15] cancers.[16] The potential hTERT tracers may add valuable information in cases where proliferation tracers (like 3'-deoxy-3'[18F]-fluorothymidine, [18F]FLT) exhibit certain limits.[17] Also non-tumor-specific FDG-uptake in inflamed tissue would not pose a problem when using the potential oxadiazole based imaging agents.[16,18–20]The class of 1,3,4-oxadiazole derivatives has been chosen to be developed as tracers for positron emission tomography. In a first approach two compounds will be prepared and suitable precursors will be labeled with [18F]fluorine, a positron emitting nuclide. After first distribution studies and in vitro tests a central decision on further research will determine further investigations on a very early stage of the proposed research, using the fluorescent properties of 1,3,4-oxadiazole derivatives as an indicator for late accumulation of the potential tracers. To be able to respond to long tracer accumulation times, different labeling strategies are taken into account. The potential final tracers will be fully evaluated in vitro and in vivo, using tumor models arising from hTERT expressing and non-expressing cell lines.

人类端粒可以被称为染色体的“端帽”。它们由特定的重复核苷酸序列和相关蛋白质组成。[1]端粒酶主要由（人）端粒酶逆转录酶（（h）TERT）催化亚基和端粒RNA（TR或TERC）组分组成。其主要功能是维持并因此在线性染色体的等位基因末端合成端粒重复单位。[2，3]一旦端粒达到临界长度，相应的细胞进入复制性衰老或诱导凋亡。不断分裂的细胞，如生殖细胞，干细胞，最重要的是，绝大多数癌细胞（85-95%）依赖于高端粒酶活性，以确保其生存。相反，端粒酶活性在大多数成人体细胞中几乎检测不到。[4-6]鉴于上述特征，提示端粒酶可作为肿瘤成像的靶点。尽管hTERT具有用于开发成像剂的理想性质和许多研究工作以及定向（放射）治疗[7，8]和间接成像[9-12]的实例，但迄今为止还没有已知的标记用于诊断成像模式的小分子抑制剂。通过正电子发射断层扫描（PET）对这些配体进行放射性标记以用于靶向、非侵入性成像，对于不积累或不充分积累临床确定的代谢示踪剂（例如[18F]氟脱氧葡萄糖（FDG）或[18F]氟乙基酪氨酸（FET））的肿瘤，特别是前列腺癌[13]、乳腺癌[14]和肾癌[15]，可能是特别有吸引力的方法。[16]在增殖示踪剂（如3 '-脱氧-3'[18F]-氟胸苷，[18F]FLT）表现出某些限制的情况下，潜在的hTERT示踪剂可以增加有价值的信息。[17]当使用潜在的基于恶二唑的成像剂时，发炎组织中的非肿瘤特异性FDG摄取也不会造成问题。[16已选择一类1，3，4-恶二唑衍生物作为正电子发射断层扫描的示踪剂。在第一种方法中，将制备两种化合物，并且将用[18F]氟（一种正电子发射核素）标记合适的前体。在第一次分布研究和体外试验之后，关于进一步研究的中心决定将确定在拟议研究的非常早期阶段的进一步研究，使用1，3，4-恶二唑衍生物的荧光特性作为潜在示踪剂后期积累的指标。为了能够响应长的示踪剂积累时间，考虑不同的标记策略。将使用由hTERT表达和非表达细胞系产生的肿瘤模型在体外和体内充分评价潜在的最终示踪剂。