TSPO Ligands for Cancer Imaging

用于癌症成像的 TSPO 配体

• 批准号: 9248709
• 负责人: Henry Charles Manning
• 金额: $ 17.89万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-30 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248709
• 关键词: TSPO; Ligands; Cancer; Imaging

DESCRIPTION (provided by applicant): This multidisciplinary proposal seeks to develop and validate a novel class of cancer imaging biomarkers for rapid clinical deployment. Leveraging advances in basic and clinical cancer biology, innovative medicinal chemistry, and high-throughput, small molecule screening, our laboratory has identified tumor-selective translocator protein (TSPO) ligands that are promising candidates for further development as positron emission tomography (PET) imaging agents. TSPO is an 18 kDa high-affinity cholesterol- and drug-binding protein that participates in cholesterol metabolism, steroid biosynthesis, proliferation, and apoptosis. Elevated levels of TSPO are well-documented in oncology, where levels correlate with tumor proliferation, invasion, and metastasis. Furthermore, our laboratory has mechanistically linked TSPO ligand binding to mitogen-activated protein kinase (MAPK) signaling in glioma. Capitalizing upon this observation, we have shown that TSPO ligand PET can be used to evaluate MAPK pathway inhibition in this setting. Collectively, these data demonstrate the potential significance of TSPO ligand PET as a predictive imaging biomarker in oncology. The overall goal of this study is to develop clinically translatable, tumor-selective TSPO imaging ligands that facilitate improved detection, molecular characterization, and prognosis of human gliomas. Our Specific Aims are [1] to optimize novel, tumor-selective TSPO ligand leads for in vivo PET imaging, [2] to develop methods for labeling promising TSPO ligands with the positron-emitting isotope fluorine-18, and [3] to evaluate promising TSPO imaging ligands in vivo.

描述（由申请人提供）：该多学科建议旨在开发和验证一种新型的癌症成像生物标志物，以快速临床部署。利用基础和临床癌症生物学，创新药物化学和高通量，小分子筛查的进展，我们的实验室已经确定了肿瘤选择性转运蛋白（TSPO）配体，这些配体是有希望的候选者，这些候选者可以作为正电子发射术（PET）成像代理人的正面发育。 TSPO是一种18 kDa的高亲和力胆固醇和药物结合蛋白，参与胆固醇代谢，类固醇生物合成，增殖和凋亡。 TSPO水平升高在肿瘤学中有充分记录，其中水平与肿瘤增殖，侵袭和转移相关。此外，我们的实验室在神经胶质瘤中具有机械机械的TSPO配体与有丝分裂原激活的蛋白激酶（MAPK）信号的结合。利用这一观察结果，我们表明TSPO配体PET可用于评估在这种情况下MAPK途径抑制。总的来说，这些数据证明了TSPO配体PET作为肿瘤学中预测成像生物标志物的潜在意义。这项研究的总体目标是开发可临床翻译的肿瘤选择性TSPO成像配体，以促进人神经胶质瘤的改善检测，分子表征和预后。我们的具体目的是[1]优化用于体内PET成像的新型肿瘤选择性TSPO配体铅[2]，以开发使用具有正电子的同位素氟-18和[3]的有希望的TSPO配体标记有希望的TSPO配体的方法，以评估有希望的TSPO Imaging Figands In Vivo中的TSPO成像。