TSPO Ligands for Cancer Imaging

描述(由申请人提供)：这项多学科的提案寻求开发和验证一类新的癌症成像生物标记物，用于快速临床部署。凭借在基础和临床癌症生物学、创新药物化学和高通量小分子筛选方面的进展，我们的实验室已经确定了肿瘤选择性转运蛋白(TSPO)配体，这些配体有望作为正电子发射断层扫描(PET)显像剂进一步开发。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、增殖和细胞凋亡。TSPO水平的升高在肿瘤学中得到了很好的证明，肿瘤水平与肿瘤的增殖、侵袭和转移有关。此外，我们的实验室已经机械地将TSPO配体与胶质瘤中的丝裂原活化蛋白激酶(MAPK)信号联系在一起。利用这一观察结果，我们已经证明了TSPO配体PET可以在这种情况下用于评估MAPK通路的抑制。总而言之，这些数据证明了TSPO配体PET作为肿瘤学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临床可翻译的、对肿瘤具有选择性的TSPO成像配体，以促进改善人脑胶质瘤的检测、分子特征和预后。我们的具体目标是[1]优化用于体内PET成像的新型、肿瘤选择性的TSPO配体，[2]开发用正电子发射同位素氟-18标记有前景的TSPO配体的方法，以及[3]在体内评价有前景的TSPO成像配体。 公共卫生相关性：这项多学科提案旨在开发、评估和验证新型转位蛋白(TSPO)正电子发射断层扫描(PET)成像配体作为潜在的癌症成像探针。我们将验证TSPO配体可以被开发和优化用于癌症成像研究的假设。我们预计，这些研究将为未来最有希望的新型TSPO配体的临床应用奠定基础，用于患者的癌症成像研究。

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. PUBLIC HEALTH RELEVANCE: This multidisciplinary proposal seeks to develop, evaluate, and validate novel translocator protein (TSPO) positron emission tomography (PET) imaging ligands as potential cancer imaging probes. We will test the hypothesis that TSPO ligands can be developed and optimized for cancer imaging studies. We anticipate that these studies will lay the framework for future advancement of the most promising novel TSPO ligands to the clinic for cancer imaging studies in patients.