The Development of Radiolabeled Positional isomers of [11C]Pyruvate for Imaging Cancer Metabolism

癌症筛查和诊断策略的目标是在窗口期内发现疾病 避免过度治疗和治疗不足。成像生物标志物的发现，改善了 对侵袭性和非侵袭性疾病变异的鉴别将增强我们治疗患者的能力 适当地。与正常细胞相反，癌细胞通常将丙酮酸盐还原为乳酸盐，这是已知的现象。 瓦尔堡效应。这种代谢的改变为区分肿瘤和健康组织提供了机会 通过非侵入性分子成像。代谢重编程癌细胞对葡萄糖的需求增加 正电子发射断层扫描（PET）成像利用[18 F]氟脱氧葡萄糖，[18 F]FDG， 通常以高灵敏度描绘肿瘤。然而，前列腺癌（PCa）通常不表现出 瓦尔堡效应，PCa中[18 F]FDG摄取较低。[18F]FDG的替代生物标志物将是有价值的工具 PCa是美国男性中最常诊断的癌症。随着PCa的发展 对阻断雄激素受体（AR）信号传导的治疗产生抗性，它转变为糖酵解表型 以丙酮酸还原为乳酸为特征。丙酮酸是细胞代谢的关键，因此 一个有吸引力的候选人成像癌症代谢的PET。碳-11标记的丙酮酸将 PET的优点，包括增强的灵敏度和生化分辨率，对一种必需的代谢物， 特定的代谢命运对疾病分期和预后、监测治疗和 寻找新的治疗靶点我们建议在C-1位置（[1- 11]）用碳-11标记丙酮酸盐。 11 C]丙酮酸）或C-3位（[3- 11 C]丙酮酸）。通过在不同的位置标记这个简单的分子， 可以推断丙酮酸的代谢命运，从而确定PCa肿瘤的侵袭性。 目前这些分子的合成不足以满足成像需要。[1- 11 C]-的自动化合成 和[3- 11 C]丙酮酸经D-[11 C]丙氨酸是本发明的第一个目的。我们将评估[1- 11 C]-和[3- 11 C]-。 11 C]丙酮酸流量在两个临床前异种移植模型的前列腺癌：雄激素敏感的LNCaP，我们预计， 主要将丙酮酸氧化为乙酰辅酶A和CO2，以及雄激素不敏感的、过表达N-Myc的PC 3， 我们预计它主要将丙酮酸还原为乳酸。我们假设放射性的清除 从LNCaP肿瘤中释放的[1- 11 C]丙酮酸盐的施用将显著快于 给予[3- 11 C]丙酮酸盐。相比之下，我们预计PC 3肿瘤的清除率相似。最后， 我们将利用PCa细胞系中已知的代谢差异来测量PCa细胞中丙酮酸的代谢命运。 雄激素的存在或不存在。我们的预期是，攻击性和AR信号阻断将是一个很好的选择。 与磷酸化Akt、N-Myc和LDHA水平升高相关，因此增加了 丙酮酸转化为乳酸。在此基础上，我们的目标是验证[1- 11 C]-和[3- 11 C]丙酮酸作为癌症的成像生物标志物 代谢和工具的非侵入性评估肿瘤的侵略性。

The objectives of screening and diagnostic strategies in cancer are to detect disease within the window of curability and avoid over- and under-treatment. The discovery of imaging biomarkers that improve the identification of aggressive versus non-aggressive variants of disease would enhance our ability to treat patients appropriately. In contrast to normal cells, cancer cells typically reduce pyruvate to lactate, a phenomenon known as the Warburg effect. This altered metabolism provides an opportunity to distinguish tumors from healthy tissue by non-invasive molecular imaging. Increased demand for glucose by metabolically reprogrammed cancer cells is exploited by positron emission tomography (PET) imaging using [18F]fluorodeoxyglucose, [18F]FDG, which typically delineates tumors with high sensitivity. Prostate cancer (PCa), however, does not typically exhibit the Warburg effect, and [18F]FDG uptake in PCa is low. Alternative biomarkers to [18F]FDG would be valuable tools with which to diagnose and stage PCa, the most frequently diagnosed cancer in men in the US. As PCa develops resistance to therapies that block androgen receptor (AR) signaling, it transitions to a glycolytic phenotype characterized by reduction of pyruvate to lactate. Pyruvate is at the nexus of cellular metabolism, and is therefore an attractive candidate for imaging cancer metabolism by PET. Carbon-11-labeled pyruvate couples the advantages of PET, including enhanced sensitivity and biochemical resolution, to an essential metabolite whose specific metabolic fate has important implications for disease staging and prognosis, monitoring therapy, and identifying new therapeutic targets. We propose to label pyruvate with carbon-11 at either the C-1 position ([1- 11C]pyruvate) or the C-3 position ([3-11C]pyruvate). By labeling this simple molecule at different positions, it will be possible to infer the metabolic fate of pyruvate and therefore determine the aggressiveness of PCa tumors. Current syntheses of these molecules are inadequate for imaging needs. The automated synthesis of [1-11C]- and [3-11C]pyruvate via D-[11C]alanine is the first aim of this proposal. We will evaluate [1-11C]- and [3- 11C]pyruvate flux in two preclinical xenograft models of PCa: androgen-sensitive LNCaP, which we expect to predominantly oxidize pyruvate to acetyl-CoA and CO2, and androgen-insensitive, N-Myc overexpressing PC3, which we expect to predominantly reduce pyruvate to lactate. We hypothesize that the clearance of radioactivity from LNCaP tumors will be significantly faster following administration of [1-11C]pyruvate than following administration of [3-11C]pyruvate. By contrast, we expect the clearance rates to be similar in PC3 tumors. Finally, we will exploit known metabolic differences in PCa cell lines to measure the metabolic fate of pyruvate in the presence or absence of androgens. Our expectation is that aggressiveness and AR signaling blockade will be associated with elevated levels of phospho-Akt, N-Myc, and LDHA, and consequently increased reduction of pyruvate to lactate. On this basis, we aim to validate [1-11C]- and [3-11C]pyruvate as imaging biomarkers of cancer metabolism and tools for non-invasive assessment of tumor aggressiveness.