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内发现疾病 可治愈性，避免治疗过度和不足。成像生物标记物的发现改善了 识别侵袭性和非侵袭性疾病的变种将增强我们治疗患者的能力 恰如其分。与正常细胞不同，癌细胞通常将丙酮酸还原为乳酸，这是一种众所周知的现象。 作为华宝效应。这种新陈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。代谢重新编程的癌细胞对葡萄糖的需求增加 是通过使用[18F]氟脱氧葡萄糖，[18F]FDG的正电子发射断层扫描(PET)成像来开发的， 通常以高敏感度勾画肿瘤。然而，前列腺癌(PCA)通常不会表现出 Warburg效应和[18F]FDG在PCA中的摄取较低。替代[18F]FDG的生物标志物将是有价值的工具 用它来诊断和分期前列腺癌，这是美国最常见的男性癌症。随着PCA的发展 对阻断雄激素受体(AR)信号的治疗产生抵抗，它会转变为糖酵解表型 以丙酮酸还原为乳酸为特征的。丙酮酸是细胞新陈代谢的结点，因此 利用正电子发射计算机断层扫描成像癌症代谢的一个有吸引力的候选者。碳-11标记的丙酮酸偶联 PET的优点，包括对一种基本代谢物的增强敏感性和生物化学分辨率，其 特定的代谢命运对疾病的分期和预后、监测治疗和 确定新的治疗靶点。我们建议在C-1位([1-])上用碳-11标记丙酮酸 11C]丙酮酸)或C-3位([3-11C]丙酮酸)。通过在不同的位置标记这种简单的分子，它将 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。[1-11C]-的自动合成 通过D-[11C]丙氨酸合成的[3-11C]丙酮酸是本方案的首要目标。我们将评估[1-11C]-和[3- 11C]两种临床前PCa异种移植模型中的丙酮酸流量：雄激素敏感型LNCaP，我们预计 主要是将丙酮酸氧化成乙酰辅酶A和二氧化碳，以及雄激素不敏感的N-Myc过度表达PC3， 我们预计这主要是将丙酮酸还原为乳酸。我们假设放射性物质的清除 使用[1-11C]丙酮酸后，LNCaP肿瘤的消退速度明显快于 给药[3-11C]丙酮酸。相比之下，我们预计PC3肿瘤的清除率与此类似。最后， 我们将利用PCA细胞系中已知的代谢差异来测量丙酮酸在 雄激素存在或不存在。我们的预期是攻击性和AR信号封锁将是 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[1-11C]-和[3-11C]丙酮酸作为癌症的成像生物标志物 用于非侵入性评估肿瘤侵袭性的代谢和工具。

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.