Radiolabeled FASN Inhibitors for PET Imaging

代谢重编程是许多癌症的标志。首先由瓦尔堡观察到，肿瘤细胞从 线粒体氧化磷酸化（MOP）转化为有氧糖酵解（AG）。AG的能源效率低于 MOP，但它似乎通过形成代谢性的- 这些产物可以被掺入膜脂质、信号分子、氨基酸和核苷酸中。 已经证明，有助于从头脂肪生成（从乙酰辅酶A合成脂肪酸）的酶 在许多人类癌症中过度表达。脂肪酸合成酶（Fatty acid synthase，FATCH）催化脂肪酸的合成。 棕榈酸来源于乙酰辅酶A和丙二酰辅酶A，近年来已体外显示 在包括乳腺癌、前列腺癌、结肠直肠癌和神经胶质瘤在内的癌症中过表达，并有助于药物治疗。 阻力过表达FXR与不良预后相关。正常对照组FGFAP表达 组织是非常低的，并且FGFAP似乎在肿瘤增殖和恶性化中起重要作用， 已被提议作为各种癌症的治疗靶点。已显示抑制FGFAP可诱导 细胞凋亡，减少肿瘤生长，并在包括乳腺癌和前列腺癌在内的多种癌症中赋予化学敏感性。 前列腺癌的临床诊断包括前列腺特异性抗原血液筛查和活检。患者 通常根据临床T评分、PSA计数和Gleason评分进行分层。目前，仍难以 区分患有侵袭性和惰性形式疾病的患者， 前列腺癌是必要的，以更好地预测结果和对治疗的反应。Festival被提议作为一个 有希望的候选生物标志物，但其相关性尚未通过非侵入性手段在体内评估。 正电子发射断层扫描（PET）成像是一个快速发展的诊断领域，使非- 对疾病的侵入性研究。本项目拟开发一个小系列的标记有 用于成像前列腺癌细胞系和小鼠异种移植物中的FcR表达的碳-11或氟-18 模型为了评估FIGH 3的表达，将基于11 C或18F合成一系列标记有11 C或18F的新型示踪剂。 迄今为止报道的最有效的Festival抑制剂。据我们所知，这个项目是第一次尝试 通过使用酶抑制剂的分子成像来研究Festival的表达。如果成功，该计划将 提供新的放射性标记探针，使用非侵入性PET识别和定量体内FASN表达 显像这种能力将提供一种工具，用于研究FXR生物学，鉴定FXR阳性肿瘤并鉴定 可能受益于抗叶酸治疗的患者。非侵入性的检查可能获得重要的预后价值。 监测疾病进展期间和治疗干预过程中的FcB表达。 这是特别有趣的，因为最近有报道称，在携带肿瘤的动物中使用了Festival疗法， 在早期临床试验中有很好的抗肿瘤作用。

Metabolic reprogramming is a hallmark of many cancers. First observed by Warburg, tumor cells switch from mitochondrial oxidative phosphorylation (MOP) to aerobic glycolysis (AG). AG is less energy efficient than MOP, but it appears to confer advantages to rapidly proliferating cells through formation of metabolic by- products that can be incorporated into membrane lipids, signaling molecules, amino acids and nucleotides. Enzymes that contribute to de novo lipogenesis, the synthesis of fatty acids from acetyl-CoA, have been shown to be overexpressed in a number of human cancers. Fatty acid synthase (FASN) catalyzes the synthesis of palmitic acid from acetyl-CoA and malonyl-CoA and in recent years has been shown ex v ivo to be overexpressed in cancers, including breast, prostate, colorectal and glioma, and to contribute to drug resistance. Overexpression of FASN is associated with a poor prognosis. As e xpression of FASN in normal tissue is very low, and FASN appears to play an i mportant role in tumor proliferation and malignancy, it has been proposed as a therapeutic target in various cancers. Inhibition of FASN has been shown to induce apoptosis, reduce tumor growth and impart chemosensitivity in multiple cancers including breast and prostate. Clinical diagnosis of prostate cancer involves prostate-specific antigen blood screening and biopsy. Patients are typically stratified according to clinical T-score, PSA count and Gleason score. At present, it remains difficult to distinguish between patients with aggressive and indolent forms of the disease, and new biomarkers for prostate cancer are necessary to better predict outcome and response to therapy. FASN has been proposed as a promising candidate biomarker, but its relevance has not been assessed in vivo by non-invasive means. Positron emission tomography (PET) imaging is a r apidly growing diagnostic field that enables the non- invasive study of disease. This project proposes to develop a small series of FASN inhibitors labeled with carbon-11 or fluorine-18 for imaging FASN expression in prostate cancer cell lines and mouse xenograft models. To assess FASN expression, a series of novel tracers labeled with 11C or 18F will be synthesized based on the most potent FASN inhibitors reported to date. To our knowledge this project represents the first attempt to study FASN expression via molecular imaging using inhibitors of the enzyme. If successful, this program will provide new radiolabeled probes to identify and quantify FASN expression in vivo using non-invasive PET imaging. This capability will provide a tool to study FASN biology, identify FASN positive tumors and identify patients who may benefit from anti-FASN therapy. Significant prognostic value may be attained by noninvasive monitoring of FASN expression during disease progression and over the course of therapeutic interventions. This is particularly intriguing in light of the recent reports of FASN therapies in tumor bearing animals and promising antitumor effects in early clinical trials.