Molecular Imaging of Pyruvate Kinase M2

丙酮酸激酶 M2 的分子成像

• 批准号: 10672270
• 负责人: Corinne Beinat
• 金额: $ 19.69万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672270
• 关键词: Adopted; Binding; Biodistribution; Biological Models; Blood - brain barrier anatomy; Brain; Cardiovascular system; Cell Culture Techniques; Cell Proliferation; Cell division; Cell physiology; Cells; Cellular Metabolic Process; Clinical Research; Data; Development; Disease; Dose; Enzymes; Evaluation; Fluorine; Formulation; Gallbladder; Generations; Glioblastoma; Glucose; Glycolysis; Goals; Heart failure; Human; Image; Impairment; Learning; Link; Malignant Neoplasms; Mediating; Mediator; Metabolic; Metabolism; Modeling; Mus; Myocardial dysfunction; Myocardium; Neurologic; Normal tissue morphology; Nucleotides; Pathologic; Pathology; Patients; Penetration; Phosphorylation; Play; Positron-Emission Tomography; Primary Brain Neoplasms; Proliferating; Property; Protein Isoforms; Pyruvate Kinase; Quality Control; Radiation Dose Unit; Radiolabeled; Radiometry; Radiopharmaceuticals; Reporting; Research; Rodent; Role; Scanning; Signal Transduction; Site; Small Interfering RNA; Solubility; Specificity; Structure; Technology; Testing; Translating; Translations; Visualization; Work; absorption; blood glucose regulation; clinical candidate; clinical translation; clinically relevant; first-in-human; glucose metabolism; glucose transport; healthy volunteer; human model; human study; human subject; imaging modality; improved; in vivo; innovation; intravenous administration; knock-down; lipophilicity; molecular imaging; neuroinflammation; non-invasive imaging; novel; painful neuropathy; patient population; pharmacologic; preclinical study; radiotracer; response; small molecule; success; tissue regeneration; uptake; white matter

ABSTRACT. Glucose homeostasis plays a critical role in multiple cellular processes, and impaired or altered glucose metabolism is associated with a wide range of pathological states. A key step in glucose metabolism is catalyzed by the glycolytic enzyme pyruvate kinase. Proliferating cells almost universally express the pyruvate kinase M2 (PKM2) isoform, which can assume either an active or inactive state. PKM2 is at the nexus of cellular metabolism, and determines whether cells metabolize glucose into ATP or use it to make more of the necessary building blocks for cell division. Multiple studies have demonstrated how dynamic changes in PKM2 expression contribute to altered glucose metabolism in different contexts. The ability to non-invasively visualize and track dynamic changes in PKM2 expression will enable improved understanding of altered glucose metabolism and the downstream mediators of glycolysis in multiple disease states. The lack of PKM2 expression within the brain and myocardium make this imaging strategy highly promising for neurological and cardiovascular applications. We have recently reported the development and human translation of [18F]DASA-23, the first clinically-relevant and specific radiopharmaceutical to detect, localize, and quantify PKM2 using positron emission tomography (PET) imaging. We have determined the biodistribution, radiation dosimetry, and brain distribution of [18F]DASA- 23 in healthy volunteers, and have explored its ability to visualize PKM2 expression in one potential application of patients with primary brain tumors. Although our results highlight the potential of imaging PKM2, [18F]DASA- 23 has several limitations that impedes widespread use, and the ability to study PKM2-mediated glycolytic reprogramming in broader applications. This includes high radiation dose to the gallbladder wall, a high degree of non-specific binding within white matter in the brain, and poor solubility in radiotracer formulation vehicle. This proposal will develop novel PKM2 radiotracers to overcome the limitations of [18F]DASA-23. Development of a safe and reliable PKM2 radiotracer will enable repeat assessment of the dynamic alterations in glucose metabolism in multiple different applications and patient populations. We will establish the synthesis and fluorine- 18 radiolabeling of two candidate small molecules with improved physicochemical properties relative to DASA- 23, pharmacological activity and specificity for PKM2, and the potential for radiolabeling. We will automate the radiosyntheses and characterize uptake and specificity in cell culture (Aim 1), determine biodistribution and radiation dosimetry (Aim 2), and assess the ability to visualize PKM2 expression in one potential application of primary brain tumors (Aim 3). Success of this proposal will develop novel radiotracers for visualizing a hallmark of metabolism. This will have important ramifications for studying altered glucose metabolism in multiple applications and could improve our collective understanding of metabolic adaptations in disease. Importantly, this technology will be adopted by a wide range of users in different pre-clinical and clinical studies.

抽象的。 葡萄糖稳态在多个细胞过程中起着至关重要的作用，葡萄糖受损或改变 代谢与广泛的病理状态有关。葡萄糖代谢的关键步骤是催化的 通过糖酵解酶丙酮酸激酶。增殖细胞几乎普遍表达丙酮酸激酶M2 （PKM2）同工型，它可以假定活性状态或非活动状态。 PKM2处于细胞代谢的联系， 并确定细胞是将葡萄糖代谢为ATP还是使用它来制造更多必要的建筑物 细胞分裂的块。多项研究表明，PKM2表达的动态变化如何贡献 在不同情况下改变葡萄糖代谢。非侵入性可视化和跟踪动态的能力 PKM2表达的变化将使人们能够改善对葡萄糖代谢改变的理解和 多种疾病状态下糖酵解的下游介质。大脑中缺乏PKM2表达 心肌使这种成像策略对于神经系统和心血管应用高度有希望。 我们最近报道了[18F] DASA-23的发展和人类翻译，这是第一个与临床相关的 以及使用正电子发射断层扫描的特定放射性药物来检测，本地化和量化PKM2 （PET）成像。我们已经确定了[18f] dasa-的生物分布，辐射剂量法和大脑分布 23在健康的志愿者中，并探索了其在一个潜在应用中可视化PKM2表达的能力 原发性脑肿瘤的患者。尽管我们的结果突出了成像PKM2的潜力，但[18f] dasa- 23有几个限制，阻碍了广泛使用，并且能够研究PKM2介导的糖酵解 在更广泛的应用中重新编程。这包括高度的高辐射剂量，高度 在大脑中白质中的非特异性结合，而放射性示踪剂配方型中的溶解度差。 该提案将开发新的PKM2放射性示例，以克服[18F] DASA-23的局限性。发展 安全可靠的PKM2放射性示例将重复评估葡萄糖的动态变化 多种不同应用和患者人群中的代谢。我们将建立合成和氟 18两个候选小分子的放射标记具有改善的理化特性相对于DASA- 23，PKM2的药理活性和特异性，以及放射标记的潜力。我们将自动化 放射合成并表征细胞培养中的摄取和特异性（AIM 1），确定生物分布和 辐射剂量测定法（AIM 2），并评估在一个潜在应用中可视化PKM2表达的能力 原发性脑肿瘤（AIM 3）。该提议的成功将开发出新颖的放射性示例，以可视化标志 代谢。这将具有研究多种葡萄糖代谢改变的重要分析 应用，可以提高我们对疾病代谢适应的集体理解。重要的是， 在不同的临床和临床研究中，多种用户将采用这项技术。