Novel PET Imaging of Glucose Transport

葡萄糖转运的新型 PET 成像

• 批准号: 8322155
• 负责人: FARAMARZ ISMAIL-BEIGI
• 金额: $ 33.47万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8322155
• 关键词: 2-Fluoro-2-deoxyglucose; 6-deoxyglucose; Animal Model; Animals; Applications Grants; Biochemical; Biodistribution; Biological Assay; Blood; Blood Vessels; Brain; Carbon; Cell Culture Techniques; Clinical; Cyclotrons; Data; Data Collection; Deoxyglucose; Development; Diabetes Mellitus; Discrimination; Disease; Disease Progression; Dose; Energy-Generating Resources; Epidemic; Excretory function; Experimental Models; Eye; Future; GLUT4 gene; Glucose; Glucose Transporter; Goals; Gold; Half-Life; Heart; Hexokinase 2; Human; Hydroxyl Radical; Hyperglycemia; Image; In Vitro; Individual; Injection of therapeutic agent; Insulin; Insulin Resistance; Kidney; Kinetics; Label; Lead; Maintenance; Malignant Neoplasms; Mammalian Cell; Measurement; Measures; Metabolism; Methodology; Methods; Modeling; Monitor; Myocardium; Nerve; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Magnetic Resonance; Obesity; Organ; Patients; Pharmaceutical Preparations; Phosphorylation; Physiological; Positron-Emission Tomography; Protocols documentation; Radiation; Radioactive; Radioactivity; Radiolabeled; Radiopharmaceuticals; Rattus; Research; Running; SLC2A1 gene; Safety; Series; Site; Skeletal Muscle; Spectrum Analysis; Streptozocin; Testing; Time; Tissue Sample; Tissues; Tracer; United States; Urine; Validation; abstracting; base; bone; diabetic; dosage; glucose analog; glucose metabolism; glucose transport; hexokinase; in vivo; insight; interstitial; mathematical model; novel; pre-clinical; radiotracer; response; sugar; uptake; urinary

Abstract Diabetes mellitus is an epidemic in the United States and the world. Type 2 diabetes, the most prevalent form of diabetes, is commonly associated with insulin resistance that often precedes the onset of overt hyperglycemia. Here we propose to further develop and employ a PET-scanning-based methodology to measure glucose transport in skeletal muscle, heart and other tissues under normal and insulin-resistant states. The method has two components: a radiopharmaceutical and a mathematical model. Specifically, we have developed a new radiopharmaceutical 18F-labeled 6-fluoro-6-deoxy-D-glucose ([18F]6FDG) so that the bio- and kinetic distribution of the compound can be quantitatively measured with positron emission tomography (PET). [18F]6FDG, unlike 2-fluoro-2-deoxy-D-glucose ([18F]2FDG) that is commonly used in PET studies, lacks a hydroxyl on carbon 6, and hence is transported but not phosphorylated. The new model relates the PET-measured time-course of radioactive glucose analogs, [18F]6FDG and [18F]2FDG, to the fluxes, transport capacities, phosphorylation and concentrations of glucose. Our overall objective is to validate and apply methodologies for the in vivo quantification of glucose transport, phosphorylation and interstitial and intracellular concentrations in skeletal muscle, heart and brain in normal and abnormal conditions. We use biochemical analyses, in vitro transporter assays, in vivo animal models, PET scanning and mathematical models. We will also perform preclinical and clinical PET studies. Importantly, the PET scan data will enable us to calculate the effect of insulin and other agents on the rate of glucose transport in the above tissues in normal and disease states. The goal is to establish a method that can be used in vivo in humans to determine influx and efflux rates of glucose, intracellular and interstitial concentrations of glucose, the phosphorylation rate of glucose, and most importantly, the maximal glucose transport capacity (Vmax) from the time-series of PET images following sequential injections of [18F]6FDG and [18F]2FDG. Determination of insulin-stimulated glucose transport will provide insight into mechanisms underlying abnormal glucose metabolism in diabetes and will enable monitoring the progression of the disease and its response to specific treatments. Hence, progress on this grant proposal will significantly contribute to our ability to evaluate and optimally manage patients at the individual level.

抽象的 糖尿病是美国和世界的流行病。 2型糖尿病，最普遍 糖尿病的形式通常与胰岛素耐药性有关，胰岛素耐药性通常在明显的发作之前 高血糖。在这里，我们建议进一步开发并采用基于宠物的方法来 在正常和胰岛素耐药物下测量骨骼肌，心脏和其他组织中的葡萄糖转运 国家。该方法具有两个组成部分：放射性药物和数学模型。具体来说， 我们已经开发了一种新的放射性药物18F标记的6-氟-6-脱氧-D-葡萄糖（[18f] 6fdg），所以 可以通过正电子发射来定量测量该化合物的生物和动力学分布 断层扫描（宠物）。 [18F] 6fdg，与2-氟-2-脱氧-D-葡萄糖（[18F] 2fdg）不同，通常用于 宠物研究，缺乏碳6上的羟基，因此被运输但未被磷酸化。新的 模型将放射性葡萄糖类似物（[18F] 6fdG和[18f] 2fdg）的宠物测量时间道与 通量，转运能力，磷酸化和葡萄糖浓度。 我们的总体目标是验证和应用方法来进行体内葡萄糖定量 骨骼肌，心脏和大脑的运输，磷酸化以及间质和细胞内浓度 在正常和异常条件下。我们在体内使用生化分析，体外转运蛋白分析 动物模型，PET扫描和数学模型。我们还将执行临床前和临床宠物 研究。重要的是，PET扫描数据将使我们能够计算胰岛素和其他药物对 正常和疾病状态中上述组织中的葡萄糖转运速率。 目的是建立一种可以在人类体内使用的方法来确定涌入和外排率 葡萄糖的葡萄糖，葡萄糖的细胞内和间质浓度，葡萄糖的磷酸化速率和 最重要的是，PET图像的时间序列的最大葡萄糖运输能力（VMAX） 在[18F] 6FDG和[18F] 2FDG的顺序注射后。 胰岛素刺激的葡萄糖转运的确定将提供对基础机制的洞察力 糖尿病中葡萄糖代谢异常，将使疾病及其进展 对特定治疗的反应。因此，该赠款提案的进展将对我们的 能够评估和最佳管理个人水平的患者的能力。

项目成果

Analysis of metabolism of 6FDG: a PET glucose transport tracer.

• DOI: 10.1016/j.nucmedbio.2010.12.007
• 发表时间: 2011-07
• 期刊: Nuclear medicine and biology
• 影响因子: 3.1
• 作者: Muzic RF Jr;Chandramouli V;Huang HM;Wu C;Wang Y;Ismail-Beigi F
• 通讯作者: Ismail-Beigi F

Human radiation dosimetry of 6-[18F]FDG predicted from preclinical studies.

根据临床前研究预测的 6-[18F]FDG 人体辐射剂量测定。

• DOI: 10.1118/1.4866217
• 发表时间: 2014
• 期刊: Medical physics
• 影响因子: 3.8
• 作者: MuzicJr,RaymondF;Chandramouli,Visvanathan;Huang,Hsuan-Ming;Wu,Chunying;Hatami,Ahmad;Ismail-Beigi,Faramarz
• 通讯作者: Ismail-Beigi,Faramarz