NOVEL PET AGENT FOR MYOCARDIAL PERFUSION IMAGING

用于心肌灌注成像的新型宠物试剂

基本信息

批准号：
8883682
负责人：
Vijay Sharma
金额：
$ 37.43万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-16 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8883682
关键词：
ABCB1 gene Address Anterior Descending Coronary Artery Biochemical Blood Blood flow Canis familiaris Cardiac Myocytes Cardiovascular Diseases Cause of Death Cells Characteristics Complex Coronary Arteriosclerosis Country Cyclotrons Data Defect Developing Countries Development Diagnosis Disease Drug Kinetics Europe Excretory function FDA approved Gallium Generations Goals Gold Half-Life Heart Image Injection of therapeutic agent Investments Isotopes KB Cells Label Lead Left Left ventricular structure Ligands Ligation Liver MCF7 cell Measurement Mediating Membrane Potentials Mitochondria Modeling Molecular Target Monitor Multi-Drug Resistance Mus Myocardial Myocardial perfusion Myocardium Oryctolagus cuniculus P-Glycoprotein Pathway interactions Patients Perfusion Play Positron-Emission Tomography Production Property Radioisotopes Radiopharmaceuticals Rattus Resolution Rest Role Safety Site Stress Stroke Structure-Activity Relationship Technology Time Tissues Tracer Translating United States United States National Institutes of Health Validation X-Ray Computed Tomography abstracting arm attenuation base clinical Diagnosis comparative cost dosimetry imaging agent improved inhibitor/antagonist intravenous injection microPET microPET/CT mitochondrial membrane myocardial infarct sizing novel radiotracer single photon emission computed tomography statistics tool uptake

项目摘要

DESCRIPTION (provided by applicant): Development of Mechanism-Based PET Flow Tracer Abstract: Cardiovascular disease is among the leading causes of death in the United States. Myocardial perfusion imaging (MPI), a versatile tool in clinical diagnosis, plays an important role in the noninvasive assessment of coronary artery disease (CAD). Currently, common single-photon emission computed tomography (SPECT) MPI agents comprise 201Tl or moderately hydrophobic and cationic 99mTc-complexes, such as 99mTc-sestamibi and 99mTc-tetrofosmin, for determining myocardial blood flow (MBF) in patients. However, SPECT imaging agents have inherent limitations, including the continuing threat of serious shortages of 99mMo/99mTc-generators. Additionally, current SPECT tracers also suffer from shortcomings in pharmacokinetics, myocardial extraction, redistribution of the radiotracer to non-targeted tissues over time, and non-linearity of uptake at elevated blood flow (the "roll-off" phenomenon). By comparison, positron emission tomography (PET) provides technical advantages, including higher spatial resolution, improved attenuation correction, and the capability to perform quantitative measurements at the peak of stress. Commonly employed PET MPI tracers are: 82RbCl, 13NH3, and H215O. However, the utility of these agents is limited due to their short physical half-life (<10 min), thus posing difficulties for easy access to these agents. Other promising 18F-labeled agents such as18F- BnTP, a mitochondrial membrane potential probe, and 18F-BMS-747158, 18F-10, 18F-RP1004, and 18F-MCI27, mitochondrial complex I inhibitors, have various strengths and weaknesses, but also depend on a 18F-based distribution model, which may not be readily accessible to underserved regions of the U.S. or other developing countries. Thus, PET tracers demonstrating high myocardial first pass extraction, rapid clearance from the liver, retention within the myocardium to enable delayed imaging, and based on isotopes that could potentially be generator-produced on site (rather than cyclotron produced) would facilitate wide access to PET MPI. To address this unmet goal, we have identified a lead cationic and moderately hydrophobic radiopharmaceutical 1A based on generator-produced gallium-68 that demonstrates high extraction into the myocardium of normal mice and rats, including efficient clearance from the blood pool and liver driven by the multidrug resistance P- glycoprotein (Pgp) transporter. The agent 1A is retained in myocardium over time and remains nonmetabolized, allowing stable distribution and high count statistics that translate into high quality myocardial images. Importantly, both microPET/CT (68Ga) and nanoSPECT/CT (67Ga) reveal high accumulation of 1A in heart followed by facile clearance from liver 60 min post intravenous injection in rats. Finally, following intravenous injection of 67Ga-1A, nanoSPECT/CT imaging clearly visualized the non-perfused region of the left ventricle wall indicating the potential of our lead agent to noninvasively image the myocardial perfusion defect in rat models. Thus, armed with these pilot data, specific objectives of this R01 proposal are: 1) Perform a focused SAR study to further optimize biochemical targeting and pharmacokinetics of our lead 68Ga- radiopharmaceutical as a potential MPI agent. 2) Perform mechanism-based assessment and validation of novel 68Ga-radiopharmaceuticals derived from our focused SAR studies in cardiomyocytes, HEPG2 cells, Pgp- expressing KB cells, Pgp-transfected MCF-7 cells, and correlate these data with 99mTc-Sestamibi, a well- validated and FDA approved SPECT probe under similar conditions. 3) Evaluate promising leads via pharmacokinetic analysis in rats, determining extraction fractions of radiopharmaceuticals into myocardium and comparative analysis of heart/liver ratios under similar conditions with 99mTc-Sestamibi and other potential 18F MPI agents. 4) Characterize and validate the lead 68Ga-radiopharmaceutical 1A or other potential leads emerging through SAR studies as a noninvasive MPI agent by assessment of myocardial infarct size, first pass extraction, and flow-extraction correlation under stress/rest conditions in rats, followed by assessment of leads in rabbits, using microPET imaging. 5) Characterize the potential of our lead agent or a second-generation 68Ga- radiopharmaceutical as a MPI agent in canine models; perform safety pharmacological profile studies, dosimetry analysis, and prepare eIND filing materials. Successful execution of the outlined objectives should provide a molecular-targeted 68Ga-PET agent for MPI and management of CAD.

描述（由申请人提供）：基于机制的宠物流示踪剂摘要的开发：心血管疾病是美国的主要死亡原因之一。心肌灌注成像（MPI）是一种临床诊断的多功能工具，起着重要作用在冠状动脉疾病（CAD）的无创评估中。目前，常见的单光子发射计算机断层扫描（SPECT）MPI代理包含201TL或中度疏水和阳离子99MTC-复合物，例如99MTC-SESTAMIBI和99MTC-四膜氨基蛋白，用于确定患者的心肌血流（MBF）。但是，SPECT成像剂具有固有的局限性，包括持续的99mmo/99mTC发电机的严重短缺威胁。此外，当前的SPECT示踪剂还遭受了药代动力学，心肌提取，放射性示踪剂的重新分布，随着时间的流逝，将放射性示踪剂重新分布到非靶向组织以及在升高血流时摄取的非线性（“滚动”现象）。相比之下，正电子发射断层扫描（PET）提供了技术优势，包括更高的空间分辨率，改善的衰减校正以及在应力峰值下进行定量测量的能力。通常使用的PET MPI示踪剂为：82RBCL，13NH3和H215O。但是，由于它们的身体半衰期短（<10分钟），这些代理的效用受到限制，因此在容易获得这些代理方面遇到了困难。其他有希望的18F标记剂，例如18F-BNTP，线粒体膜电位探针和18F-BMS-747158、18F-10、18F-RP1004和18F-MCI27和18F-MCI27，和线粒体复杂的I抑制剂，但对居民的依赖，但依赖于18F的模型，该区域的分配均可依赖于18F的模型。美国或其他发展中国家。因此，表现出高心肌第一通过提取，肝脏的快速清除，在心肌内的保留以实现延迟成像的宠物示踪剂，并且基于同位素有可能在现场产生的同位素（而不是产生的转基因），可以促进对PET MPI的广泛访问。为了解决这个未满足的目标，我们确定了基于发电机生产的甘油-68的铅阳离子阳离子和中等疏水的放射性药物1a，该甘露仪表现出高度提取到正常小鼠和大鼠的心肌中，包括从血液池中有效清除，以及由多种耐药性P-Glycoprote priver驱动的肝脏和肝。代理1a随着时间的推移保留在心肌中，并保持未代谢，从而允许稳定的分布和高计数统计量转化为高质量的心肌图像。重要的是，Micropet/CT（68GA）和Nanospect/CT/CT（67GA）均显示1A的心脏高积聚，然后在大鼠静脉注射后60分钟内易于清除。最后，在静脉注射67GA-1A之后，纳米光谱/CT成像清楚地表达了左心室壁的非灌注区域，这表明我们的铅剂在大鼠模型中无创图像心肌灌注缺陷的潜力。因此，使用这些试点数据武装，该R01提案的特定目标是：1）进行重点的SAR研究，以进一步优化我们的铅68GA-Ga-radiopharemaceutical的生物化学靶向和药代动力学，作为潜在的MPI药物。 2）基于机制的评估和验证，对我们在心肌细胞，HEPG2细胞，PGP表达KB细胞，PGP转染的MCF-7细胞中的专注SAR研究得出的新型68GA-Radiopharmaceuticals，由99MTC-SESTAMIBI（在良好的情况下，pgp cypected and Spect和FDA）将这些数据相关联。 3）通过大鼠的药代动力学分析评估有希望的铅，确定放射性药物的提取部分在与99mtc-Sestamibi和其他潜在的18F MPI药物的相似条件下的心脏/肝比对心脏/肝比的比较分析。 4）通过评估心肌梗塞大小，首次通过提取和在大鼠的压力/休息条件下，通过评估心肌梗塞大小，首次通过提取和流动性相关性来表征和验证通过SAR研究作为无创MPI剂的铅68GA-radiopharmaceutical 1a或其他潜在的潜在客户，然后使用兔子的铅来评估Micropet Imaging。 5）表征我们的铅剂或第二代68ga-radiopharmaceutical在犬模型中的MPI剂；进行安全药理学研究，剂量法分析并准备申请材料。成功执行概述的目标应为MPI和CAD管理提供分子定位的68GA-PET代理。