NOVEL PET AGENT FOR MYOCARDIAL PERFUSION IMAGING

用于心肌灌注成像的新型宠物试剂

• 批准号: 8511806
• 负责人: Vijay Sharma
• 金额: $ 36.18万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-16 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511806
• 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; Technetium Tc 99m Sestamibi; Technology; Time; Tissues; Tracer; Translating; United States; United States National Institutes of Health; Validation; abstracting; arm; attenuation; base; clinical Diagnosis; comparative; cost; dosimetry; improved; inhibitor/antagonist; intravenous injection; mitochondrial membrane; myocardial infarct sizing; novel; radiotracer; single photon emission computed tomography; statistics; technetium Tc 99m 1,2-bis(bis(2-ethoxyethyl)phosphino)ethane; tool; uptake

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 PET 血流示踪剂的开发 摘要：心血管疾病是美国的主要原因之一。心肌灌注成像（MPI）作为临床诊断的多功能工具，发挥着重要作用 冠状动脉疾病（CAD）的无创评估。目前，常见的单光子发射计算机断层扫描 (SPECT) MPI 试剂包括 201Tl 或中等疏水性的阳离子 99mTc 复合物，例如 99mTc-司他米比 (sestamibi) 和 99mTc-替曲膦 (99mTc-tetrofosmin)，用于测定患者的心肌血流量 (MBF)。然而，SPECT 成像剂具有固有的局限性，包括 99mMo/99mTc 发生器严重短缺的持续威胁。此外，当前的 SPECT 示踪剂还存在药代动力学、心肌提取、放射性示踪剂随时间重新分布到非目标组织以及血流升高时摄取的非线性（“滚降”现象）方面的缺点。相比之下，正电子发射断层扫描 (PET) 具有技术优势，包括更高的空间分辨率、改进的衰减校正以及在应力峰值时进行定量测量的能力。常用的 PET MPI 示踪剂有：82RbCl、13NH3 和 H215O。然而，由于这些药物的物理半衰期短（<10分钟），其实用性受到限制，从而给获取这些药物带来了困难。其他有前途的 18F 标记试剂，例如 18F-BnTP（线粒体膜电位探针）和 18F-BMS-747158、18F-10、18F-RP1004 和 18F-MCI27（线粒体复合物 I 抑制剂）具有各种优点和缺点，但也依赖于基于 18F 的分配模型，该模型可能不容易被服务欠缺的地区使用美国或其他发展中国家。因此，PET 示踪剂显示出较高的心肌首过提取率、从肝脏中快速清除、保留在心肌内以实现延迟成像，并且基于可能由发生器现场产生（而不是回旋加速器产生）的同位素，将有助于广泛获取PET MPI。为了解决这一未实现的目标，我们已经确定了一种基于发生器产生的镓 68 的先导阳离子和中等疏水性放射性药物 1A，该药物表现出对正常小鼠和大鼠心肌的高提取性，包括从血池和肝脏中有效清除多药耐药性 P-糖蛋白 (Pgp) 转运蛋白。随着时间的推移，1A 剂保留在心肌中并保持非代谢状态，从而实现稳定的分布和高计数统计数据，从而转化为高质量的心肌图像。重要的是，microPET/CT (68Ga) 和 nanoSPECT/CT (67Ga) 均显示 1A 在大鼠静脉注射后 60 分钟后在心脏中大量积累，随后从肝脏中轻松清除。最后，静脉注射 67Ga-1A 后，nanoSPECT/CT 成像清晰地显示了左心室壁的非灌注区域，表明我们的主导药物有潜力对大鼠模型中的心肌灌注缺陷进行无创成像。因此，根据这些试点数据，该 R01 提案的具体目标是： 1) 进行重点 SAR 研究，以进一步优化我们作为潜在 MPI 药物的领先 68Ga 放射性药物的生化靶向和药代动力学。 2) 对源自我们针对心肌细胞、HEPG2 细胞、表达 Pgp 的 KB 细胞、Pgp 转染的 MCF-7 细胞的 SAR 研究的新型 68Ga 放射性药物进行基于机制的评估和验证，并将这些数据与 99mTc-Sestamibi（a）相关联。在类似条件下经过充分验证并获得 FDA 批准的 SPECT 探头。 3) 通过大鼠药代动力学分析、确定放射性药物进入心肌的提取分数以及在类似条件下与 99mTc-Sestamibi 和其他潜在 18F MPI 药物进行心脏/肝脏比率的比较分析来评估有希望的先导化合物。 4) 通过评估大鼠应激/休息条件下的心肌梗塞大小、首过提取和血流提取相关性，表征和验证通过 SAR 研究出现的先导 68Ga-放射性药物 1A 或其他潜在先导作为无创 MPI 药物，然后使用 microPET 成像对兔子体内的铅进行评估。 5) 表征我们的主导药物或第二代 68Ga-放射性药物作为犬模型中的 MPI 药物的潜力；进行安全药理学概况研究、剂量测定分析并准备 eIND 备案材料。成功执行概述的目标应该为 MPI 和 CAD 管理提供分子靶向 68Ga-PET 试剂。