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死亡原因之一。心肌灌注显像（MPI）是一种多功能的临床诊断工具，在临床诊断中起着重要的作用 冠状动脉疾病（CAD）的非侵入性评估。目前，常见的单光子发射计算机断层扫描（SPECT）MPI试剂包含201 Tl或中等疏水性和阳离子99 mTc-复合物，例如99 mTc-舍他米比和99 mTc-替曲膦，用于测定患者的心肌血流量（MBF）。然而，SPECT显像剂具有固有的局限性，包括99 mMo/99 mTc发生器严重短缺的持续威胁。此外，目前的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靶组织以及在升高的血流下摄取的非线性（“滚降”现象）方面的缺点。相比之下，正电子发射断层扫描（PET）提供了技术优势，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：82 RbCl、13 NH3和H215 O。然而，由于这些药剂的物理半衰期短（<10分钟），其效用有限，因此难以容易地获得这些药剂。其他有前途的18F标记剂，如18F-BnTP，线粒体膜电位探针，和18F-BMS-747158、18F-10、18F-RP 1004和18F-MCI 27，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的分布模型，这对于美国或其他发展中国家服务不足的地区来说可能不容易获得。因此，PET示踪剂表现出高心肌首过提取、从肝脏快速清除、保留在心肌内以实现延迟成像，并且基于可能在现场由发生器产生（而不是回旋加速器产生）的同位素，这将促进PET MPI的广泛使用。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的铅阳离子和中度疏水性放射性药物1A，其表现出对正常小鼠和大鼠心肌的高提取，包括由多药耐药性P-糖蛋白（Pgp）转运蛋白驱动的从血池和肝脏的有效清除。药剂1A随时间保留在心肌中并且保持非代谢，允许稳定分布和高计数统计，其转化为高质量心肌图像。重要的是，microPET/CT（68 Ga）和nanoSPECT/CT（67 Ga）均显示大鼠静脉注射后60分钟，1A在心脏中的高蓄积，随后从肝脏中轻松清除。最后，在静脉注射67 Ga-1A后，nanoSPECT/CT成像清楚地显示了左心室壁的非灌注区域，表明我们的先导剂在大鼠模型中对心肌灌注缺损进行非侵入性成像的潜力。因此，有了这些试验性数据，本R 01提案的具体目标是：1）进行重点SAR研究，以进一步优化我们的铅68 Ga-放射性药物作为潜在MPI试剂的生化靶向和药代动力学。2)对源自我们在心肌细胞、HEPG 2细胞、表达Pgp的KB细胞、Pgp转染的MCF-7细胞中的集中SAR研究的新型68 Ga放射性药物进行基于机制的评估和验证，并将这些数据与99 mTc-Sestamibi（一种在类似条件下经过充分验证并获得FDA批准的SPECT探针）相关联。3)通过大鼠药代动力学分析评价有希望的电极导线，确定放射性药物进入心肌的提取分数，并在类似条件下与99 mTc-Sestamibi和其他潜在的18F MPI药物进行心脏/肝脏比的比较分析。4)通过评估大鼠在应激/静息条件下的心肌梗死面积、首过提取和血流提取相关性，然后使用microPET成像评估家兔的电极导线，表征并确认电极导线68 Ga-放射性药物1A或通过SAR研究作为无创MPI试剂出现的其他潜在电极导线。5)表征我们的先导药物或第二代68 Ga放射性药物作为犬模型MPI药物的潜力;进行安全药理学特征研究、剂量测定分析，并准备eIND申报材料。成功执行所概述的目标应提供分子靶向的68 Ga-PET剂MPI和CAD的管理。