CM-65, a Targeted Contrast Agent for Cardiac Magnetic Resonance Perfusion Imaging

描述（由申请人提供）：心肌灌注评估是一项门房诊断检查，对识别缺血性心脏病个体具有很高的敏感性。在美国，每年有数以百万计的灌注研究使用应激/休息模式，放射性示踪剂随后进行核成像。虽然这是一种有效的检查，但它需要向患者提供一定剂量的电离辐射，而且该技术的空间分辨率相当低，这限制了对较小或心内膜下灌注缺陷的检测。心血管磁共振成像（CMR）被认为是一种具有竞争力的一线检查，可用于评估缺血性心脏病等常见适应症。CMR不涉及辐射，空间分辨率比核技术高一个数量级。CMR可以同时评估心肌灌注和梗死在一次独立的技术。然而，目前的CMR灌注评估涉及患者在扫描仪中的腺苷应激和快速成像，以评估MR造影剂的第一次灌注。在这个项目中，我们的目标是开发一种技术，使用CM-65，一种针对I型胶原蛋白的新型MR显像剂，可以实现高质量，长时间的心肌灌注可视化。我们已经在猪的初步研究中表明，CM-65可以在应激（充血）期间使用，即使在应激停止后也可以识别心脏的灌注缺陷。在第一阶段的研究中，我们将在大型动物模型中开发一种临床可行的CM-65应激灌注方案，该方案可以直接适用于人类。在第二阶段，我们将在大型动物模型中测试优化的临床可行的CM-65方案，包括心肌梗死和非心肌梗死的血流减少范围。我们还将讨论IND提交所需的一些安全性和药代动力学研究。总之，这些数据将构成CM-65增强MR在缺血性心脏病背景下临床试验的IND申请的基础。

DESCRIPTION (provided by applicant): Assessment of myocardial perfusion is a gatekeeper diagnostic exam that has high sensitivity for identifying individuals with ischemic heart disease. Millions of perfusion studies are performed annually in the US using a stress/rest paradigm with a radioactive tracer followed by nuclear imaging. While this is an effective exam, it involves delivering a dose of ionizing radiation to the patient and the spatial resolution of the technique s rather low which limits detection of smaller or subendocardial perfusion defects. Cardiovascular magnetic resonance imaging (CMR) is considered a competitive first-line test for common indications such as the evaluation of ischemic heart disease. CMR involves no radiation and has an order of magnitude higher spatial resolution than nuclear techniques. CMR can assess both myocardial perfusion and infarction with independent techniques in a single session. However current CMR assessment of perfusion involves adenosine-stress of the patient while in the scanner and rapid imaging to assess perfusion of first pass of the MR contrast agent. With this project, we aim to develop a technique that allows high quality, prolonged visualization of myocardial perfusion, using CM-65, a novel MR imaging agent targeted to type I collagen. We have shown in preliminary studies in pigs that CM-65 can be administered during stress (hyperemia) and identify perfusion defects in the heart even after stress is ceased. In Phase I of the study, we will develop a clinically feasible CM-65 stress perfusion protocol in a large animal model that can be directly adapted for use in humans. In Phase II, we will test the optimized clinically, feasible CM-65 protocol across a range of flow reduction with and without myocardial infarction in large animal models. We will also address several of the safety and pharmacokinetic studies required for IND submission. Together, these data will form the basis for an IND submission for clinical testing of CM-65 enhanced MR in the context of ischemic heart disease.