Manganese-based Contrast Agent for Cardiovascular MRI

项目摘要。缺血性心脏病是美国发病和死亡的主要原因 占美国和全球死亡人数的三分之一（每年1700万人死亡）。对比增强计算机 断层扫描（CT）和磁共振成像（MRI）在管理心脏病方面发挥着关键作用， 心肌灌注、梗死和存活率的非侵入性评估。对比增强扫描是 缺血性心脏病的诊断和治疗计划以及评估 治疗效果因此，心脏成像是欧洲MRI市场增长最快的部分， 最近的随机对照MR-INFORM试验表明， 有创插管和对比增强MRI之间的等效性。不幸的是，两个碘化CT 放射性造影剂和基于钆的MRI造影剂禁忌用于患有中度至 重度肾损害。碘化造影剂可引起急性和不可逆的肾损伤， 受损患者和钆基MRI造影剂（GBCA）直接与肾源性 肾损害患者的全身性纤维化（NSF）。慢性肾病（CKD）困扰着16%的美国成年人， 由于糖尿病和肥胖症的流行以及人口老龄化，心脏和肾脏输出量 有着千丝万缕的联系-肾功能不全存在于33%的心力衰竭患者中， 尽管非侵入性心脏MRI明显优于侵入性经皮 插管因此，当对患有CKD的心脏病患者进行成像时，临床医生要么面临有限的 放射学信息或通过使用GBCA将患者置于并发症的较高风险中。 使用更安全的替代品进行对比增强心血管成像的临床需求尚未得到满足， 钆基造影剂。Reveal制药公司正在开发一种无钆造影剂 基于马萨诸塞州总医院开发的技术。我们的先导化合物RVP-001 具有与GBCA相似的弛豫性和药代动力学的锰螯合物，导致等效成像 特性. RVP-001合理设计用于部分肝胆消除，这提供了一种代偿性 肾功能受损患者的消除机制。我们的最终目标是开发RVP-001作为造影剂 用于肾损害受试者以及一般患者群体。 在本SBIR应用中，我们将证明RVP-001在猪心脏成像模型中的有效性， 心肌梗死，以证明和验证RVP-001与市售GBCA的等效性。我们 将首先确定RVP-001最适合大剂量给药的配方，然后证明RVP-001是 用于评估心肌灌注和存活力的等效或优于商业GBCA Gd-DOTA。的 拟议的成像将支持RVP-001作为心血管造影剂的商业化， 庞大且不断增长的肾功能受损患者群体。

Project Summary. Ischemic heart disease is the leading cause of morbidity and death in the United States representing 1 in 3 American deaths and globally (17 million deaths annually). Contrast enhanced computed tomography (CT) and magnetic resonance imaging (MRI) play a key role in managing heart disease by enabling non-invasive assessment of myocardial perfusion, infarction, and viability. Contrast enhanced scans are increasingly relied upon for ischemic heart disease diagnosis and treatment planning, and for assessing treatment efficacy. Thus, cardiac imaging is the fastest growing segment of the MRI market in Europe and increasing in the United States with the recent randomized controlled MR-INFORM trial demonstrating equivalency between invasive catherization and contrast enhanced MRI. Unfortunately, both iodinated CT radiocontrast and gadolinium-based MRI contrast agents are contraindicated in patients suffering moderate to severe renal impairment. Iodinated contrast media can cause acute and irreversible kidney injury in renally impaired patients and gadolinium-based MRI contrast agents (GBCAs) are directly linked to nephrogenic systemic fibrosis (NSF) in renally impaired patients. Chronic kidney disease (CKD) afflicts 16% of US adults and is increasing due to the diabetes and obesity epidemics and the aging population. Cardiac and renal output are inextricably linked - renal dysfunction is present in 33% of patients with heart failure complicating their diagnostic workup and management despite the clear benefit of non-invasive cardiac MRI over invasive percutaneous catherization. As a result, when imaging heart disease patients with CKD, clinicians are either faced with limited radiologic information or placing the patient at higher risk for complications by using GBCA. There is a major unmet clinical need for contrast-enhanced cardiovascular imaging using safer alternatives to gadolinium-based contrast agents. Reveal Pharmaceuticals is developing a gadolinium-free contrast agent based on technology developed at Massachusetts General Hospital. Our lead compound RVP-001 is an stable manganese chelate with relaxivity and pharmacokinetics similar to GBCAs resulting in equivalent imaging properties. RVP-001 is rationally designed for partial hepatobiliary elimination, which provides a compensatory elimination mechanism for renally impaired patients. Our ultimate goal is to develop RVP-001 as a contrast agent for use in renally impaired subjects as well as the general patient population. In this SBIR application we will demonstrate the efficacy of RVP-001 for cardiac imaging in a porcine model of myocardial infarction to demonstrate and validate RVP-001 equivalency to a commercially available GBCA. We will first identify a formulation of RVP-001 best suited for bolus delivery, and then demonstrate that RVP-001 is equivalent or better than the commercial GBCA Gd-DOTA for assessing myocardial perfusion and viability. The proposed imaging will support the commercialization of RVP-001 as a cardiovascular contrast agent for use in the large and growing population of renally impaired patients.