Manganese-based Contrast Agent for Cardiovascular MRI

项目摘要。在美国，缺血性心脏病是导致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(每年有1700万人死亡)。对比度增强计算 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，使 无创性评估心肌灌注、梗死和存活情况。增强扫描是 越来越多地依赖于缺血性心脏病的诊断和治疗计划以及评估 治疗效果。因此，心脏成像是欧洲和欧洲MRI市场增长最快的部分 在美国增加，最近的随机对照MR-INFORM试验显示 有创插管与增强磁共振成像的等效性。不幸的是，两种碘化CT 放射造影剂和含Gd的MRI造影剂禁忌用于中度到 严重的肾脏损害。含碘造影剂可导致急性不可逆性肾损伤 肾功能受损患者和含Gd的磁共振造影剂(GBCA)与肾源性疾病直接相关 肾功能受损患者的系统性纤维化(NSF)。慢性肾脏疾病(CKD)困扰着16%的美国成年人和 由于糖尿病和肥胖症的流行以及人口老龄化，这一数字正在增加。心和肾输出量为 千丝万缕的联系--33%的心力衰竭患者存在肾功能障碍，这使他们的诊断复杂化 检查和管理，尽管无创心脏MRI明显优于有创经皮检查 导管插入术。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 或通过使用GBCA将患者置于更高的并发症风险中。 使用更安全的替代品来增强心血管成像的主要临床需求尚未得到满足 以钆为基础的造影剂。Display制药公司正在开发一种不含Gd的造影剂 基于马萨诸塞州综合医院开发的技术。我们的先导化合物RVP-001是一种稳定的 具有与GBCA相似的弛豫度和药代动力学的锰络合物，导致等效成像 属性。RVP-001是合理设计的部分肝胆清除剂，它提供了一种补偿性 肾功能受损患者的排泄机制。我们的最终目标是开发RVP-001作为造影剂 用于肾功能受损的受试者以及普通患者群体。 在这项SBIR应用中，我们将展示RVP-001在猪心脏成像中的有效性。 心肌梗死证明并验证RVP-001与商用GBCA的等效性。我们 将首先确定最适合团注输送的RVP-001配方，然后证明RVP-001是 在评估心肌灌注和存活方面，与商用GBCA Gd-DOTA相当或更好。这个 拟议的成像将支持RVP-001作为心血管造影剂的商业化，用于 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.