Manganese based MRI contrast agent

项目摘要-未修改的父R44补助金 慢性肾脏疾病（CKD）困扰着14%的美国成年人，是公众面临的最大挑战。 健康CKD患者的合并症患病率较高，代表了一个经常需要 医疗干预。然而，患者管理混淆，因为造影剂常规与 计算机断层扫描（CT）和磁共振（MR）成像禁忌用于中度 严重的CKD。CT造影剂可对肾损害患者造成急性和不可逆的肾损伤。 用作MR造影剂的钆基造影剂（GBCA）与肾源性 肾损害患者的全身性纤维化（NSF）。合并症的患病率和相关风险 两者均随肾功能下降而增加。因此，随着患者变得越来越脆弱， 医生被迫在有限的放射学信息下做出关键决定或使用造影剂， 将患者置于肾衰竭或NSF的高风险中。对于更安全的造影剂，存在重大未满足的医疗需求 媒体选择。 GBCA最近也被证明在大脑和其他器官中存款少量的钆， 即使在肾功能正常的患者中，Gd沉积也随着暴露量的增加而增加。而 这些沉积物的医学意义仍然是未知的，这是FDA积极关注的领域。 Reveal Pharmaceuticals正在开发一种基于以下技术的无钆造影剂： 马萨诸塞州综合医院。我们的先导化合物RVP-001是一种非常稳定的锰螯合物， 与GBCA具有等同的成像性能，但不使用有毒的钆离子。RVP-001是10万倍 比Teslascan更稳定，Teslascan是另一种以前用于临床成像的锰基化合物。RVP- 001在功能上等同于具有相似松弛性和生物分布的GBCA，并且从 尸体完好无损在相同动物模型中，RVP-001增强MRI等同于GBCA增强MRI。我们 最终目标是开发RVP-001用于肾功能受损受试者，并作为通用MR造影剂 剂 至关重要的是，RVP-001不会导致锰在体内蓄积并产生毒理学效应。在 在此FastTrack应用中，我们将使用发射正电子的Mn-52同位素（t1/2 = 5.2d）来研究保留， 急性和亚急性给药下的Mn排泄与未螯合Mn和GBCA相比。我们还将 进行RVP-001的临床前安全性评价。用于临床开发，并最终与 GBCA我们需要一种非常经济有效的合成方法，不需要HPLC纯化。我们已经确定 RVP-001的不同合成路线，将对这些路线进行系统评价， 将制定分析控制措施。

Project Summary – Unmodified from Parent R44 Grant Chronic kidney disease (CKD) afflicts 14% of US adults and represents a foremost challenge facing public health. CKD patients have a higher prevalence of co-morbidities and represent a population that often requires medical intervention. However patient management is confounded because contrast media routinely used with computed tomography (CT) and magnetic resonance (MR) imaging is contra-indicated in patients with moderate to severe CKD. CT contrast media can cause acute and irreversible kidney injury to renally impaired patients. Gadolinium-based contrast agents (GBCAs) used as MR contrast media are directly linked to nephrogenic systemic fibrosis (NSF) in renally impaired patients. The prevalence of co-morbidities and the risk associated with contrast media both increase with decreased renal function. Thus as patients grow increasingly vulnerable physicians are forced to make key decisions with limited radiologic information or to use contrast media and place the patient at high risk for renal failure or for NSF. There is a major unmet medical need for a safer contrast media alternative. GBCAs have also recently been shown to deposit small amounts of gadolinium in the brain and other organs, even in patients with normal renal function, and that Gd deposition increases with increasing exposure. While the medical implications of these deposits are still unknown, this is an area of active concern for the FDA. Reveal Pharmaceuticals is developing a gadolinium-free contrast agent based on technology developed at Massachusetts General Hospital. Our lead compound, RVP-001, is a very stable manganese chelate with equivalent imaging properties to GBCAs but without using the toxic gadolinium ion. RVP-001 is 100,000 times more stable than Teslascan, another manganese-based compound previously used in clinical imaging. RVP- 001 is functionally equivalent to GBCAs having similar relaxivity and biodistribution, and is excreted from the body intact. RVP-001 enhanced MRI is equivalent to GBCA enhanced MRI in the same animal model. Our ultimate goal is to develop RVP-001 for use in renally impaired subjects and as a general purpose MR contrast agent. It is critical that RVP-001 does not lead to Mn accumulation in the body and result in a toxicological effect. In this FastTrack application we will use the positron emitting Mn-52 isotope (t1/2 = 5.2d) to study the retention and excretion of Mn under acute and subacute dosing with comparison to unchelated Mn and to GBCA. We will also perform preclinical safety evaluations of RVP-001. For clinical development and ultimately to compete with GBCAs we will need a very cost effective synthesis that does not involve HPLC purification. We have identified different synthetic routes to RVP-001 and these will be systematically evaluated and a chemical process with analytical controls will be developed.