Manganese based MRI contrast agent

锰基MRI造影剂

基本信息

批准号：
10010976
负责人：
Vera Hoffman
金额：
$ 100万
依托单位：
REVEAL PHARMA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-11 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10010976
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Adult Affect Animal Model Area Authorization documentation Autopsy Behavior Biodistribution Biological Assay Blood Vessels Bone Marrow Books Brain Cessation of life Chelating Agents Chemicals Chemistry Chronic Kidney Failure Clinical Clinical Chemistry Collaborations Conscious Contrast Media Data Deposition Development Disease Dose Equilibrium Erythrocytes European Evaluation Excretory function Funding Gadolinium General Hospitals Genetic Goals Hematology Hepatobiliary High Pressure Liquid Chromatography High Prevalence Histopathology Image Impairment Industry Standard Injections Injury to Kidney Intervention Investigational Drugs Investigational New Drug Application Ions Isotopes Kidney Kidney Failure Lead Link Macaca fascicularis Magnetic Resonance Magnetic Resonance Imaging Malignant Neoplasms Manganese Marketing Massachusetts Medical Medicine Monitor Monkeys Mus Nephrogenic Systemic Fibrosis Organ Papio Parents Patient imaging Patients Peripheral arterial disease Pharmacologic Substance Pharmacology Study Phase Physicians Plethysmography Population Positron Prevalence Process Public Health R44 grant Radiology Specialty Rattus Readiness Renal function Respiration Risk Rodent Route Safety Sensorimotor functions Source Technology Time Toxic effect Toxicokinetics Toxicology Urinalysis Work Writing X-Ray Computed Tomography base bone clinical development clinical imaging commercialization comorbidity contrast enhanced contrast imaging cost effective glomerular filtration high risk human study imaging properties in vivo manufacturing process meetings neuromuscular function patient population preclinical efficacy preclinical safety respiratory response safety study side effect tumor

项目摘要

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.

项目摘要 - 未修改父母R44赠款慢性肾脏疾病（CKD）折磨了美国成年人的14％，这是公众面临的首要挑战健康。 CKD患者的合并症患病率较高，代表通常需要的人口医疗干预。但是，患者管理是混淆的，因为对比媒体通常与现代患者的计算机断层扫描（CT）和磁共振（MR）成像是相互指示的严重的CKD。 CT对比培养基会导致肾脏受损的患者急性和不可逆的肾脏损伤。用作MR造影剂的基于Gadolinium的对比剂（GBCA）直接与肾病有关肾脏受损患者的全身纤维化（NSF）。合并症的患病率和与风险相关的风险随着对比介质，均随肾功能降低而增加。随着患者越来越脆弱医师被迫使用有限的放射学信息做出关键决定，或使用对比媒体和将患者处于肾衰竭或NSF的高风险。对更安全的对比度有很大的未满足医疗需求媒体替代方案。最近还显示，GBCA在大脑和其他器官中沉积了少量的gadolinium 即使在具有正常肾功能的患者中，并且GD沉积物随着暴露的增加而增加。尽管这些沉积物的医学含义仍然未知，这是FDA积极关注的领域。揭示药品正在开发一种基于在马萨诸塞州综合医院。我们的铅化合物RVP-001是一种非常稳定的锰樱桃等效成像特性与GBCA，但不使用有毒的gadolinium离子。 RVP-001是100,000次比特斯拉斯坎（Teslascan）更稳定，这是另一种以前用于临床成像的基于锰的化合物。 rvp- 001在功能上等同于具有相似松弛性和生物分布的GBCA，并且超过了身体完整。 RVP-001增强的MRI等效于同一动物模型中GBCA增强的MRI。我们的最终目标是开发用于肾脏受损的受试者的RVP-001，作为一般性MR对比代理人。至关重要的是，RVP-001不会导致MN在体内积累并产生毒理学作用。在此FastTrack应用程序我们将使用正电子发射MN-52同位素（T1/2 = 5.2d）来研究保留率和与未固定的MN和GBCA相比，我们还将在急性和亚急性给药下排泄MN。对RVP-001进行临床前安全评估。进行临床发展，并最终与 GBCAS我们将需要一个非常具有成本效益的合成，不涉及HPLC纯化。我们已经确定了到RVP-001的不同合成途径，这些路线将进行系统评估，并具有化学过程将开发分析控制。