Manganese based MRI contrast agent

Chronic kidney disease CKD afflicts 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 is a very stable manganese chelate with equivalent imaging properties to GBCAs but without using the toxic gadolinium ion RVP is times more stable than Teslascan another manganese based compound previously used in clinical imaging RVP is functionally equivalent to GBCAs having similar relaxivity and biodistribution and is excreted from the body intact RVP enhanced MRI is equivalent to GBCA enhanced MRI in the same animal model Our ultimate goal is to develop RVP for use in renally impaired subjects and as a general purpose MR contrast agent It is critical that RVP 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 isotope t d 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 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 and these will be systematically evaluated and a chemical process with analytical controls will be developed Patients with chronic kidney disease or acute kidney injury are often denied needed imaging exams because the contrast media used can produce serious side effects such as kidney failure and death in these patients The goal of this proposal is to develop a new contrast agent for magnetic resonance imaging that would be safe for use with these patients