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.
Public Health Relevance Statement: 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.
Project Terms: adulthood; Adult Human; 21+ years old; Adult; postmortem; necropsy; Autopsy; Blood Reticuloendothelial System; Blood; Encephalon; Brain Nervous System; Brain; Cell Degranulation; Cell Body; Cells; Complexons; Chelators; Chelating Agents; Chemistry; High Speed Liquid Chromatography; High Performance Liquid Chromatography; HPLC; High Pressure Liquid Chromatography; Clinical Trials; co-morbidity; Comorbidity; Radiopaque Media; Contrast Drugs; Contrast Agent; Contrast Media; Death; Cessation of life; domestic dog; canine; Dogs Mammals; Dogs; Canine Species; Canis familiaris; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Pharmaceutical Preparations; Environment; blood corpuscles; Red blood corpuscule; Red Cell; Red Blood Cells; Marrow erythrocyte; Erythrocytic; Erythrocytes Reticuloendothelial System; Blood normocyte; Blood erythrocyte; Erythrocytes; Fibrosis; Gd element; Gadolinium; Goals; cGMP; Guanosine Cyclic Monophosphate; Cyclic GMP; General Hospitals; In Vitro; Injection of therapeutic agent; Injections; Ions; Isotopes; Kidney; renal; Kidney Urinary System; Chronic Kidney Failure; chronic kidney disease; Chronic Renal Failure; Chronic Renal Disease; Lead; heavy metal lead; heavy metal Pb; Pb element; Magnetic Resonance Imaging; Zeugmatography; Nuclear Magnetic Resonance Imaging; NMR Tomography; NMR Imaging; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MRI; MR Tomography; MR Imaging; Manganese; Mn element; Massachusetts; mast cell; mastocyte; Tissue Basophils; Marrow Mast Cell; Basophilic Histiocyte; Metabolic Activation; Metabolism; Metabolic Processes; Intermediary Metabolism; Microsomes; Nephrectomy; Patients; Drug Kinetics; Pharmacokinetics; Physicians; Plasma Proteins; Positron-Emission Tomography; positron emitting tomography; positron emission tomographic imaging; positron emission tomographic (PET) imaging; Rad.-PET; Positron Emission Tomography Scan; Positron Emission Tomography Medical Imaging; PETT; PETSCAN; PET imaging; PET Scan; PET; Positron; Public Health; Radiology Specialty; Radiology; General Radiology; Rattus; Rats Mammals; Rat; Common Rat Strains; Kidney Failure; Renal Insufficiency; Renal Failure; Kidney Insufficiency; Risk; Safety; Technology; Time; Tissues; Body Tissues; computerized tomography; computerized axial tomography; computed axial tomography; catscan; Xray Computed Tomography; X-Ray Computerized Tomography; X-Ray CAT Scan; Tomodensitometry; EMI scan; Computed Tomography; CT scan; CT imaging; CT X Ray; CAT scan; X-Ray Computed Tomography; Toxicology; Vendor; Gd-DTPA; Gadopentetic Acid; Gadolinium DTPA; manganous chloride; manganese dichloride; MnCl2; manganese chloride; Measures; Injury to Kidney; analytical method; base; Organ; Procedures; Area; Acute; Phase; Medical; Link; Chemicals; Evaluation; excretion; Excretory function; Liver Cells; Hepatic Parenchymal Cell; Hepatic Cells; Hepatocyte; kidney function; Renal function; bound protein; Protein Binding; Ligand Binding Protein Gene; Ligand Binding Protein; Binding Proteins; Technology Transfer; Metabolic; Deposition; Deposit; Route; Drug Formulations; Acute Renal Failure with Renal Papillary Necrosis; acute kidney injury; immunotoxicity; toxic reaction in immunology; genotoxicity; Animal Model; model organism; model of animal; Animal Models and Related Studies; Toxic effect; Toxicities; Drug Interactions; Modeling; Cardiotoxicity; Cardiotoxic; Cardiac Toxicity; Adverse effects; treatment adverse effect; therapy adverse effect; side effect; Treatment Side Effects; Intervention; interventional strategy; Intervention Strategies; Magnetic Resonance; Binding; Molecular Interaction; Pharmacologic Substance; Pharmacological Substance; Pharmaceuticals; Pharmaceutical Agent; Dose; Data; High Prevalence; Ames Test; Ames Salmonella/microsome mutagenicity assay; AMES mutagen test; Ames Assay; Process; developmental; Development; imaging; Image; preclinical; pre-clinical; Biodistribution; scale up; cost effective; cost-effective; Population; Prevalence; Impairment; high risk; preclinical safety; clinical imaging; clinical development; imaging properties
