Context

Science

Noteworthy

Clinical Need
Current Solutions
Safety Issues
Regulatory Response
Patients and Physicians
Environmental Impact
Motivation
Magnetic Resonance Imaging
MRI Contrast Agents
Gadolinium vs Manganese
Reveal: A Safer MRI Contrast Agent
Clinical Need
Over 30 million contrast-enhanced (CE) MRI scans are performed worldwide each year; a total of 450 million CE-MRI scans to date. CE-MRI scans provide information that is not available with any other methodology, granting vital medical insight that informs diagnosis and management of cancer, cardiovascular disease, Crohn's disease, multiple sclerosis, myeloma, stroke, various genetic disorders, and many other conditions.
Current Solutions
All current MRI contrast agents are based on gadolinium, a rare earth element which is alien to biology. Gadolinium is a potent calcium antagonist and is highly toxic in its ionic form. Gadolinium-based contrast agents (GBCAs) utilize chelating ligands to bind the metal and render it less toxic for intravenous administration. Despite this even the most stable GBCAs release some gadolinium.
Safety Issues
In 2006 it was found that GBCAs trigger devastating nephrogenic systemic fibrosis (NSF) in renally impaired patients. Subsequently, deposition of gadolinium in bone, skin, and other organs was documented. In 2013 it was discovered that GBCAs cause cumulative gadolinium deposition in the brains of all patients regardless of renal function. Studies have shown that all GBCAs cause deposition of gadolinium in the brain, bone, and other organs of all patients.
Regulatory Response
The FDA instituted a boxed warning on all GBCAs in 2007, cautioning that they should not be used in renally impaired patients due to the risk of NSF. After the discovery of brain deposition of gadolinium, worldwide regulators responded with suspensions, restrictions, label changes, and safety warnings. There is continuing unease and uncertainty about GBCAs. Even the most stable GBCAs release gadolinium which is deposited in the brain, bone, and other organs, and remains in the body indefinitely. The long term biological activity of gadolinium – and consequent implications for patients – are not well understood.
Patients and Physicians
People with significant health conditions frequently require contrast enhanced imaging to guide diagnosis and clinical management. Accurate diagnosis and appropriate treatment may dramatically improve each patient’s prognosis and quality of life. However, many people who are gravely ill also have kidney dysfunction and are contraindicated for all current MRI and CT contrast agents. As a result these patients are either inadequately assessed or are put at risk from contrast agents.

Gadolinium deposition in the brain, bone, and other organs affects all patients. People at highest potential risk from GBCAs include children, those with renal impairment, surveillance patients, and people who require repeated CE-MRI scans. e.g. brain cancer survivors, women at high risk of breast cancer, many cancer patients, people with cardiorenal syndrome, chronic kidney disease, Crohn's disease, multiple sclerosis, myeloma, and certain genetic disorders.

CE-MRI provides critical medical information which often cannot be obtained using other methods. Patients and physicians face a dilemma: balancing the risks posed by GBCAs with the need for important medical imaging. Individual decisions on whether or when to use GBCA-enhanced MRIs should be based on thoughtful consultation between patients and their physicians.
Environmental Impact
Increasing use of CE-MRI has resulted in rapidly rising levels of gadolinium in water around major metropolitan areas. GBCAs enter the sewage system when they are excreted after CE-MRIs. GBCAs are not removed by standard waste water treatment methods: consequently the GBCAs remain in the clear water discharge from sewage treatment plants and are transferred to surface water, where they reenter the agricultural and urban drinking water supply. Unlike biocompatible elements, gadolinium has no established ecological cycle. The biological activity of the rising amount of gadolinium in the aquatic ecosystem is as yet undetermined, with unknown consequences for downstream human health.
Motivation
The impact of contrast enhanced (CE) MRI is enormous, with more than 30 million CE-MRI scans worldwide each year, and over 450 million CE-MRI scans performed to date. Like so many others, Reveal’s team has been personally impacted by the benefits of – and concerns surrounding – contrast-enhanced MRI.

Peter Caravan and Eric Gale set out to invent a contrast agent that would be safe for people with renal impairment, who are often contraindicated for current CT and MRI contrast agents. As more concerns around gadolinium retention were discovered it became clear that all patients need a safer contrast agent that does not deposit gadolinium in their brains, bones, and other organs.

Our goal is a safer MRI contrast agent for all patients.
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) is a sophisticated non-invasive imaging technology which produces detailed three-dimensional images of internal anatomy. MRI contrast agents typically increase MRI signal and create greater contrast between different tissue types or between normal and diseased tissue. Contrast-enhanced MRI often provides information that cannot be obtained without contrast agents. CE-MRI is used to detect disease, provide prognosis, guide treatment planning, and to monitor therapeutic interventions.
MRI Contrast Agents
MRI contrast agents alter the signal in tissue via their influence on the local magnetic environment. The best MRI contrast agents are strongly paramagnetic (i.e. they become temporarily magnetized when placed in a magnetic field) and are able to influence the orientation of water nuclei in tissue, amplifying the MRI signal. Gadolinium and manganese are uniquely suited for MRI because they are paramagnetic and each have a half-shell of unpaired electrons, producing a strong magnetic moment.

Free metal ions are reactive and may have toxic effects. To improve safety, organic molecules (ligands) are used to bind (chelate) the metal ion. To enable a strong MRI signal, these chelating agents leave an open location for a water molecule to temporarily bind. Rapid exchange of this bound water with water molecules in the surrounding tissue amplifies the MRI signal, increasing contrast.
Gadolinium vs Manganese
Gadolinium (Gd3+) is a large, strongly charged ion which is very similar in size to calcium (Ca2+). Gadolinium readily forms relatively stable chelates allowing sufficient space for water exchange. For this reason gadolinium was historically chosen as the paramagnetic ion for most MRI contrast agents. However, gadolinium is alien to biology and there are no natural mechanisms to control and manage Gd3+ should it be released from its ligand. Free gadolinium is toxic: it is a potent calcium antagonist, irreversibly outcompeting calcium in biological processes.

Manganese (Mn2+) is an essential element which is vital for life. It is regulated by natural mechanisms and is readily processed, transported, and excreted by the body. Mn2+ is smaller and more weakly charged than Gd3+. Consequently it is challenging to create stable Mn2+ complexes that allow space for water exchange.

The MRI contrast agent Teslascan was based on manganese. Teslascan dissociated after administration and the resulting free Mn2+ ion was rapidly excreted via the liver. Teslascan was approved as a liver-specific MRI contrast agent by the FDA and the European Medicines Agency in 1997, but its rapid dissociation made it unsuitable for use as a general purpose contrast agent.
Reveal: A Safer MRI Contrast Agent
Given the safety issues of gadolinium-triggered nephrogenic systemic fibrosis and deposition of gadolinium in the brain, bone, and other organs, it is clear that a safer MRI contrast agent should be gadolinium-free. The essential element manganese is the obvious biocompatible alternative to gadolinium, but is accompanied by the technical difficulty of achieving both stability and a strong MRI signal.

Eric Gale and Peter Caravan set out to solve this challenge by designing a unique chelating ligand with a cage structure to capture and securely hold the manganese ion while maintaining an open location for water exchange. To further enhance safety for people with renal impairment, they designed the new contrast agent to have a dual excretion path via both the liver and kidneys. Working at the Martinos Center for Biomedical Imaging and the Institute for Innovation in Imaging at Massachusetts General Hospital and Harvard Medical School, they invented a new class of contrast agents, with the archetype MnPyC3A.

Reveal’s contrast agent, RVP-001, draws on this work. We are advancing RVP-001 toward clinical use, where it has the potential to benefit millions of patients worldwide.
Radiology: Gadoterate meglumine (Dotarem) detected in human CSF after intravenous administration.
FDA Pediatric Advisory Committee: Approach to GBCA safety
RSNA Radiology Special Report: Gadolinium Retention: A Research Roadmap

Reveal News

SCBTMR 2018:  Advisor Scott Reeder discusses Gadolinium: The Debate Continues
Vera Hoffman selected for Harvard Business School Rock 100 Summit
Imaging in 2020:  Peter Caravan speaks on The Future of MRI Contrast Agents
Journal of Medicinal Chemistry   Eric Gale and Peter Caravan:  Manganese-based Contrast Agents for MRI of Liver Tumors
Advisor Mike Tweedle co-authors Gadolinium Retention: A Research Roadmap from the 2018 NIH/ACR/RSNA Workshop on Gadolinium Chelates
Peter Caravan participates in NIDDK Renal Imaging Workshop
Vera Hoffman/Reveal selected as inaugural Mass Next Gen awardee and grant recipient
Pediatric Radiology   Eric Gale and Peter Caravan:  Gadolinium-based contrast agents in pediatric magnetic resonance imaging
American Association for Cancer Research (AACR) abstract:  A novel manganese MRI contrast agent for the evaluation of hepatic neoplasms
Aunt Minnie:  Workshop aims to answer mystery of gadolinium deposition
Peter Caravan participates in NIH, ACR, and RSNA-convened workshop Gadolinium Deposition: what we know and don't know, a research roadmap
ACS Chemical Neuroscience Viewpoint   Peter Caravan and Eric Gale:  Gadolinium-Free Contrast Agents for Magnetic Resonance Imaging of the Central Nervous System
Advisor Greg Sorensen named to Supervisory Board of Siemens Healthineers
RSNA 2017 coverage by Diagnostic Imaging:  U.S. Patients Left Fending For Themselves with Gadolinium Safety Risks
Health Imaging:  New contrast agent alternative may replace gadolinium in MRI
Radiology Business:  Is Mn-PyC3A a viable alternative to gadolinium-based contrast agents?
Healthcare in Europe:  Promising first steps for alternative MRI contrast agent
Nephrology News and Issues:  Manganese-based MRI contrast agent may be safer alternative to gadolinium-based agents
The Wall Street Journal  A question for anyone getting an MRI

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The gadolinium-free MRI contrast agent