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, and people who require repeated CE-MRI scans for surveillance, ongoing disease management, or clinical trials. 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 just beginning to be explored, and has 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.

Peter Caravan and Eric Gale 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.
American Journal of Neuroradiology:  Manganese-Enhanced MRI of the Brain in Healthy Volunteers
Research from The National Institute of Neurological Disorders and Stroke (NINDS)
Gadolinium Deposition Workshop:  Presentations from a workshop at the National Institutes of Health (NIH) exploring concerns about the safety of gadolinium-based contrast agents (GBCAs) and gadolinium retention. This workshop was co-sponsored by NIH, the Radiological Society of North America (RSNA) and the American College of Radiology (ACR).
FDA Pediatric Advisory Committee:  Approach to GBCA safety
RSNA Radiology Special Report:  Gadolinium Retention: A Research Roadmap
The Wall Street Journal:  A question for anyone getting an MRI
FDA Medical Imaging Drugs Advisory Committee:  potential risk of gadolinium retention: September 2017 meeting materials

 Reveal  Results


  Investigative Radiology   (2019)
Tumor Contrast Enhancement and Whole-Body Elimination of the Manganese-Based Magnetic Resonance Imaging Contrast Agent Mn-PyC3A

Mn-PyC3A provides comparable tumor contrast enhancement to Gd-DOTA in a mouse breast cancer model and is more completely eliminated than Gd-DOTA; partial hepatobiliary elimination of Mn-PyC3A enables conspicuous delayed phase visualization of liver metastases.



  Radiology   (2018)
A Manganese-based alternative to gadolinium: contrast-enhanced MR angiography, excretion, pharmacokinetics, and metabolism

Mn-PyC3A enables contrast-enhanced MR angiography with comparable contrast enhancement to gadolinium-based agents and may overcome concerns regarding gadolinium-associated toxicity and retention.




  Journal of the American Chemical Society   (2015)
A Manganese Alternative to Gadolinium for MRI Contrast

We present the new manganese(II) complex Mn-PyC3A as a Gd alternative.
+   Mn-PyC3A is among the most stable Mn(II) complexes at pH 7.4.
+   Relaxivity of Mn-PyC3A in blood plasma is comparable to commercial Gd contrast agents.
+   Mn-PyC3A clears via a mixed renal/hepatobiliary pathway with >99% elimination by 24 h.
+   Mn metabolite analysis reveals no evidence of dechelation and the probe was >99% eliminated after 24 h.
+   (Targeted derivative) Mn-FBP provided equivalent thrombus enhancement to the Gd analogue, EP-2104R.


Reveal  Research

European Radiology   European Gadolinium Retention Evaluation Consortium (GREC) Task Force position statement

"The scientific debate about this finding is kept alive by the fact that SI differences do not unequivocally represent the amount of gadolinium retained.
... every effort should be made to protect patients from any side effect related to retention or exposure to GBCAs, and concern for public safety is paramount, particularly in children and patients who need several follow-up exams."

Radiology   First-Trimester Exposure to Gadolinium-based Contrast Agents: A Utilization Study of 4.6 Million U.S. Pregnancies

FDA research - "This study identified higher rates of gadolinium-based contrast agent (GBCA) exposure during the first few weeks of pregnancy, suggesting inadvertent exposure to GBCAs might occur before pregnancy is recognized."

British Journal of Dermatology   Image Gallery: A case of gadolinium‐associated plaques

"GAP is likely on a spectrum of fibrotic skin conditions associated with gadolinium exposure, similar to NSF."

Investigative Radiology   Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases With Reduced Kinetic Stability of the Agent

"These results demonstrate a toxic effect of gadolinium-containing MRI contrast agents on mitochondrial respiratory function and cell viability."

British Journal of Radiology   Quantitative analysis of Gd in the protein content of the brain following single injection of gadolinium-based contrast agents (GBCAs) by size exclusion chromatography

"Intact GBCA are able to penetrate a series of brain barrier immediately after administration regardless the type of the chelate. Gadolinium may be bound with macromolecules that may cause Gd retention in the brain."

Neuroradiology   Gadolinium retention in gliomas and adjacent normal brain tissue

"Gadolinium can be detected in both enhancing and non-enhancing gliomas, neighboring normal brain, and necrosis."

Reveal  Patient  Experience

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 Physician  Voices


Reveal  Reveal  News

Peter Caravan speaks on contrast agent safety at ISMRM Workshop on MR Safety
Massachusetts General Hospital:   New contrast agent could make MRIs safer
Reveal is awarded a Fast Track SBIR by the National Cancer Institute (NCI)
MALSI 2019: Reveal is selected as a winner in the MTTC poster competition
ISABC15: Peter Caravan presents Biomedical Imaging Across the Periodic Table
ISMRM 2019: Peter Caravan presents Molecular & Cellular Probes
ISMRM 2019: Caravan & Gale groups present six posters in Molecular Imaging
Eric Gale recognized as early career professional “One to Watch” in 2019 by the Society of Nuclear Medicine and Molecular Imaging
Peter Caravan presents Molecular Imaging of Fibrosis at the Weizmann Institute Minerva-Gentner Symposia on MR Spectroscopy & Molecular Imaging
Chemistry   Molecular Probes for Imaging Fibrosis and Fibrogenesis by Pauline Désogère, Sydney B. Montesi, and Peter Caravan
Journal of Clinical Investigation   Molecular imaging of fibrosis: recent advances and future directions by Sydney B. Montesi, Pauline Désogère, Bryan C. Fuchs, and Peter Caravan
Cardiovascular Magnetic Resonance Imaging   Targeted MR Imaging in Cardiovascular Disease by David E Sosnovik and Peter Caravan
Cardiovascular Magnetic Resonance (Third Edition)   Cardiovascular Magnetic Resonance Contrast Agents by Eric Gale and Peter Caravan
Chemical Reviews   Chemistry of MRI contrast agents: Current challenges and new frontiers by Jessica Wahsner, Eric Gale, Aurora Rodríguez-Rodríguez, and Peter Caravan
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   Manganese-based Contrast Agents for MRI of Liver Tumors by Eric Gale, Peter Caravan, et al
Radiology   Advisor Mike Tweedle co-authors Gadolinium Retention: A Research Roadmap from the 2018 NIH/ACR/RSNA Workshop on Gadolinium Chelates
Chemistry–A European Journal   Molecular probes for imaging fibrosis and fibrogenesis by Pauline Desogere, Sydney B Montesi, and Peter Caravan
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
Reveal is selected to participate in  MassChallenge 2017

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The gadolinium-free MRI contrast agent