Gadolinium-based MRI contrast agent

MRI contrast agents are contrast agents used to improve the visibility of internal body structures in magnetic resonance imaging (MRI). The most commonly used compounds for contrast enhancement are gadolinium-based. Such MRI contrast agents shorten the relaxation times of nuclei within body tissues following oral or intravenous administration.

In MRI scanners, sections of the body are exposed to a strong magnetic field causing primarily the hydrogen nuclei ("spins") of water in tissues to be polarized in the direction of the magnetic field. An intense radiofrequency pulse is applied that tips the magnetization generated by the hydrogen nuclei in the direction of the receiver coil where the spin polarization can be detected. Random molecular rotational oscillations matching the resonance frequency of the nuclear spins provide the "relaxation" mechanisms that bring the net magnetization back to its equilibrium position in alignment with the applied magnetic field. The magnitude of the spin polarization detected by the receiver is used to form the MR image but decays with a characteristic time constant known as the T1 relaxation time. Water protons in different tissues have different T1 values, which is one of the main sources of contrast in MR images. A contrast agent usually shortens, but in some instances increases, the value of T1 of nearby water protons thereby altering the contrast in the image.

Most clinically used MRI contrast agents work by shortening the T1 relaxation time of protons inside tissues via interactions with the nearby contrast agent. Thermally driven motion of the strongly paramagnetic metal ions in the contrast agent generate the oscillating magnetic fields that provide the relaxation mechanisms that enhance the rate of decay of the induced polarization. The systematic sampling of this polarization over the spatial region of the tissue being examined forms the basis for construction of the image.

MRI contrast agents may be administered by injection into the blood stream or orally, depending on the subject of interest. Oral administration is well suited to G.I. tract scans, while intravascular administration proves more useful for most other scans.

MRI contrast agents can be classified by their:

* chemical composition
* administration route
* magnetic properties
* biodistribution and applications:
** Extracellular fluid agents (intravenous contrast agents)
** Blood pool agents ( intravascular contrast agents)
** Organ specific agents (gastrointestinal contrast agents and hepatobiliary contrast agents)
** Active targeting/cell labeling agents (tumor-specific agents)
** Responsive (smart or bioactivated) agents
** pH-sensitive agents

Gadolinium(III)

Gadolinium(III) containing MRI contrast agents (often termed simply "gado" or "gad") are the most commonly used for enhancement of vessels in MR angiography or for brain tumor enhancement associated with the degradation of the blood–brain barrier. Over 450 million doses have been administrated worldwide from 1988 to 2017. For large vessels such as the aorta and its branches, the dose can be as low as 0.1 mmol / kg of body mass. Higher concentrations are often used for finer vasculature. At much higher concentration, there is more T2 shortening effect of gadolinium, causing gadolinium brightness to be less than surrounding body tissues. However at such concentration, it will cause greater toxicity to bodily tissues.

Gd³⁺ chelates are hydrophilic and do not pass the intact blood–brain barrier. Thus, they are useful in enhancing lesions and tumors where blood-brain barrier is compromised and the Gd(III) leaks out. In the rest of the body, the Gd³⁺ initially remains in the circulation but then distributes into the interstitial space or is eliminated by the kidneys.

Available Gadolinium-based contrast agents (GBCAs) (''brand names'', approved for human use by EMA and by the FDA in 1988. (''standard dose'')):

Extracellular fluid agents

* Macrocyclic
** ionic
*** gadoterate (''Dotarem'', ''Clariscan'') : EMA FDA (''SD: 0.1 mmol/kg)''
**non-ionic
*** gadobutrol (''Gadovist U/ Gadavist S') EMA FDA ''(SD: 0.1 mmol/kg)''
*** gadoteridol (''ProHance'') : EMA FDA ''(SD: 0.1 mmol/kg)''
* Linear (suspended by EMA)
**ionic
*** gadopentetate (''Magnevist, EU: Magnegita,'' ''Gado-MRT ratiopharm)'' FDA ''(SD: 0.1 mmol/kg)'')
*** gadobenate (''MultiHance'') : FDA EMA (liver) ''(SD: 0.1 mmol/kg)''
*** gadopentetic acid dimeglumine (''Magnetol'')
*** gadoxentate (''Eovist'', EU: ''Primovist'') FDA
** non-ionic
*** gadoversetamide (''OptiMARK'') FDA ''(SD: 0.1 mmol/kg)''
*** gadodiamide (''Omniscan'') : FDA ''(SD: 0.1 mmol/kg)''

Blood pool agents

* Albumin-binding gadolinium complexes
** gadofosveset (''Ablavar, formerly Vasovist)'' FDA ''(SD: 0.03 mmol/kg)''
** gadocoletic acid
* Polymeric gadolinium complexes
** gadomelitol
** gadomer 17

Hepatobiliary (liver) agents

* gadoxetic acid (''Primovist U/ Eovist S') is used as a hepatobiliary agent as 50% is taken up and excreted by the liver and 50% by the kidneys.

Safety

As a free solubilized aqueous ion, gadolinium (III) is highly toxic, but chelated compound are generally regarded as safe enough to be administered. Free Gd³⁺ has a median lethal dose of 0.34 mmol/kg (IV, mouse) or 100–200 mg/kg, but the LD50 is increased by a factor of 50 when Gd³⁺ is chelated.

The use of Gd³⁺ chelates in persons with acute or chronic kidney disease can cause nephrogenic systemic fibrosis (NSF), a rare but severe systemic disease resembling scleromyxedema and to some extent scleroderma. It may occur months after contrast injection. Patients with deteriorated kidney function are more at risk for NSF, with dialysis patients being more at risk than patients with chronic kidney disease. NSF can be caused by linear and macrocyclic (macrocyclic ionic compounds have been found the least likely to release the Gd³⁺), gadolinium-containing MRI contrast agents although much more frequently by linear.

Gadolinium has been found to remain in the brain, heart muscle, kidney, liver, and other organs after one or more injections of a linear or macrocyclic GBCA, even after a prolonged period of time. The amount differs with the presence of kidney injury at the moment of injection, the molecular geometry of the ligand, and the dose administered.

In vitro studies have found GBCAs to be neurotoxic, and a study found signal intensity in the dentate nucleus of MRI (indicative of gadolinium deposition) to be correlated with lower verbal fluency. Confusion is often reported as a possible clinical symptoms. The FDA has asked doctors to limit the use of Gadolinium contrast agents only when necessary information is made available through its use. Intrathecal injections of doses higher than 1 mmol are associated with severe neurological complications and can lead to death. The glymphatic system could be the main access of GBCA to the brain in intravenous injection.

Continuing evidence of the retention of gadolinium in brain and other tissues following exposure to gadolinium containing contrast media, has led to a safety review by the Committee for Medicinal Products for Human Use (CHMP) which led the EMA to suspend linear gadolinium-based media, in which Gd³⁺ has a lower binding affinity, in 2017.

In the United States, the research has led the FDA to revise its class warnings for all gadolinium-based contrast media. It is advised that the use of gadolinium-based media is based on careful consideration of the retention characteristics of the contrast. Extra care being taken in patients requiring multiple lifetime doses, pregnant, and paediatric patients, and patients with inflammatory conditions. Minimizing repeated GBCA imaging studies when possible, particularly closely spaced MRI studies. However, do not avoid or defer necessary GBCA MRI scans.

In December 2017, the FDA announced in a drug safety communication it is requiring these new warnings to be included on all GBCAs. The FDA also called for increased patient education and requiring gadolinium contrast vendors to conduct additional animal and clinical studies to assess the safety of these agents.

The French health authority recommends to use the lowest possible dose of a GBCA and only when essential diagnostic information cannot be obtained without it.

The World Health Organization issued a restriction on use of several gadolinium contrast agents in November 2009 stating that "High-risk gadolinium-containing contrast agents (Optimark, Omniscan, Magnevist,