Are there alternative contrast agents to Gd-based?

April 19, 2019

 

Perhaps among the most asked questions - why Gadolinium (Gd) [that has made us sick] and not some other agent? Are there other agents?

 

This is a brief treatment on that subject, designed for the lay audience.

 

To begin with, contrast agents in MRI generally are not directly visualized, but their presence is demonstrated by their effect on adjacent water molecules. This is quite a remarkable concept - we are not seeing Gd directly, but rather its effect on surrounding water. This is different for example than Iodine contrast, as used in CT, where we are actually seeing directly the presence of iodine, because it is directly blocking the passage of x-rays in the body.

 

So for us to see a contrast agent's effect it has to be either magnetic (that is the ability to act like a magnet independently) or paramagnetic (that is, acting like a magnet in the presence of a strong magnetic field [an MRI system]) or devoid of protons/signal generating ability (signal void). Due to its atomic structure, ability to create a positive charge state, large magnet moment, and ability to be composed into a chelate, Gadolinium has been considered the optimal atom to generate magnetic effects (ability to effect adjacent water molecules to create an image) in MRI. Gd is the premier paramagnetic atom.

 

Iron is magnetic, and has/is used as an MR contrast agent. Many metals, copper and nickel as examples, are neither magnetic or paramagnetic, and actually appear signal void (black) on all MR sequences. Feridex is an iron-based contrast agent and is FDA approved. It is termed an SPIO (small particle iron oxide) agent. It has been off the market for years because of limited clinical use. It has been used as a T2-weighted contrast agent that causes darkening on T2-weighted images. It was marketed for the liver, with the effect that normal liver became darker, and liver metastases would as a result appear brighter and easier to see on T2-weighted images. It was only used as a late post-contrast image, and had no early vascular/perfusion capability. It turns out the early perfusion capability is extremely important for essentially all applications of an MRI contrast agent.

 

     Resovist is another iron-based contrast agent. It is smaller in size than Feridex and hence termed an USPIO (ultra small iron oxide) agent. Unlike Feridex, because of its size Resovist actually does show perfusion capabilities. On perfusion images this agent is bright, and on delayed images it is dark. The first instance, in the dilute phase, T1 features dominate (tissue brightening on T1 images) in the later stage in concentrated form T2 features dominate (tissue darkening on T2 images). This combination of early bright on T1 and late dark on T2 incidentally can also be observed with Gd, but the concentration of Gd to render tissue dark is much greater than for iron agents, hence with Gd relatively rarely seen. So with Resovist, early perfusion imaging is also possible. This is enormously important for imaging. Resovist was marketed in Europe, but Schering (now Bayer) never attempted to bring it to the US market. My opinion is that since Feridex was a bust for them, they did not want to go to the enormous expense of FDA approval (100 million - 1 billion dollars) for an agent that would not be able to compete with Gd-based agents. As created, although Resovist did show perfusion imaging findings, the spatial resolution for this event was far inferior to what Gd could render. 

 

      Another agent that was FDA approved but taken off the market because of limited use is a Manganese based agent, Teslascan (Mn-DPDP). It too was marketed as a liver contrast agent (although it showed good pancreas enhancement as well). It also did not show early perfusion capability. So image acquisition was only in late phase imaging and where hepatocytes took up the agent. Again, similar to with Feridex, it expanded the difference in signal between liver metastases and back ground liver - but with Teslascan the background liver became bright on late T1 weighted images, and liver metastases remained dark - thereby expanding the signal difference. Teslascan quietly went off the market, my understanding (although I have not scientifically confirmed it) is because the interesting aspect that normal pancreas became bright on T1 weighted images was a reflection that the agent dissociated and a more pure Mn effect was observed. The dissociation worried (understandably) the manufacturer.

     As created, my impression of Feridex and Teslascan was that they were no significant benefit, because they only really expanded signal difference between liver and a number of histologic lesions (liver metastases most importantly) and a better solution was better image quality to begin with, without their use. 

 

      Also iron particulate agents (both with imaging and with medical treatment drugs) is that they can cause relatively intense back pain early following injection. So a troubling adverse reaction.

 

      There are a whole host of other metals that have been described in animal models for intravenous use, Dysprosium comes to mind. My opinion, if we are worried about Gd, I am at least as worried about dysprosium.

 

       An interesting novel approach for imaging has been to make use of the magnetic properties of iron in hemoglobin, to visualize different states of oxygenation of hemoglobin, with paramagnetic/magnetic  properties of deoxyhemoglobin compared to oxyhemoglobin. In this case no use of any exogenous agent at all. Obviously a challenging issue as this has never taken off, besides discussion of its use in stroke, and similar abnormal vascular states.

 

        Various other agents have been used as inhalation agents in MRI or oral agents in MRI, including orally administered agents (I believe Mn based) that is absorbed and enhances the liver through delivery by the portal venous system.

 

Conclusion

 

   Because of the nature that MR is a magnetism-based imaging technique, contrast agents used have to be magnetic or paramagnetic to be useful. Pure signal void (proton-absent) agents generally have not panned out- essentially impossible to see something black. Perhaps of the above mentioned contrast agents that have been in clinical use, Resovist may be the agent worth looking at again. My opinion is that it should first be re-examined to see if it can be modified to result in higher quality/higher spatial resolution T1 perfusion weighted capability. This may be possible. Iron being native to the body, this makes sense that it should not elicit the heavy metal toxicity that Gd can.

 

Perhaps Mn also can be re-examined and reformulated into an agent that can be used as a perfusion agent as well. Is it as simple as just adding the Gd ligands to Mn: DTPA, BOPTA, DOTA, etc? I don't know, I imagine not or otherwise it would have already been done. Mn is clearly not as ideal a paramagnetic agent as Gd, but it is native to the body, and again should not generate heavy metal toxicity effects. Perhaps its use mainly for individuals with predisposing factors for GDD, or those who are very nervous.

 

Dysprosium/other heavy metals. If there are problems with Gd, maybe the problems will be worse with other heavy metals. One has to remember that Gd based agents have been used in over 300 million individuals, and despite acute severe anaphylactoid reactions (which maybe essentially everything can cause in the rare individual, incidence about 0.003%) and GDD (I have discussed ways that exist to minimize its occurrence, and future direction - gene detection) which in my opinion has developed in 100,000 individuals (0.03%), and severe disease in 10,000 (0.003%). Ofcourse if you are one of the 10,000 it is an awful disease. Do not misinterpret my words that I am dismissing the importance of GDD. So I am not really keen on other heavy metals. I think we will be in the situation of the devil you know versus the devil you don't know scenario.

Lastly, what about other metals native to the body, do any others besides Mn have reasonable paramagnetic properties?  I suspect not, otherwise I am sure they would have been explored > although I could be wrong about that.

 

So maybe scientists should tool around with Resovist as a starting point: make it a better spatial resolution perfusion agent.

 

Richard Semelka MD Consulting 

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