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Some Notes on MR Contrast Agents

A short chemistry lesson to help guide safe usage of gadolinium compounds.

Peter A. Rinck and Robert N. Muller

Clinical low-molecular-weight paramagnetic contrast agents distribute into the intravascular and extracellular fluid space of the body. They are water-soluble and not tissue-specific. The majority do not bind to protein. Their contrast-enhancing effect in MR imaging is caused by the metal ion in their center that contains unpaired electrons. It depends on dose and/or magnetic field strength.

At present, paramagnetic gadolinium- based contrast agents are the most frequently used compounds in MRI. With its seven unpaired electrons and relatively long electron-spin relaxation time, gadolinium possesses the highest ability to alter the relaxation times of adjacent protons (the highest relaxivities r1 and r2).

Because the gadolinium ion is rather toxic, it has to be bound in stable complexes in which it is assumedly kept until the contrast agent is excreted. This binding organic molecule acting is called a chelator, after the Greek word for claw. The bond should be as tight as possible to counteract the lability of the compound and to prevent the release of “free” gadolinium into the human body.

Among these chelators are DTPA, DTPA-BMA, DTPABMEA, DOTA, DO3A-butrol, and HP-DO3A. Bound to them, gadolinium forms low-molecular- weight water-soluble complexes, the contrast agents, which are excreted through the kidneys. Gd-DTPA and Gd-DOTA are called ionic agents, whereas Gd- DTPA-BMA, Gd-DTPA-BMEA, Gd-DO3A-butrol, and Gd-HPDO3A are called nonionic. In this context, the terms “globally charged” and “globally neutral” would be better.

The relaxivities of all these agents are similar water, but can differ in serum (Figure 1).

Their effect on T1 and T2 is similar, but since T1 of tissues is much higher than T2, the predominant effect at low doses is that of T1 shortening. Thus, tissues taking up such agents will become bright in a T1-weighted sequence [1].

Further compounds include gadolinium bound to BOPTA, EOB-DTPA, and similar ligands that are slightly more lipophilic and excreted via the kidney but also via the liver. The relaxivities of such compounds can be higher because they may bind to protein.

Chelates come as stretched, or linear, or cyclic or macrocyclic molecules. In the early days of research and development of these contrast agents, their feared toxicity was associated with the possible competition with endogenous ions such as zinc and calcium. Such an exchange, called transmetalation, frees gadolinium from the chelate into the body. When dissolved in water, all commercially available complexes are very stable. Only one molecule over several millions or billions releases its gadolinium. When in the body, however, challenged by other ions that want to replace the gadolinium, these molecules behave differently.

Gadolinium ions carry three positive charges. If the chelator brings three negative charges (as in Omniscan, ProHance, Gadovist, and Optimark), the global charge is zero (globally neutral). If it brings more (as in Dotarem, Magnevist, MultiHance, and Vasovist), the global charge is negative (globally charged).

This is not the key to stability, however, since the macrocyclic structures are the most stable regardless of their charged (Dotarem) or neutral (Pro- Hance and Gadovist) character. For the other contrast agents, the so-called open-chain chelates (Omniscan, Magnevist, MultiHance, Vasovist, and Optimark), the situation is clearly different: Simple analytical tests show that their ability to retain their gadolinium ion is weaker (Table 1).

It has been shown, however, that, submitted to the same tests, the negatively charged Magnevist, MultiHance, Vasovist, and Optimark are more stable than the neutral Omniscan. In addition, branching the organic backbone of the chelate increases the stability of the former ones [2-6].

Thus, from a chemical point of view, certain agents minimize the risk of late side effects and are to be preferred over others.

Table 1: Classification of some magnetic resonance contrast agents approved, or to be approved, for clinical use. EMRF does not recommend or disapprove of any of these agent. This is just a lis which is not exhaustive. Some of the agents mentioned have been withdrawn from the market; there are numerous other agents in development. Some agents have different trade names, depending on the markets.

SPIO = superparamagnetic iron oxides, USPIO = ultrasmall SPIO. * or short description; ** ™ or ®; ***with high local concentrations and/or appropriate pulse sequence parameters, negative contrast can be achieved (e.g., first-track bolus); ****all ECF space agents are also kidney-specific agents.

References

1. Rinck PA, Muller RN. Field strength and dose dependence of contrast enhancement by gadolinium- based MR contrast agents. Eur Radiol 1999;9:998-1004.
2. Laurent S, Vander Elst L, Muller RN. Comparative study of the physicochemical properties of six clinical low molecular weight gadolinium contrast agents. Contrast Media Mol Imaging 2006;1:128- 137.
3. Laurent S, Vander Elst L, Copoix F, Muller RN. Stability of MRI paramagnetic contrast media: a proton relaxometric protocol for transmetallation assessment. Invest Radiol 2001;36:115-122.
4. Vander Elst L, Maton F, Laurent S, et al. A multinuclear MR study of Gd-EOB-DTPA: comprehensive preclinical characterization of an organ specific MRI contrast agent. Magn Reson Med 1997;38:604-614.
5. Sieber MA, Lengsfeld P, Frenzel T, et al. Preclinical investigation to compare different gadolinium-based contrast agents regarding their propensity to release gadolinium in vivo and to trigger nephrogenic systemic fibrosis-like lesions. Eur Radiol 2008;18:2164-2173.
6. Pietsch H, Lengsfeld P, Jost G, et al. Long-term retention of gadolinium in the skin of rodents following the administration of gadolinium-based contrast agents. Eur Radiol. 2009; 19(6): 1417-1424.

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