Metal Chelates as MRI Contrast Agents

A compound that is able to influence the relaxation times of water protons has to be paramagnetic. In the Periodic System paramagnetic ions are to be found amongst the transition metals and the rare earth metals (lanthanides). However, it was well known, that the free ions of heavy metals are toxic. Lanthanide ions form soluble complexes with ligands such as phospholipids, amino acids and proteins that are present in plasma. The liver and the skeleton are the major sites of accumulation of free metal ions. Uptake in the liver is mediated by the hepa-tocytes [2]. 

The challenge was to render the metal ions safe without impairing their paramagnetic properties. This problem could succesfully be solved by the complex-ation of the metal ions with suitable ligands. 

These ligands are frequently used as metal ion traps to bind undesired metal ions, e. g. in formulations of X-ray contrast agents. Chelated cations may associate electrostatically with anionic compounds and with solvent molecules by weak interactions. This results in the formation of an outer coordination sphere. Instead of the term complex the term chelate is very frequently used meaning that the metal ion is covered by the ligand like a claw ( chela word from the Greek for claw). 

For the use as a contrast agent the stability of the complex in vivo is most important. It depends significantly on the thermodynamic stability defined by Eq.(l). 

Most frequently the logK(therm)-values of the complexes are used. They have been compiled in special compendia [3,4]. A variety of approaches for the measurement of stability constants is available. However, thermodynamics alone is an insufficient predictor of the behaviour of the complexes in the organism. Other features have to be considered, particularly the stability of the aqueous solution under the physiological conditions at pH 7.4 which is characterized by the selective stability constant K (sel) that can be calculated from K (therm) [5]. Normally K(sel) is lower than K (therm). Expectedly, the toxicity of the chelate correlates best with K(sel). 

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