Gadolinium chelation

Dawson, P. Gadolinium Chelates Chemistry. In Textbook of Contrast Media, Dawson, P. Cosgrove, D. O. Grainger, R. G., Eds. Isis Medical Media Oxford, 1999 p 295. 

Figure 1.17 The texaphyrin-gadolinium chelate structure used as a photosensitizer and MRI contrast agent in the detection and treatment of cancer.

Scheme 2.2-11. Synthesis of gadolinium-chelating molecule with an 0-C2B10 moiety.

Two types of micellar systems have been described, the first one includes Gd complexes capable of self-organization resulting in a supramolecular assembly 103), while the other class of micelles, also named mixed micelles is made of several components a lipophilic gadolinium chelate, one or several phospholipid(s) and a non-ionic surfactant containing a polyoxyethylene chain 104,105). 

All currently available extracellular contrast agents are gadolinium chelates. This rare earth metal ion exhibits the strongest effect of all elements on the longitudinal relaxation time Tl. The ligands of these chelates belong to two different types of structure Acyclic (open-chain) compounds and macrocyclics. 

Two extracellular contrast agents which contain neutral gadolinium chelates have entered the market gadodiamide (Omniscan) (Fig. 4 a) and gadoverse-tamide (Optimark) (Fig. 4b). 

Table 3. Thermodynamic stability constants and relaxivities in water at 20 MHZ and 40 °C of commercially available gadolinium chelates...

The development of low osmolar non-ionic X-ray contrast agents has resulted in a distinct reduction in the toxicity and the observed side-effects in patients. However, as already mentioned the osmotic activity of MRI contrast agents is less important in view of the smaller injection volumes which are used. All the formulations of extracellular gadolinium chelates are hypertonic when compared with blood. But the overall increase in osmolality after injection of even 0.3 mmol/kg body weight is insignificant. Osmololatiy-induced adverse reactions have been observed rarely not only because of the relatively small injection volumes but also because of the rapid dilution of the injected agent in the blood. 

The extra-renal excretion of the extracellular gadolinium complexes is negligible and no significant absorption after enteral application has been observed. The elimination half-life depends on the glomerular filtration rate, and on the cardiovascular function. No significant differences between the gadolinium chelates have been observed, their terminal half-lives in blood are in the range of 15 to 75 minutes in animals and 1-2 h in humans [65-67]. 

Since the gadolinium chelates are unable to pass the intact blood brain barrier (BBB), they are very suitable for investigating any disturbances in this region of interest. They are particullarly useful for increasing the detection rate of... 

The pharmacokinetic parameters of the extracellular gadolinium chelates do not exhibit any dose dependency. The analysis of plasma and urine samples gave no evidence for any biotransformation of the compounds [69-71]. 

The relaxivity induced by gadolinium chelates due to inner-sphere water molecules, riIS, is well understood on the microscopic scale as can be seen from the above discussion. The contribution to the overall relaxation enhancement due to all other water molecules is normally summed up in the term r, generally called the outer-sphere contribution. The interaction between the water proton nuclear spin I and the gadolinium electron spin S is supposed to be a dipolar intermolecular interaction whose fluctuations are governed by random translational motion. The corresponding relaxation rate, l/Tly for unlike spins is given by Eq. (23) [88-90]... 

Low molecular weight gadolinium chelating agents have been coupled to high molecular weight polymers whether natural [22] (proteins such as HSA) or artificial [23] (polyaminoacids like polylysine, oligosaccharides such as dextrans, dendrimers). 

Increasing the molecular weight of a gadolinium chelate does indeed provide a contrast agent with enhanced relaxivity, provided that free rotation at the metal ion is sufficiently hindered. It is not however the only way to improve the efficacy of a contrast agent as described later (see smart contrast agents). 

Tombach B, Benner T, Reimer P et al (2003) Do highly concentrated gadolinium chelates improve MR brain perfusion imaging Intraindividually controlled randomized... 

Several investigators have described the time course of contrast enhancement with gadolinium chelate in patients with ischemic stroke (Crain et al. 1991 Elster 1991 Essig et al. 1996 Karonen et al. 2001 Vo et al. 2003). Contrast-enhanced MRI on days 1, 2 and 7 post-stroke revealed two different patterns, namely intravascular and parenchymal enhancement of the contrast agent. Whereas intravascular enhancement in the infarcted area was detected in 78% of the cases on day 1 and in 30% of cases at 1 week, parenchymal enhancement was observed with increasing frequency over 7 days (Karonen et al. 2001). 

The structures of some gadolinium chelates used as contrast reagents are shown in Fig. 12.37. 

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