Gd-DOTA

In the macrocydic structure the metal binding site within the ligand is more encapsulated and the entropy is decreased upon metal incorporation. As a result the stability of the majority of macrocydic metal chelates is higher than that of acyclic complexes (Table 3) [27,28]. Generally the macrocydic complexes exhibit a higher kinetic stability. 

The formulations of Dotarem (Gd-DOTA) consist of aqueous solutions of gadoterate as its N-methylglucamine salt in concentrations of 0.5 and 1.0 mo 1/1. The latter solution displays relatively high osmolality and viscosity (Table 2) [29]. 

Generic name log K (therm) References 1/T1 relaxivity (1/mmol1 s 1) References 

The LD50 after intraveneous injection in rats is approx. 18 mmol/kg (Table 1) [30]. 

Pharmacological behaviour and clinical use of Dotarem correspond to the acyclic extracellular agents. 

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Figure 2 The molecular dynamics simulation picture of [Gd(DOTA)(H20)] in aqueous solution shows the inner sphere water, directly bound to the metal (its oxygen is dark) the second sphere water molecules, bound to the carboxylates of the ligand through hydrogen bridges (their oxygens are gray) and outer sphere or bulk water molecules without preferential orientation (in white).

Figure 5 Typical NMRD curves of monomer Gdm complexes with one ([Gd(DOTA)(H20)] and [Gd(DTPA)(H20)]2 ) and with two inner-sphere water molecules ([Gd(HTTAHAXH20)2]2 ).

This method represents one of the first attempts towards macromolecular agents.121-123 As many as 60-90 [Gd(DTPA)]2- or [Gd(DOTA)] chelates were first linked to a polylysine chain, then covalently conjugated to a HSA molecule.124 The increase in relaxivity per Gd, as compared with the monomeric chelate, was remarkable (two- to threefold), though far from optimal. However, the development of these albumin conjugates was abandoned at an early stage, since their synthesis is not easily controlled, and there are also toxicity concerns due to the retention of gadolinium observed in the bones and liver.125... 

In particular, the self-assembled metallostar system, Fe[Gd2 (bpy-DTTA2)(H20)4]3 4, has remarkable relaxivity at high magnetic fields. MRI studies conducted at 4.7 T in mice have confirmed that the metallostar displays approximately four times higher in vivo relaxivity than the commercially available [Gd(DOTA) (H20)] (38). [Gd3(mes-DTTA3)(H20)6]3 contains three DTTA... 

Fig. 12. X-ray crystal structure of complex 72, Na[Gd(DOTA)(H20)], an MRI contrast agent used clinically for detection of blood-brain barrier abnormalities. Adapted from (306).

Paramagnetic amphiphilic complexes embedded in micelles have their hydrophilic head and thus the paramagnetic ion in contact with the surrounding water. If the complex has only one hydrophobic chain, the access of water to the ion should be easy but when two hydrophobic chains are involved like in DTPA bisamides complexes, the incorporation of both chains in the micellar structure could reduce either the accessibility of water to the ion or the water exchange rate. It has been reported that micellar Gd-DOTA complexes substituted by one hydrophobic chain are characterized by a water residence time similar to that of Gd-DOTA 200 ns) and that their enhanced relax-... 

A second class of MRI contrast agents contains ligands that are derivatives of the macrocydic tetramine, 1.4.7.10-tetraazacyclododecane (cyclen). Gadoterate (Dotarem, Gd-DOTA, Scheme 3, formula 5) was the first macrocydic gadolinium complex which has entered the market. 

Tetrabenzylcyclen 7 has been prepared in nearly quantitative yield by refluxing a mixture of 6 and p-toluenesulfonic acid in alcohol for 6 hours. Debenzyla-tion of 7 can be carried out by treatment with 10% Pd-C under hydrogen. Cyclen 4 is obtained in a high yield. Alkylation with chloro- or bromo acetic acid leads to the ligand DOTA 9 [25]. Subsequent complexation with gadolinium chloride or gadolinium oxide in the usual manner yields Gd-DOTA 5 (Scheme 3). 

From a structural point of view a number of different isomers could be present. In principal the three different hydroxyl groups in the ligand are able to interact with the central metal ion thus giving rise to three different constitutional isomers. The stereochemistry of the different configurational isomers of gadobutrol is best described in view of the stereochemistry of the parent compound Gd-DOTA. In this complex chirality results from the restriction of free rotation around the bonds of the ligand caused by the inclusion of the central metal ion. Thus four stereoisomers are generated upon complexation of Gd(III) by DOTA. 

The success of [Gd(DOTA)] as a CA has initiated an intensive search for derivatives with improved properties, such as complexes of D03A derivatives. The nonionic reagents Gd(HP-D03A) and Gd(D03A-butrol), in which one of the acetate groups of DOTA is replaced by a hydroxyalkyl group, have recently been introduced. 

Fig. 8. NMRD profile of [Gd(teta)] (top) and [Gd(dotp)]5 (bottom) ,profiles incorporating the electron relaxation parameters determined by Powell et al. for [Gd(dota)(H20] ...

In the course of the development of CAs, the question of the stability of Gd3+ chelates in the serum has often been raised. Besides, the possibility of the metal and ligand-assisted dissociation of Gd3+ complexes, which was mentioned above, the formation of precipitates of Gd(P04) and Gd2(C03)3 was additionally assumed to be possible [2]. The concentration of phosphate (0.38 mM) and particularly carbonate ions (24.5 mM) in the plasma is relatively high [21], while the solubilities of Gd(P04) and Gd2(C03)3 are very low. Many experimental data and also the calculations carried out by Cacheris et al. indicate the stability of the clinically used CAs in the serum [17,22]. However, Magerstadt et al. observed a decrease in the concentration of Gd(DTPA)2- in the serum at 37°C, while the concentration of the more inert Gd(DOTA)- remained practically unchanged. They assumed the formation of a precipitate of GdP04 [35]. 

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