Complex Gd-DTPA

The complex [Gd(DTPA-SA)]-, which has a sulfonamide function at the central glycine unit of DTPA has been been proposed as a CA targeting the enzyme carbon anhydrase [191]. The complex shows a strong interaction with this enzyme (K = 15,000 M-1), supposedly through the catalytic Zn2+ ion and the active site. 

In 1984, Laniado et al. [16] reported the first in vivo use of a Gd + complex, [Gd(DTPA)], a CA that was approved for clinical application in 1988. Nowadays, complexes containing gadolinium are among the most popular CAs used regularly in Medicine, and the ligands that complex the metal ion are mainly DTPA or DOTA (l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid) derivatives. In Table 46.1, the major characteristics of several clinically approved CAs are represented. 

The Gd-H distance, /-GdH, which enters at the inverse sixth power into the expression of inner-sphere relaxivity, is a difficult parameter to obtain experimentally. It is generally estimated on the basis of Gd-coordinated water oxygen distances, determined by solid-state X-ray analysis. Solid-state distances are good estimates of the aqueous solution state, as was experimentally proven by an X-ray absorption fine-structure study on [Gd(D0TA)(H20)] and [Gd(DTPA)(H20)]2, which gave identical values for the Gd-0 distances for both complexes in solid and solution states.20... 

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 ).

In practice, some contrast agent formulations also include a small amount of the corresponding Ca11 chelate ( 5%) which acts as a sacrificial complex to pre-empt displacement of Gdm from GdL by adventitious Zn2+. As a result, the LD50 value for Gd(DTPA-BMA) increased from 14.8 mmol kg-1 to 38.2 mmol kg-1 upon addition of the adjuvant Ca11 complex.103... 

The competitive equilibria based on the different plasma models cannot solely explain the in vivo behaviour of Gd111 complexes. The excretion of low molecular weight Gd111 chelates from the body is very rapid (e.g., t1/2 = 1.6 h for [Gd(DTPA)]2 ),M0 whereas the dissociation and trans-metallation of the Gd111 complexes is relatively slow. Therefore, the system is far from equilibrium and kinetic factors could substantially change the predicted amount of free Gd3+. 

Fig. 8 Nanosystems that may function as simultaneous drug delivery and imaging agents for targeting T cells (a) liposomal systems, (b) solid biodegradable nanoparticulates, and (c) macro-molecular dendrimer complexes. PEG polyethylene glycol, Gd-DTPA gadolininum-diethylene triamine penta acetic acid. (Adapted from [48])...

Figure 7.19 Several ligands and gadolinium(III) complexes used in MRI imaging. (A) DTPA ligand (B) [Gd(DTPA)(H20)]2, Magnevist (C) MS-264-L, ethylene-bridge-substituted DTPA (D) BOPTA, acetate-substituted DTPA (E) [Gd(B0PTA)(H20)]2, MultiHance (F) AngioMARK . (Adapted with permission from Chart 1 of Caravan, P. Ellison, J. J. McMurry, T. J. Lauffer, R. B. Chem. Rev., 1999, 99(9), 2293-2352. Copyright 1999, American Chemical Society.)...

Figure 7.21 indicates the several neutral complexes used as MRI imaging agents. Neutrality is accomplished through bisamide substituents on DTPA [Gd(DTPA-BMA)(H20)], Omniscan (Figure 7.21A,B) or via the cyclic ligand HP-D03A [Gd(HP-D03A)(H20)], ProHance (Figure 7.21C.D).

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