The design of a Gd(III)-based complex whose relaxivity is pH-dependent requires that at least one of the structural or dynamic parameters determining its relaxivity is rendered pH-dependent. In most of the examples so far reported, the pH dependence of the relaxivity reflects changes in the hydration of the metal complex.
For instance, Lowe et al. showed that the relaxivity of a series of macrocyclic Gd(III) complexes bearing ^-arylsulfonamide groups is markedly pH-dependent (Figure 28.5) on passing from about 8s~1mM~1 at pH<4 to about 2.2s~1mM~1 at pH >8.26
It has been demonstrated that the observed decrease (about 4-fold) ofr1 is the result of a switch in the number of water molecules coordinated to the Gd(III) ion from 2 (at low pH values) to 0 (at basic pH values). This corresponds to a change in the coordination ability of the ^-arylsulfonamide arm, that binds the metal ion only when it is in the deprotonated form.
In some cases the pH dependence of the relaxivity is associated with changes in the structure of the second hydration shell. Two such systems have been reported by Sherry's group. The first case deals with a macrocyclic tetramide derivative of DOTA (DOTA-4AmP, Figure 28.6) that possesses an unusual r1 versus pH dependence.27 In fact, the relaxivity of this complex increases from pH 4 to pH 6, decreases up to pH 8.5, remains constant up to pH 10.5 and, then, increases again. The authors suggested that this behaviour is related to the formation/disruption of the hydrogen bond network between the pendant phosphonate groups and the water bound to the Gd(III) ion. The deprotonation of phosphonate occurring at pH >4 promotes the formation of the hydrogen bond network that slows down the exchange of the metal-bound water protons.
Figure 28.6 Schematic representation of the ligand DOTA-4AmP, whose Gd(III) complex has been proposed as pH-responsive probe
On the contrary, the behaviour observed at pH >10.5 was accounted for in terms of a shortening of rM catalyzed by OH~ ions. Recently, it has been demonstrated that this complex can be successfully used 'in vivo' for mapping renal and systemic pH.28 pH-dependent probes can also be obtained when the proton concentration is able to affect the rotational tumbling of a slowly moving Gd(III)-based system. An interesting example is represented by a macromolecular Gd(III) construction formed by 30 Gd(III) units covalently linked, by a squaric acid moiety, to a poly-ornithine (114 residues, Figure 28.7).29 At acidic pH the unreacted amino groups of the polymer are protonated and, therefore, tend to be localized as far apart as possible, whereas at basic pH the progressive deprotonation of the NH3+ groups determines an overall rigidifica-tion of the polymer structure owing to the formation of intramolecular hydrogen bonds between adjacent peptidic linkages. As expected, the reduced rotational mobility of the polymeric backbone upon increasing pH enhances the relaxivity of the system (Figure 28.8). Nevertheless, even if the enhancement is not particularly remarkable (ca. 40% in the 3-8 pH interval), it is worthy to note that the relaxivity of this system is considerably higher than the previous examples over the entire pH range, thus allowing, in principle, the detection of pH changes at lower concentration of the responsive probe.
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