PH-dependent relaxivity

The Lipari-Szabo approach was used to understand the cause of the pH-dependent relaxivities of PAMAM-type dendrimeric Gdm complexes (74). Three different generations (5,7,9) of PAMAM dendrimers loaded with the [Gd(EPTPA)(H20)]2 chelate via a benzyl-thiourea linkage have been investigated (Scheme 8). The relaxivities show a strong and reversible pH dependency for all three dendrimer complexes,... 

Complexes that show a pH dependent relaxivity around physiological pH values are of particular interest since they may afford a way to distinguish tumor tissue (pH = 6.9) from healthy tissue (pH = 7.4). Protonation of a donor atom (0 or N) can lead to competitive binding of a water molecule and thus affect the relaxivity. The development of a ligand exhibiting a pH dependent coordination number has not been successful so far [174], but is definitely a promising approach. 

A Gd3+ complex of a hexaazamacrocyclic ligand, cy(TPyDAPy) [175] displays a pH dependent relaxivity in the range 6 < pH <10 which may be applied to study in vivo pH gradients. The relaxivity values measured varied from about 13 mM 1 s 1 (pH < 6) to 2 nfiVTV1 (pH = 11). In previous studies these values... 

A conjugate of a poly(aminoacid) and a D03A chelate [177] has been reported to have a pH dependent relaxivity. Here, this originates from conformational changes of the poly( amino acid) carrier as the pH varies from 4 to 8, which affect overall and local rotational motions in the macromolecule. 

Lowe et al. [7] and Frias et al. [8] described complexes of cyclene-based molecules with lanthanoids. A gadolinium complex which would exhibit pH-dependent relaxivity thanks to a switch in hydration state was prepared. [7] Cyclene bore a sulphonamide substituent in order to achieve a variation of the coordination environment of the lanthanide centre as a function of pH (Scheme 7). 

T.L. Brown [109] studied the temperature dependence of the H-nmr resonance of the cobalt-bound methyl group and the C-nmr resonance of 90% C-enriched methylcobalamin. From analyses of the line shapes, the activation parameters for benzimidazole dissociation were calculated to be dG = 12.7 + 0.1 kcal/mole, AH = 11.1 +0.6 kcal/mole, and AS = —5.9 2.4 eu, leading to a calculated rate constant of 2060/sec at 25°C. In contrast, K.L. Brown and coworkers [110] studied the pH dependence of this reaction (Eqn. 63) at 5°C by temperature-jump spectroscopy and observed two relaxations, the faster of which (T / ca. 4.4 jusec) was pH-independent over the range pH 0.7-7.5 while the slower relaxation showed a slight pH dependence with a half-time of about 50 /tsec at pH 5.5-7.5 increasing to about 75 jusec at pH 1.6 and below. These authors assigned the faster relaxation to the reversible loss of water from the axial coordination position and the slower, pH-dependent relaxation to the reversible dissociation of benzimidazole, i.e. an S, l, or D mechanism (Eqn. 64). 

An unusual pH dependence has been reported for the Gd111 complex of a tetraamide-based ligand with extended noncoordinating phosphonate side chains (Scheme 12).169,170 The relaxivity increases from pH 4 to 6, followed by a decrease until pH 8.5, then from pH 10.5 it increases again. The system, as well as isostructural lanthanide complexes, was characterized by various techniques such as 31P and 170 NMR and fluorescence measurements. The pH dependence could be attributed to protonation equilibria of the noncoordinating phosphonate groups, which can... 

The pH dependence of the inverse of the fast relaxation time constant, Xp, is shown in Figure 10 (error bars represent 95% confidence level) for pressure-jump magnitudes of 70-140 atmospheres. 

Absorption and extinction coefficients are generally less pH dependent than fluorescence spectra and quantum yields because the radiative rates often compete with intra- and intermolecular relaxation precesses. 

A sizeable contribution of the term rf has also been evidenced in the study of the pH-dependence of the relaxivity in the case of the Gd(III) complexes with tetraamide DOTA derivatives. As previously discussed, these cationic monoaqua complexes are characterized by a slow rate of exchange of the coordinated water molecule, which strongly limits the inner sphere... 

As far as Gd(III) agents are concerned, several systems have so far been investigated (mostly in vitro). 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 macro-cyclic Gd(III) complexes bearing (3-arylsulfonamide groups is markedly pH-dependent (Fig. 15) on passing from about 8 s mM at pH < 4 to ca. 2.2 s mM at pH > 8 in one selected case (Chart 12, ligand 2) (130). It has been demonstrated that the observed decrease (about 4-fold) of ri 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 pHs). This corresponds to a change in the coordination ability of the p-arylsulfonamide arm that binds the metal ion only when it is in the deprotonated form (Fig. 15). 

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 tetraamide derivative of DOTA (DOTA-4AmP, Chart 12) that possesses an unusual ri vs. pH dependence (131). 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 behavior is related to the formation/disruption of the hydrogen bond network between... 

Akaganeite particles Both Ti and T2 are strongly pH-dependent (Pigs. 17 and 19). The amplitudes of the longitudinal NMRD profiles drastically decrease when the pH increases from 3.35 to 9.45. The correlation time associated with the first dispersion is only weakly pH dependent, consistent with its former interpretation as an electron relaxation time. However, T2, the correlation time characteristic of the second dispersion, increases from 30 8 ns at pH 3.35 to 280 32 ns at pH 9.45, which eliminates its interpretation as a diffusion time T2 can be identified as a proton exchange time. 

The PEDM is able to explain the anomalous relaxation of solutions of ferritin and akaganeite particles, especially its linear dependence with Bq, the external magnetic field. The model is compatible with the observed dependence of the rate on pH. The relaxation rate predicted by the PEDM is proportional to the number of adsorption sites per particle (q) the values deduced for q from the adjustment of the model to experimental results (from NMR and magnetometry in solutions) are reasonable for hydrated iron oxide nanoparticles (63). 

Mechanisms for the formation of [W60i9(0H)3] (paratungstate A) have been discussed. The relaxation spectra of aqueous molybdate have been determined by the temperature-jump technique at 25 °C(/i = 1.0 M, pH = 5.5— 6.8, and monomer concentration = 0.01—0.25 M). The results indicate two concentration-dependent relaxation effects, which are sensitive to heptamer, [Mo7 0 24] , and octamer, [Mog026]", formation. ... 

The 13C shifts were not significantly pH dependent above pH 9, and selective relaxation experiments revealed no uncoordinated carboxylates at pH 12.5. The complex in solution was therefore formulated as a hexadentate species AgI(CyDTA)3-. 

---