Gd(DTPA-bisamide)alkyl Copolymers: A Hint for the Formation of MRI Contrast Agents with Very High Relaxivity

Abstract

A variable-temperature, multiple-field 17 O NMR and EPR spectroscopic study has been performed on three Gd(DTPA-bisamide)alkyl copolymers, [Gd(DTPAÀBA)À(CH 2 ) n ] x (n 6, 10,12;N,N',N'',. The rate and mechanism of water exchange is identical for the polymer complexes and [Gd(DTPAÀBMA)(H 2 O)], which can be considered as the monomer unit of the polymers. Transverse electronic relaxation rates, measured by EPR, increase with increasing rotational correlation time. Rigid intramolecular micellelike structures form in aqueous solutions of the Gd(DTPA-bis-amide)alkyl copolymers. Consequently, the longitudinal 17 O relaxation rates for [Gd(DTPA À BA) À (CH 2 ) 10 ] x and [Gd(DTPA À BA) À (CH 2 ) 12 ] x , were interpreted with the Lipari ± Szabo treatment. This involves the inclusion of a global correlation time, representing the motion of the whole micellelike association, and a local correlation time, representing the motion of the GdÀO vector. The global correlation time ob-tained for the two polymers reflects the ratio of the molecular weights, whereas the local correlation times and the general order parameters are similar for both copolymers. The proton relaxivity difference can be explained by the different global correlation times. Thus, contrary to linear polymers in general, for the present polymers the global motion significantly contributes to relaxivity. Relaxivity is limited by water exchange; simulations show that proton relaxivities over 100 mm À1 s À1 could be obtained by substituting the Gd(DTPAbisamide) units with a gadolinium chelate with fast water exchange.

Synthesis, Characterization, and Relaxivity of Two Linear Gd(DTPA)−Polymer Conjugates

“…SEC chromatograms of the polymers DTPA-HMD and DTPA-CHD, and of the respective Gd 3+ complexes. 4) are comparable to those reported by Toth et al (27) (from this publication, a τ M value of 1.03 ms can be calculated at 310 K for the compound with n ) 6). The observed constancy of τ M is in line with the general observation that derivatization has hardly any effect on the water exchange rate of bisamides, which limit the relaxivity values.…”

“…Other studies with this type of DTPA copolymers, containing as linking units long hydrophilic poly(ethyleneglycol) (PEG) (40), or hydrophobic alkyl chains with a varying number (n) of methylenes (29), showed that higher relaxivities were obtained only for long hydrophobic chains with n g 10. For these polymers, hydrophobic interactions between different chains lead to intramolecular aggregates and the formation of more rigid compact, globular structures, with slower local motions and global rotation, leading to higher relaxivity (27,29). Studies with other polymeric carriers (15,16) have also shown that higher relaxivities are obtained for more rigid compact, globular structures, for example by increasing the degree of substitution of the carrier.…”

“…For this purpose, low molecular weight Gd 3+ -chelate complexes, such as Gd-(DTPA) 2-or Gd(DOTA) -, have been conjugated to natural or synthetic polymeric materials, like polysaccharides (7)(8)(9)(10)(11)(12)(13)(14)(15)(16), albumin (17,18), polyamino acids such as polylysine and polyornithine (19)(20)(21)(22)(23)(24)(25) or dendrimers (26). Some linear polymers of DTPA have also been prepared in which the chelate is incorporated directly in the polymeric chain (27)(28)(29). These macromolecules lead to an increase in blood pool lifetime and should be more efficient in respect to their relaxivity, as a consequence of their increased rotational correlation time resulting from their high molecular weight.…”

Enhanced imaging properties of a GdIII complex with unusually large relaxivity

“…The latter parameter influences significantly the relaxivity profile in the Larmor frequency range 10-100 MHz. Theoretically, the relaxivity versus frequency curve should present a peak of relaxivity, whose theoretical value should culminate at approximately 100-200 mM −1 s −1 for large Gd-containing particles [4].…”

Optimising the design of paramagnetic MRI contrast agents: influence of backbone substitution on the water exchange rate of Gd-DTPA derivatives

“…Efforts are thus devoted to optimise the water residence time, s M , and therefore to alleviate the limitation of the complex's relaxivity. Amide linkages have to be avoided since they are known to prolong the water residence time [6][7][8][9][10][11][12][13][14]. On the contrary, a C4-substitution of the ethylenic bridge of DTPA by an ethoxybenzyl group, a benzyl, or a MAGMA (2004) 16: 235-245 Abstract Among other factors influencing the residence time of the coordinated water (s M…”