Designing novel contrast agents for magnetic resonance imaging. Synthesis and relaxometric characterization of three gadolinium(III) complexes based on functionalized pyridine-containing macrocyclic ligands

The three novel pyridine-containing 12-membered macrocyclic ligands 1-3 were synthesized. The coordinating arms are represented by three acetate moieties in 1 and 3 and by one acetate and two phosphonate moieties in 2. In all three ligands, the acetate arm in the distal position is substituted, with a benzyl group in 1 and 2 and with an arylmethyl moiety in 3. The relaxivities r(1p) (20 MHz, 25degrees) of Gd-III complexes are: GD .1, r(1p) = 8.3 mm(-1) s(-1); GD . 2, r(1p) = 8.1 mm(-1) s(-1); Gd . 3, r(1p) =10.5 mm(-1) s(-1). H-1-NMRD and O-17-NMR T-2 data show that Gd . 1 and Gd . 3 contain two H2O molecules in the inner sphere, whereas the presence of two phosphonate arms allows the coordination of only one H2O molecule in Gd-2. Interestingly, the exchange lifetime of coordinated H2O in the three complexes is similar in spite of the difference in the coordination number of the Gd-III ion (i.e., 9 in Gd . 1 and Gd . 3, and 8 in Gd . 2). H-1-Relaxometric measurements at different pH and in the presence of lactate and oxalate were carried out to get some insight into the formation of ternary complexes from Gd . 1 and Gd . 3. Finally, it was found that binding to human-serum albumin (HSA) of Gd . 1 and Gd . 2, though weak, yields limited relaxivity enhancements, likely as a consequence of effects on the hydration sphere caused by donor atoms on the surface of the protein.