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 r1p (20 MHz, 25°) of GdIII complexes are: Gd⋅1, r1p=8.3 mM−1 s−1; Gd⋅2, r1p8.1 mM−1 s−1; Gd⋅3, r1p10.5 mM−1 s−1. 1H-NMRD and 17O-NMR T2 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 GdIII ion (i.e., 9 in Gd⋅1 and Gd⋅3, and 8 in Gd⋅2). 1H-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.