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, 25°) of Gd III complexes are: GD⋅1 , r 1p =8.3 m M −1 s −1 ; GD⋅2 , r 1p 8.1 m M −1 s −1 ; Gd⋅3 , r 1p 10.5 m M −1 s −1 . 1 H‐NMRD and 17 O‐NMR T 2 data show that Gd⋅1 and Gd⋅3 contain two H 2 O molecules in the inner sphere, whereas the presence of two phosphonate arms allows the coordination of only one H 2 O molecule in Gd⋅2 . Interestingly, the exchange lifetime of coordinated H 2 O 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 ). 1 H‐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.