Probing the structure-relaxivity relationship of bis-hydrated Gd(DOTAla) derivatives.

Two structural isomers of the heptadentate chelator DO3Ala were synthesized, with carboxymethyl groups at either the 1,4- or 1,7-positions of the cyclen macrocycle. To interrogate the relaxivity under different rotatational dynamics regimes, the pendant primary amine was coupled to ibuprofen to enable binding to serum albumin. These chelators 6a and 6b form bis(aqua) ternary complexes with Gd(III) or Tb(III) as estimated from relaxivity measurements or luminescence lifetime measurements in water. The relaxivity of [Gd(6a)(H2O)2] and [Gd(6b)(H2O)2] was measured in the presence and absence of coordinating anions prevalent in vivo such as phosphate, lactate, and bicarbonate and compared with data attained for the q = 2 complex [Gd(DO3A)(H2O)2]. We found that relaxivity was reduced through formation of ternary complexes with lactate and bicarbonate, albeit to a lesser degree then the relaxivity of Gd(DO3A). In the presence of 100-fold excess phosphate, relaxivity was slightly increased and typical for q = 2 complexes of this size (8.3 mM(-1) s(-1) and 9.5 mM(-1) s(-1), respectively, at 37 °C, 60 MHz). Relaxivity for the complexes in the presence of HSA corresponded well to relaxivity obtained for complexes with reduced access for inner-sphere water (13.5 and 12.7 mM(-1) s(-1) at 37 °C, 60 MHz). Mean water residency time at 37 °C was determined using temperature-dependent (17)O-T2 measurements at 11.7 T and calculated to be (310)τM = 23 ± 1 ns for both structural isomers. Kinetic inertness under forcing conditions (pH 3, competing DTPA ligand) was found to be comparable to [Gd(DO3A)(H2O)]. Overall, we found that the replacement of one of the acetate arms of DO3A with an amino-propionate arm does not significantly alter the relaxometric and kinetic inertness properties of the corresponding Gd complexes; however, it does provide access to easily functionalizable q = 2 derivatives.