Synthesis and physicochemical characterization of carbon backbone modified [Gd(TTDA)(H2O)]2- derivatives

The present study was designed to exploit optimum lipophilicity and high water-exchange rate (k(ex)) on low molecular weight Gd(III) complexes to generate high bound relaxivity (r(1)(b)), upon binding to the lipophilic site of human serum albumin (HSA). Two new carbon backbone modified TTDA (3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid) derivatives, CB-TTDA and Bz-CB-TTDA, were synthesized. The complexes Gd(CB-TTDA)(H(2)O)](2-) and Gd(Bz-CB-TTDA)(H(2)O)](2-) both display high stability constant (log K(GdL) = 20.28 and 20.09, respectively). Furthermore, CB-TTDA (log K(Gd/Zn) = 4.22) and Bz-CB-TTDA (log K(Gd/Zn) = 4.12) exhibit superior selectivity of Gd(III) against Zn(II) than those of TTDA (log K(Gd/Zn) = 2.93), EPTPA-bz-NO(2) (log K(Gd/Zn) = 3.19), and DTPA (log K(Gd/Zn) = 3.76). However, the stability constant values of Gd(CB-TTDA)(H(2)O)](2-) and Gd(Bz-CB-TTDA)(H(2)O)](2-) are lower than that of MS-325. The parameters that affect proton relaxivity have been determined in a combined variable temperature (17)O NMR and NMRD study. The water exchange rates are comparable for the two complexes, 232 × 10(6) s(-1) for Gd(CB-TTDA)(H(2)O)](2-) and 271 × 10(6) s(-1) for Gd(Bz-CB-TTDA)(H(2)O)](2-). They are higher than those of Gd(TTDA)(H(2)O)](2-) (146 × 10(6) s(-1)), Gd(DTPA)(H(2)O)](2-) (4.1 × 10(6) s(-1)), and MS-325 (6.1 × 10(6) s(-1)). Elevated stability and water exchange rate indicate that the presence of cyclobutyl on the carbon backbone imparts rigidity and steric constraint to Gd(CB-TTDA)(H(2)O)](2-)and Gd(Bz-CB-TTDA)(H(2)O)](2-). In addition, the major objective for selecting the cyclobutyl is to tune the lipophilicity of Gd(Bz-CB-TTDA)(H(2)O)](2-). The binding affinity of Gd(Bz-CB-TTDA)(H(2)O)](2-) to HSA was evaluated by ultrafiltration study across a membrane with a 30 kDa MW cutoff, and the first three stepwise binding constants were determined by fitting the data to a stoichiometric model. The binding association constants (K(A)) for Gd(CB-TTDA)(H(2)O)](2-) and Gd(Bz-CB-TTDA)(H(2)O)](2-) are 1.1 × 10(2) and 1.5 × 10(3), respectively. Although the K(A) value for Gd(Bz-CB-TTDA)(H(2)O)](2-) is lower than that of MS-325 (K(A) = 3.0 × 10(4)), the r(1)(b) value, r(1)(b) = 66.7 mM(-1) s(-1) for Gd(Bz-CB-TTDA)(H(2)O)](2-), is significantly higher than that of MS-325 (r(1)(b) = 47.0 mM(-1) s(-1)). As measured by the Zn(II) transmetalation process, the kinetic stabilities of Gd(CB-TTDA)(H(2)O)](2-), Gd(Bz-CB-TTDA)(H(2)O)](2-), and Gd(DTPA)(H(2)O)](2-) are similar and are significantly higher than that of Gd(DTPA-BMA)(H(2)O)](2-). High thermodynamic and kinetic stability and optimized lipophilicity of Gd(CB-TTDA)(H(2)O)](2-) make it a favorable blood pool contrast agent for MRI.