Synthesis and Physicochemical Characterization of Carbon Backbone Modified [Gd(TTDA)(H₂O)]²⁻ Derivatives

Abstract

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.

Lanthanide Probes for Bioresponsive Imaging

“…Chang et al developed a derivative of 3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid (TTDA) containing a cyclobutane ring and a benzyl group (Bz-CB-DDTA, Figure 35). 189 While this complex has a lower affinity for HSA than MS-325, its relaxivity following protein binding is significantly higher (66.7 mM −1 s −1 at 20 MHz, as compared to 47 mM −1 s −1 for MS-325) owing to faster water exchange properties imparted by the cyclobutyl moiety.…”

Cu(ii), Ga(iii) and In(iii) complexes of 2-acetylpyridine N(4)-phenylthiosemicarbazone: synthesis, spectral characterization and biological activities

“…3,14 Lipophilicity, which dominates the rate of molecules entering cells, may be improved through complexing. 19,20 Moreover, in many cases the metal complex may display higher bioactivities than free ligands and certain side effects likely decline via complexing. [21][22][23] Hence the synthesis and application of thiosemicarbazones and their complexes have attracted continuous interest and become one of the most promising research areas.…”

Development of a Gd(III)-Based Receptor-Induced Magnetization Enhancement (RIME) Contrast Agent for β-Glucuronidase Activity Profiling

“…Because of the hydrophilic nature of the pro-RIME [Gd­(DOTA-FPβGu)], partition coefficients were measured in butanol/PBS instead of octanol/PBS. The partition coefficient of the [Gd­(DOTA-FPβGu)] in butanol/water (PBS buffer) was determined following previously reported method. , The log P value of [Gd­(DOTA-FPβGu)] is −2.84 ± 0.15 which is comparatively lower than that of MS-325 (−2.11 ± 0.06) . This is reflected in the lower binding constant ( K A ) (9.0 ± 0.1 × 10 2 M –1 ) of [Gd­(DOTA-FPβGu)] to HSA.…”

“…Aliquots (5 mL) from each phase were removed and analyzed via inductively coupled plasma–atomic emission spectroscopy (ICP-AES, PerkinElmer OPTIMA 2000 PV). The partition coefficient ( P ) was calculated by eq − P = avg .25em conc .25em of .25em Gd ( III ) .25em complex .25em in .25em bu tan ol avg .25em conc .25em of .25em Gd ( III ) complex .25em in .25em PBS …”