Thermodynamic Stability and Physicochemical Characterization of Ligand (4 S )‐4‐Benzyl‐3,6,10‐tris(carboxymethyl)‐3,6,10‐triazadodecanedioic Acid (H 5 [( S )‐4‐Bz‐ttda]) and Its Complexes Formed with Lanthanides, Calcium(II), Zinc(II), and Copper(II) Ions

Abstract A derivative of H 5 ttda (=3,6,10‐tris(carboxymethyl)‐3,6,10‐triazadodecanedioic acid= N ‐{2‐[bis(carboxymethyl)amino]ethyl}‐ N ‐{3‐[bis(carboxymethyl)amino]propyl}glycine), H 5 [( S )‐4‐Bz‐ttda] (=(4 S )‐4‐benzyl‐3,6,10‐tris(carboxymethyl)‐3,6,10‐triazadodecanedioic acid= N ‐{(2 S )‐2‐[bis(carboxymethyl)amino]‐3‐phenylpropyl}‐ N ‐{3‐[bis(carboxymethyl)amino]propyl}glycine; 1 ) carrying a benzyl group was synthesized and characterized. The stability constants of the complexes formed with Ca 2+ , Zn 2+ , Cu 2+ , and Gd 3+ were determined by potentiometric methods at 25.0±0.1° and 0.1 M ionic strength in Me 4 NNO 3 . The observed water proton relaxivity value of [Gd{( S )‐4‐Bz‐ttda}] 2− was constant with respect to pH changes over the range pH 4.5–12.0. From the 17 O‐NMR chemical shift of H 2 O induced by [Dy{( S )‐4‐Bz‐ttda}] 2− at pH 6.80, the presence of 0.9 inner‐sphere water molecules was deduced. The water proton spin‐lattice relaxation rate for [Gd{( S )‐4‐Bz‐ttda}] 2− at 37.0±0.1° and 20 MHz was 4.90±0.05 m M −1  s −1 . The EPR transverse electronic relaxation rate and 17 O‐NMR transverse‐relaxation time for the exchange lifetime of the coordinated H 2 O molecule ( τ M ), and 2 H‐NMR longitudinal‐relaxation rate of the deuterated diamagnetic lanthanum complex for the rotational correlation time ( τ R ) were thoroughly investigated, and the results were compared with those previously reported for the other lanthanide(III) complexes. The exchange lifetime ( τ M ) for [Gd{( S )‐4‐Bz‐ttda}] 2− (2.3±1.3 ns) was significantly shorter than that of the [Gd(dtpa)(H 2 O)] 2− complex (dtpa=diethylenetriaminepentaacetic acid). The rotational correlation time τ R for [Gd{( S )‐4‐Bz‐ttda}] 2− (70±6 ps) was slightly longer than that of the [Gd(dtpa)(H 2 O)] 2− complex. The marked increase of relaxivity of [Gd{( S )‐4‐Bz‐ttda}] 2− mainly resulted from its longer rotational time rather than from its fast water‐exchange rate. The noncovalent interaction between human serum albumin (HSA) and the [Gd{( S )‐4‐Bz‐ttda}] 2− complex containing the hydrophobic substituent was investigated by measuring the solvent proton relaxation rate of the aqueous solutions. The association constant ( K A ) was less than 100  M −1 , indicating a weaker interaction of [Gd{( S )‐4‐Bz‐ttda}] 2− with HSA.