Synthesis and characterization of various benzyl diethylenetriaminepentaacetic acids (dtpa) and their paramagnetic complexes, potential contrast agents for magnetic resonance imaging

摘要

Four derivatives of diethylenetriaminepentaacetic acid (= 3,6,9-tris(carboxymethyl)-3,6,9-triazaundecane-dioic acid (H(5)dtpa)), potential contrast agents for magnetic resonance imaging (MRI), carrying benzyl groups at various positions of the parent structure were synthesized and characterized by a thorough multinuclear NMR study, i.e., the (S)- and (R)-stereoisomers 1a and 1b of 4-benzyl-3,6,9-tris(carboxymethyl)-3,6,9-triazaundecanedioic acid (H-5[(S)-(4-Bz)dtpa] and H-5[(R)-(4-Bz)dtpa] the diamide derivative N,N'-bis{[benzylcarbamoyl)methyl}diethylenetriamine-N,N',N "-triacetic acid (= 3,9-bis[2-(benzylamino)-2-oxoethyl]-6-(carboxymethyl)-3,6,9-triazaundecane dioic acid: H-3[dtpa(BzA)(2)]: 2), and the diester derivative N,N "-bis([(benzyloxy)carbonyl]methyl]diethylenetriamine-N,N',N "-triacetic acid (= 3,9-bis[2-(benzyloxy)-2-oxoethyl]-6-(carboxymethyl)-3,6,9-triazaundecanedi oic acid; H-3[dtpa(BzE)(2)]: 3). From the O-17-NMR chemical shift of H2O induced by their dysprosium complexes with ligands 1-3, it was concluded that only one H2O molecule is contained in the first coordination sphere of these lanthanide complexes. The rotational correlation times (tau(R)) of the complexes were estimated from the H-2-NMR longitudinal relaxation rate of the deuterated diamagnetic lanthanum complexes. The exchange lime of the coordinated H2O molecule (tau(M)) was studied through the temperature dependence of the O-17-NMR transverse relaxation rate. As compared to [Gd(dtpa)](2), the H2O-exchange rate is faster fur [Gd{(S)-(4-Bz)dtpa}](2) and [Gd{(R)-(4-Bz)dtpa}](2)-, slower for [Gd{dtpa(BzA)(2)}], and almost identical for [Gd{dtpa(BzE)(2)}]. The analysis of the H-1-relaxivity of the gadolinium complexes recorded from 0.02 to 300 MHz established that i) the relaxivity of [Gd{dtpa(BzE)(2)}] is similar to that of [Gd(dtpa)](2-), ii) the slightly slower molecular rotation of [Gd{dtpa(BzA)(2)}] induces a mild enhancement of its relaxivity, and iii) the marked increase of relaxivity of [Gd{(S)-(4-Bz)dtpa}](2) and [Gd{(R)-(4-Bz)dtpa}](2-) mainly results from an apparently shorter distance between the gadolinium ion and the H2O protons of the coordinated H2O molecule. [References: 36]