Rigid and Compact Binuclear Bis-hydrated Gd-complexes as High Relaxivity MRI Agents

Abstract

The first binuclear Gd-complex of the 12-membered pyridine-based polyaminocarboxylate macrocyclic ligand PCTA was synthesized by C-C connection of the pyridine units through two different synthetic procedures. A dimeric AAZTA-ligand was also synthesized with the aim to compare the relaxometric results or the two ditopic Gd-complexes. Thus, the ¹ H relaxometric study on [Gd₂ PCTA₂ (H₂ O)₄ ] and on [Gd₂ AAZTA₂ (H₂ O)₄ ]^2- highlighted the remarkable rigidity and compactness of the two binuclear complexes, which results in molar relaxivities (per Gd), at 1.5 T and 298 K of ca. 12-12.6 mM^-1 s^-1 with an increase of ca. 80 % at 1.5 T and 298 K (+70 % at 310 K) with respect to the corresponding mononuclear complexes.

Keywords: binuclear complexes; contrast agents; gadolinium; macrocycles; relaxometry.

Scheme 1

Ligands discussed in the text.

Scheme 2

Synthesis of PCTA₂. i. K₂CO₃, CH₃CN; ii. NiCl₂, PPh₃, Zn, DMF; iii. HBr 33 % in AcOH; iv. BrAcOtBu, NEt₃, N‐methylpyrrolidone; v. NaBH₄, CaCl₂, EtOH; vi. SOBr₂; vii. diethylentriamine‐N,N’,N’’‐tris‐tertbutyl acetate, Na₂CO₃, CH₃CN; viii. TFA/DCM 1 : 1.

Scheme 3

Synthesis of AAZTA₂.

Figure 1

Plots of the ¹H relaxivity for [Gd₂PCTA₂(H₂O)₄] (black squares) and for [Gd₂AAZTA₂(H₂O)₄]²⁻ (red circles) as a function of pH (A, 20 MHz and 298 K) and temperature (B, 20 MHz, pH 7).

Figure 2

1/T ₁ ¹H NMRD relaxivity data for [Gd₂PCTA₂(H₂O)₄] (top) and for [Gd₂AAZTA₂(H₂O)₄]²⁻ (bottom) at pH=7.0: 283 K (blue squares); 298 K (black circles); 310 K (red diamonds). The solid lines represent the best results of the fitting to the experimental points (see Table 1).

Figure 3

Plot of the ionic relaxivity values of [Gd₂PCTA₂(H₂O)₄] and [Gd₂AAZTA₂(H₂O)₄]²⁻ at 0.5, 1.5 and 3.0 T and at 310 K compared to the corresponding mononuclear complexes.