Reaction of DOTA-NCSA [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono(p-isothiocyanatoanilide)] with O-(aminopropyl)inulin (degree of polymerization 25) provided a chelate that formed a kinetically extremely stable Gd(3+) complex. No transmetalation was observed with Zn(2+). The conjugate has a relaxivity of 21.7 s(-1) mM(-1) at 20 MHz and 37 °C, and each molecule of the inulin carries on average 35 Gd(3+) ions. The parameters governing the relaxivity of this material and of a low-molecular-weight model compound prepared by conjugation of DOTA-NCSA and propylamine were evaluated by investigation of their water (1)H longitudinal relaxation rate enhancements at different magnetic fields (NMRD) and by studying variable temperature (17)O NMR data. The high relaxivity of the inulin conjugate can be ascribed to the efficient slowing down of the molecular tumbling by this carrier. The rotational correlation time at 37 °C of this material is 1460 ps, whereas that of the model compound is 84 ps. Furthermore, both complexes do not interact significantly with human serum albumin, as shown by their NMRD profiles, and do not undergo transmetallation by zinc ions. The inulin conjugate thus has potential for application as a contrast agent for MRI, particularly as a blood pool agent.

Thanks to the understanding of the relationships between the residence lifetime τ of the coordinated water molecules to macrocyclic Gd-complexes and the rotational mobility τ of these structures, and according to the theory for paramagnetic relaxation, it is now possible to design macromolecular contrast agents with enhanced relaxivities by optimizing these two parameters through ligand structural modification. We succeeded in accelerating the water exchange rate by inducing steric compression around the water binding site, and by removing the amide function from the DOTA-AA ligand [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono(p-aminoanilide)] (L) previously designed. This new ligand 10[2(1-oxo-1-p-propylthioureidophenylpropyl]-1,4,7,10-tetraazacyclodecane-1,4,7-tetraacetic acid (L ) was then covalently conjugated to API [O-(aminopropyl)inulin] to get the complex API-(GdL )x with intent to slow down the rotational correlation time (τ ) of the macromolecular complex. The evaluation of the longitudinal relaxivity at different magnetic fields and the study of the O-NMR at variable temperature of the low-molecular-weight compound (GdL ) showed a slight decrease of the τ value (τM310 = 331 ns vs. τM310 = 450 ns for the GdL complex). Consequently to the increase of the size of the API-(GdL )x complex, the rotational correlation time becomes about 360 times longer compared to the monomeric GdL complex (τ = 33,700 ps), which results in an enhanced proton relaxivity.

The synthesis of poly[N,N‐bis(3‐aminopropyl)glycine] (PAPGly) dendrons Gd‐based contrast agents (GdCAs) via an orthogonal protection of the different functional groups and an activation/coupling strategy wherein a specific number of synthetic steps add a generation to the existing dendron has been described. The aim of this protocol is to build up two different generations of dendrons (G‐0 or dendron's core, and G‐1) with peripheral NH2 groups to conjugate a 1,4,7,10‐tetraazacyclododecane‐1,4,7‐triacetic acid (DO3A) derivative and afterwards to chelate with Gd3+ paramagnetic ions. These complexes, which have a well‐defined molecular weight, are of relevance to MRI as an attempt to gain higher 1H relaxivity by slowing down the rotation of molecule compared to monomeric Gd(III) complexes used as contrast agents and to increase the number of paramagnetic centers present in one molecular structure. From the study of their water 1H longitudinal relaxation rate at different magnetic fields (NMRD, Nuclear Magnetic Relaxation Dispersion) and by evaluating the variable temperature 17O‐NMR data we determined the parameters characterizing the water exchange rate and the rotational correlation time of each complex, both affecting 1H relaxivity. Furthermore, these two novel PAPGly GdCAs were objects of i) an in vivo study to determine their biodistributions in healthy C57 mice at several time points, and ii) the Dynamic Contrast‐Enhanced MRI (DCE‐MRI) approach to assess their contrast efficiency measured in the tumor region of C57BL/6 mice transplanted subcutaneously with B16‐F10 melanoma cells. The aim of the comparison of these two dendrons GdCAs, having different molecular weights (MW), is to understand how MW and relaxivity may influence the contrast enhancement capabilities in vivo at low magnetic field (1 T). Significant contrast enhancement was observed in several organs (vessel, spleen and liver), already at 5 min post‐injection, for the investigated CAs. Moreover, these CAs induced a marked contrast enhancement in the tumor region, thanks to the enhanced permeability retention effect of those macromolecular structures.

Cover Picture. As reported by Granato et al. in their full paper at 10.1002/cbdv.201900322, the cover picture shows a branched coral structure that organic molecules such as dendrimers are mimicking. The article describes the MRI properties of zero‐ and first‐generation dendrimers grafted with gadolinium complexes so that they are both superimposed on the coral structure, and compared to the monomeric gadolinium complex. The MRI images show an interesting accumulation of the dendrimers in the tumor regions of the mice, making these molecules very promising as contrast agents for MRI.