Synthesis, Potentiometric, Kinetic, and NMR Studies of 1,4,7,10-Tetraazacyclododecane-1,7-bis(acetic acid)-4,10-bis(methylenephosphonic acid) (DO2A2P) and its Complexes with Ca(II), Cu(II), Zn(II) and Lanthanide(III) Ions

This review aims at assessing the role of nanosized systems as MR-imaging reporters in Molecular Imaging applications. The possibility of delivering a high number of imaging agents at the target of interest appears the solution of choice to overcome the drawback associated with the low sensitivity of the MRI approach. The use of metal-based particles entered very early in the armoury of MRI contrast agents with the Superparamagnetic Iron Oxides' family that are still among the most sensitive systems. The review devotes much attention to the design and use of self-assembled systems based on lipophilic molecules, reporting examples taken by products and processes developed in the authors' laboratory. The imaging reporters are invariantly represented by highly stable lanthanide(III) complexes. In general, whether is the paramagnetic lanthanide(III) ion, the particles act as T 2-susceptibility agents, whose contrasting abilities increase by increasing the magnetic field strength. In the case of Gd(III)-complexes, the systems mainly act as T 1-relaxation agents, whose efficiency is eventually enhanced by the long reorientational time of the supramolecular aggregate. In addition to tackle sensitivity issues, such systems may also be designed in order to become responsive to a specific physical or biochemical parameter of the microenvironment in which they distribute. Moreover, nanosized carriers for Gd(III)-complexes based on naturally occurring systems (apoferritin and lipoproteins) have also been considered for targeting specific epitopes on diseased cells. Finally, liposomes have been exploited to generate a novel class of highly sensitive CEST (Chemical Exchange Saturation Transfer) agents dubbed LIPOCEST. Such systems are characterized by a shifted resonance for the large pool of water molecules entrapped in the liposomal cavity that can be selectively irradiated in order to transfer saturated magnetization to the bulk water signal.