Optimizing the relaxivity at high fields: systematic variation of the rotational dynamics in polynuclear Gd-complexes based on the AAZTA ligand

Magnetic Resonance Imaging (MRI) is one of the most important and prominent techniques in in clinical diagnostic medicine, in preclinical studies and in biomedical research. As well as many other imaging modalities, MRI also makes extensive use of contrast agents (CAs) that allow achieving remarkable improvements in medical diagnosis in terms of higher specificity, better tissue characterization and functional information. For the vast majority, the clinically used CAs are coordination complexes in which a GdIII ion is encapsulated within octadentate chelators based on polyaminocarboxylate anions and has a directly bound water molecule. Their use is widespread and is estimated to correspond to approximately 40 million administrations per year of GdIII chelates worldwide.

Their effectiveness (relaxivity; the increase in the relaxation rate R1 of the water protons normalized to a 1 mM concentration of the paramagnetic ion) at the magnetic fields of clinical interest is dominated and limited by the fast rotational dynamics and tends to decrease with the increased magnetic field. However, the current trend in MRI development is towards higher magnetic field strengths and most scanners operate at 1.5 or 3 T, while there is increasing use of those at 7 T. Therefore, a different approach for the relaxivity enhancement of Gd-based CAs becomes necessary for the modern high-field systems.

Recently, the group of Mauro Botta and colleagues from the University of Eastern Piedmont in Alessandria (Italy) investigated the optimization of the efficacy of Gd-based CAs, between 1 and 7 T, by systematically modulating the rotational dynamics through the synthesis of polynuclear systems containing between two and eight GdIII chelates (Figure 1).

Figure 1. [Gd(AAZTA)(H2O)2] and polynuclear Gd2-6L2-L6 complexes 

The [Gd(AAZTA)(H2O)2] chelate was used as a building block due to its remarkable properties: a) ease and high-yield synthesis, presence of two inner sphere water molecules in fast exchange with the bulk; b) high thermodynamic stability; c) kinetic inertness in the presence of physiological concentrations of CuII and ZnII higher than that of the clinical agent [Gd(DTPA)]2-; d) negligible tendency to formation of ternary complexes with endogenous anions. The study demonstrates that the strategy for relaxation enhancement varies with the strength of the magnetic field used.

Up to 3 T, efficacy is limited by molecular rotation and therefore increases proportionally with the increase in molecular size. Between 3 and 7 T, the issue of local flexibility or anisotropic rotation, evaluated with NMR techniques and computational models, becomes more and more relevant and medium-sized rigid systems (tri- or tetranuclear) provide the best results. At ultra-high fields (> 7 T), small and compact mono- or binuclear complexes are most effective (Figure 2).

 

Figure 2. Upper: T1-weighted phantom MR-images at 3 and 7 T on selected polynuclear complexes highlighting the effective signal enhancement of the new MRI probes at clinically relevant magnetic field strengths in comparison to the commercial MRI agent ProHance®. Lower: Signal enhancement (298 K) of Gd3L3, Gd4L4 and Gd6L6 compared to Prohance at 1, 3 and 7 T.

The results of this study allow identifying the most effective strategy for optimizing the CAs, each suited to a well-defined range of applied magnetic field strength.

 

Mauro Botta is full professor of Inorganic Chemistry in the Department of Sciences and Technological Innovation at the University of Eastern Piedmont (Italy). He received the “Laurea” cum laude in Chemistry at the University of Turin in 1985. His scientific interests have focused on the use of NMR techniques for the characterization of inorganic systems, starting from organometallic clusters and then moving on the complexes of the f-elements. Recipient of the “Raffaello Nasini” gold medal award for Inorganic Chemistry of the Italian Chemical Society and of the “GIDRM gold medal for magnetic resonance”. He has published over 280 papers (index H = 63; citation: 12800) and several book chapters on these topics and filed 5 patents.

 

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