There is an ongoing interest in developing high-relaxivity Gd-based MRI contrast agents to overcome the low sensitivity issue inherent to the technique. The relaxivity (r1) enhancement can be pursued by: a) increasing the hydration number q; b) optimizing the mean residence tM; c) lengthening the rotational molecular correlation time tR. Hexa- and heptadentate ligands for stable complexation of Gd(III) ions have been actively investigated in order to increase the hydration state (q>1) and enhance of the relaxivity, r1, of the paramagnetic complexes. One of the most promising example is represented by AAZTA, a chelator formed by a seven-membered ring with two endocyclic and one exocyclic nitrogen atoms and four carboxymethyl side arms, which represents an intermediate family between the open chain DTPA and macrocyclic DOTA ligands.[Gd(AAZTA)]- shows excellent properties in terms of thermodynamic stability and relaxivity, associated with the presence of two inner sphere water molecules that are not displaced by endogenous bidentate anions and feature a short residency time.Two AAZTA derivatives containing a reactive functional group were synthesized and used as building blocks for the development of multimeric, high relaxivity MRI contrast agents. We investigated: a) a series of multimeric Gdn-La  complexes (n = 2-32) covering a broad range of molecular weights (1200-25000 Da) and allowing a systematic investigation of the relationship between rotational dynamics and relaxometric behavior at high magnetic fields; b) a dimeric Gd-complex bearing an adamantly group (Gd2Lb ) able to form strong supramolecular adducts with specific hosts such as �-cyclodextrin, poly-�-CD, HSA and functionalized PAMAM dendrimers; c) lipophilic Gd-AAZTA multimeric complexes (Gd2-Lc and Gd4-Ld ) suitable for incorporation in lipid nanoparticles such as micelles and liposomes with the aim to combine the slow tumbling motion of these systems with the low rotational flexibility of the multimeric probes.

GdAAZTA complexes as building blocks for the development of multimeric and supramolecular assemblies

247th National Meeting (2014)

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