posted on 2022-08-09, 18:00authored byDaniela Lalli, Ivan Hawala, Marco Ricci, Fabio Carniato, Luca D. D’Andrea, Lorenzo Tei, Mauro Botta
The GdAAZTA (AAZTA = 6-amino-6-methylperhydro-1,4-diazepinetetraacetic
acid) complex represents a platform of great interest for the design
of innovative MRI probes due to its remarkable magnetic properties,
thermodynamic stability, kinetic inertness, and high chemical versatility.
Here, we detail the synthesis and characterization of new derivatives
functionalized with four amino acids with different molecular weights
and charges: l-serine, l-cysteine, l-lysine,
and l-glutamic acid. The main reason for conjugating these
moieties to the ligand AAZTA is the in-depth study of the chemical
properties in aqueous solution of model compounds that mimic complex
structures based on polypeptide fragments used in molecular imaging
applications. The analysis of the 1H NMR spectra of the
corresponding Eu(III)-complexes indicates the presence of a single
isomeric species in solution, and measurements of the luminescence
lifetimes show that functionalization with amino acid residues maintains
the hydration state of the parent complex unaltered (q = 2). The relaxometric properties of the Gd(III) chelates were analyzed
by multinuclear and multifrequency NMR techniques to evaluate the
molecular parameters that determine their performance as MRI probes.
The relaxivity values of all of the novel chelates are higher than
that of GdAAZTA over the entire range of applied magnetic fields because
of the slower rotational dynamics. Data obtained in reconstituted
human serum indicate the occurrence of weak interactions with the
proteins, which result in larger relaxivity values at the typical
imaging fields. Finally, all of the new complexes are characterized
by excellent chemical stability in biological matrices over time,
by the absence of transmetallation processes, or the formation of
ternary complexes with oxyanions of biological relevance. In particular,
the kinetic stability of the new complexes, measured by monitoring
the release of Gd3+ in the presence of a large excess of
Zn2+, is ca. two orders of magnitude higher than that of
the clinical MRI contrast agent GdDTPA.