[Gd(AAZTA)]⁻ Derivatives with n‐Alkyl Acid Side Chains Show Improved Properties for Their Application as MRI Contrast Agents**

Abstract

Herein, the synthesis and an extensive characterization of two novel Gd(AAZTA) (AAZTA=6‐amino‐6‐methylperhydro‐1,4‐diazepine tetra acetic acid) derivatives functionalized with short (C2 and C4) n‐alkyl acid functions are reported. The carboxylate functionality is the site for further conjugations for the design of more specific contrast agents (CAs). Interestingly, it has been found that the synthesized complexes display enhanced properties for use as MRI contrast agents on their own. The stability constants determined by using potentiometric titration and UV/Vis spectrophotometry were slightly higher than the one reported for the parent Gd(AAZTA) complex. This observation might be accounted for by the larger sigma‐electron donation of the acyl substituents with respect to the one provided by the methyl group in the parent complex. As far as concerns the kinetic stability, transmetallation experiments with endogenous ions (e.g. Cu2+) implied that the Gd3+ ions present in these Gd(AAZTA) derivatives show somewhat smaller susceptibility to chemical exchange towards these ions at 25 °C, close to the physiological condition. The 1H NMR spectra of the complexes with EuIII and YbIII displayed a set of signals consistent with half the number of methylene protons present on each ligand. The number of resonances was invariant over a large range of temperatures, suggesting the occurrence of a fast interconversion between structural isomers. The relaxivity values (298 K, 20 MHz) were consistent with q=2 being equal to 8.8 mm−1 s−1 for the C2 derivative and 9.4 mm−1 s−1 for the C4 one, that is, sensibly larger than the one reported for Gd(AAZTA) (7.1 mm−1 s−1). Variable‐temperature (VT)‐T2 17O NMR measurements showed, for both complexes, the presence of two populations of coordinated water molecules, one in fast and one in slow exchange with the bulk water. As the high‐resolution 1H NMR spectra of the analogs with EuIII and YbIII did not show the occurrence of distinct isomers (as frequently observed in other macrocyclic lanthanide(III)‐containing complexes), we surmised the presence of two fast‐interconverting isomers in solution. The analysis of the 17O NMR VT‐T2 profiles versus temperature allowed their relative molar fraction to be established as 35 % for the isomer with the fast exchanging water and 65 % for the isomer with the water molecules in slower exchange. Finally, 1H NMRD profiles over an extended range of applied magnetic field strengths have been satisfactory fitted on the basis of the occurrence of the two interconverting species.

LDL mediated delivery of Paclitaxel and MRI imaging probes for personalized medicine applications

“…Furthermore, the pharmacological activity of a drug can be largely improved by an intracellular drug delivery. Among the different classes of Gd-based MRI contrast agents, Gd-AAZTA [ 30 , 31 ] has been selected because of its high sensitivity due to the coordination of two water molecules in fast exchange with the bulk. The Gd-complex is functionalized with an aliphatic carbon chain to pursue the binding to LDL in order to allow a selective delivery to tumour cells overexpressing LDLRs.…”

“…Gd-AAZTA-C17 [ 21 ] (AAZTA-C17 = 6-bis(carboxymethyl)amino-4-carboxymethyl-6-heptadecyl-1,4-diazepan-1-yl]acetic acid, Fig. 2 ) was purchased by Cage Chemicals Srl (Novara, Italy).…”

Derivatives of GdAAZTA Conjugated to Amino Acids: A Multinuclear and Multifrequency NMR Study

“…Such favorable properties have promoted the development of several GdAAZTA derivatives with improved relaxivity, 11 which have found interesting applications in preclinical MRI studies. 12 In particular, the evidence that high molecular weight, slowly tumbling molecules provide greater r 1 values in the 0.5–1.5 T range of magnetic field strengths has driven the design of several GdAAZTA macromolecular systems, where the chelate is either covalently bound to large substrates or forms noncovalent macromolecular adducts.…”

“…8 Such hydration molecules are located at different positions in the coordination polyhedron of the complex, where the one occupying the more sterically hindered capping position exchanges ∼6 times faster than that residing closer to the metal center. 8 Such favorable properties have promoted the development of several GdAAZTA derivatives with improved relaxivity, 11 which have found interesting applications in preclinical MRI studies. 12 In particular, the evidence that high molecular weight, slowly tumbling molecules provide greater r 1 values in the 0.5−1.5 T range of magnetic field strengths has driven the design of several GdAAZTA macromolecular systems, where the chelate is either covalently bound to large substrates or forms noncovalent macromolecular adducts.…”