Impact of rigidification on relaxometric properties of a tricyclic tetraazatriacetic gadolinium chelate

Abstract

A constrained derivative of Gd-PCTA12, Gd-cyclo-PCTA12, in which one ethylene bridge connecting two nitrogen atoms of the triamine block is replaced by a cyclohexylene bridge, was synthesized and the impact of rigidification was studied by comparing the physicochemical and relaxometric properties of both gadolinium MRI contrast agents, Gd-PCTA12 and Gd-cyclo-PCTA12. The new complex has higher proton relaxivity than the parent compound (r(1) = 6.1 s(-1) mM(-1) at 20 MHz and 310 K). The rigidification of the PCTA12 scaffold proved to have no impact on the inertness towards transmetallation by endogenous ions such as Zn(2+). Moreover, for both contrast agents, the relaxivity was not quenched by endogenous anions. The oxygen-17 NMR study and the NMRD profile demonstrated that the rigidification of the PCTA scaffold had no impact on the electronic relaxation of Gd-cyclo-PCTA12. However, the rigidity of this complex induced an acceleration of the exchange rate of the inner-sphere water molecules as a result of steric crowding around the gadolinium ion. The value of tau(M) (310) thus approached the optimal value required to attain high relaxivity once the chelate is immobilized by covalent or non-covalent binding to macromolecules.

Facile Access to the 12‐Membered Macrocyclic Ligand PCTA and Its Derivatives with Carboxylate, Amide, and Phosphinate Ligating Functionalities

“…[30] It is also interesting to note that the relaxivity (r 1 ) of L 3 ·Gd at 298 K (8.2 s -1 mM -1 ) is close to that reported for PCP2A·Gd (r 1 298K = 8.3 s -1 mM -1 at 20 MHz), for which the phosphonate function is substituted for a phosphinate function in the central arm. [5,33] The temperature dependence of the relaxivity (r 1 ) at 20 MHz for the two complexes was also measured in the range of 278 to 318 K and is reported in Figure 5.…”

“…new PCTA [12] derivatives containing either a 4-pyridol unit, an amide or a phosphinate coordinating function in the central arm. [5] Other lanthanide complexes, Eu-PCTA and Tb-PCTA, are characterized by the presence of an antenna/sensitizer effect of the pyridine chromophore and act as long-lifetime luminophores that are compatible with the use of the time-resolved luminescence technique. The luminescence and relaxometric properties of Eu III , Tb III , and Gd III complexes derived from PCTA derivatives with mixed coordinating arms were also investigated, making these complexes possible alternatives to PCTA [12]-Ln III complexes.…”

(S)-5-(p-Nitrobenzyl)-PCTA, a Promising Bifunctional Ligand with Advantageous Metal Ion Complexation Kinetics

“…Moreover, a recent study on the transmetallation of Gd(PCTA) and its rigidified derivative, Gd(CHX-PCTA) as well as other cyclen based macrocyclic Gd(III) complexes in the presence of Zn 2+ ions and at physiological pH showed no measureable dissociation of the complexes over the time period of 9000 minutes. (37, 65)…”

Enhanced MRI relaxivity of Gd3+‐based contrast agents geometrically confined within porous nanoconstructs

“…This observation has fostered the development of novel agents where Gd 3+ ions are linked to larger structures, such as macromolecular aggregates and nanoparticles. Examples are the ‘rigidification’ of Gd 3+ complexes leading to a r 1 relaxivity of ~5.5 m m −1 s −1 at 60 MHz , the development of glycoconjugates of Gd 3+ complexes producing a relaxivity r 1 ranging between 10 and 26 m m −1 s −1 at 1.5 T, depending on the structure of the complex , the study of benzene‐core trinuclear Gd 3+ ion macromolecular aggregates providing an r 1 ≈ 21.6 m m −1 s −1 at 1.5 T , the creation of dendrimer‐based nanoprobes with Gd 3+ ions covalently attached to PAMAM (Poly(amido amine)) dendrimers that produced an r 1 ≈ 20 m m −1 s −1 at 3 T , and functionalization of gold nanoparticles with Gd 3+ chelates reaching r 1 ~60 m m −1 s −1 at 1.5 T . Although, Gd 3+ chelate compounds usually offer reasonably high relaxivities, they are also often associated with limited stability and low or negligible tissue specificity.…”