A Gadolinium(III) Complex of a Carboxylic-Phosphorus Acid Derivative of Diethylenetriamine Covalently Bound to Inulin, a Potential Macromolecular MRI Contrast Agent

Abstract

A novel conjugate of a polysaccharide and a Gd(III) chelate with potential as contrast agent for magnetic resonance imaging (MRI) was synthesized. The structure of the chelate was derived from H5DTPA by replacing the central pendant arm by a phosphinic acid functional group, which was covalently bound to the polysaccharide inulin. On the average, each monosaccharide unit of the inulin was attached to approximately one (0.9) chelate moiety. The average molecular weight is 23110 and the average number of Gd3+ ions per molecule is 24. The ligand binds the Gd3+ ion in an octadentate fashion via three nitrogen atoms, four carboxylate oxygen atoms, and one P-O oxygen atom, and its first coordination sphere is completed by a water molecule. This compound shows promising properties for application as a contrast agent for MRI thanks to a favorable residence lifetime of this water molecule (170 ns at 298 K), a relatively long rotational correlation time (866 ps at 298 K), and the presence of two water molecules in the second coordination sphere of the Gd3+ ion. Furthermore, its stability toward transmetalation with Zn(II) is as high as that of the clinically used [Gd(DTPA)(H2O)]2-.

Structure, Dynamics, and Computational Studies of Lanthanide‐Based Contrast Agents

“…Examples are modifications by replacement of carboxylic groups by phosphinic or phosphonic groups (DTTA P or DTTAP R , Chart 5.3) [224,225] or by extension of one of the ethylene bridges or pendant acetate groups with a CH 2 group (DTTA-N-CE or DTTA-N -CE, EPTPA) [226][227][228][229][230].…”

Synthesis and Coordination Behavior of Symmetrical Tetraamine Phosphinic Acids

“…lanthanide(III) ions. The introduction of the methylphosphinic acid group(s) into DTPA or DOTA skeletons has led to an interesting alteration of properties of complexes of such ligands which are studied as possible contrast agents in magnetic resonance imaging, [30][31][32][33][34][35][36][37] for utilization in nuclear medicine, [38] or for luminescence imaging. [39] Surprisingly, complexation abilities of compounds bearing two aminoalkyl substituents on one phosphorus atom have been only sparingly investigated.…”

Study of Thermodynamic and Kinetic Stability of Transition Metal and Lanthanide Complexes of DTPA Analogues with a Phosphorus Acid Pendant Arm

“…H 5 do3ap or H 4 do3ap ABn , Scheme 1) comparing to H 4 dota. [17,18] Furthermore, the relatively easy substitution on the phosphorus atom offers the possibility to attach the complex to a macromolecular carrier, [19][20][21] or to bind it non-covalently to plasma proteins (e.g. by hydrophobic interactions).…”