Rigid Bispyclen Ligand Appended with Two Malonate Groups: Fast, Highly Stable, and Inert Gd(III) Complexation

Bunda, Szilvia and Lihi, Norbert and Debretsion, Abraham Estifanos and Héry, Simon and Meudal, Hervé and Tóth, Éva and Kálmán, Ferenc Krisztián (2026) Rigid Bispyclen Ligand Appended with Two Malonate Groups: Fast, Highly Stable, and Inert Gd(III) Complexation. INORGANIC CHEMISTRY, 65 (31). pp. 18413-18422. ISSN 0020-1669 (print); 1520-510X (online)

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Abstract

In the aim of designing novel chelators for stable and inert Gd(III) complexation, we report the synthesis of the H4BPDMA ligand which combines a rigidified bispyclen macrocycle platform with two malonate pendants, and an in-depth equilibrium, kinetic relaxation, and structural investigation of its Gd(III) complex. Despite its rigid macrocyclic nature, H4BPDMA is capable of very rapid complex formation with Gd(III) even in acidic conditions. The [Gd(BPDMA)]− possesses high thermodynamic stability, and most remarkably, a conditional stability comparable to that of [Gd(DOTA)]− (pGd = 15.6 and 16.2, respectively; cGdL = 10–5 M, pH 7.4). Cu-transmetalation studies show that [Gd(BPDMA)]− dissociation occurs via proton-assisted pathways with a dissociation half-life of 3.2 years (37 °C, pH 7.4). DFT calculations predict a nine-coordinate [Gd(BPDMA)]− complex, involving coordination of one water molecule and eight ligand donor atoms, in accordance with 13C NMR data collected on the corresponding Eu(III) and Yb(III) complexes. Luminescence lifetime measurements on the Eu(III) analogue support monohydration in solution. The water proton relaxation enhancement effect of [Gd(BPDMA)]− (r1 = 4.6 mM–1s–1, 25 °C, 20 MHz) is similar to that of clinical MRI contrast agents, and 17O NMR data confirm relatively fast water exchange (kex298 = (43 ± 8) × 106 s–1).

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