55/52 Mn 2+ Complexes with a Bispidine-Phosphonate Ligand: High Kinetic Inertness for Imaging Applications.

Bispidine (3,7-diazabicyclo[3.3.1]nonane) provides a rigid and preorganized scaffold that is particularly interesting for the stable and inert complexation of metal ions, especially for their application in medical imaging. In this study, we present the synthesis of two bispidine ligands with N -methanephosphonate (H 4 L 1 ) and N -methanecarboxylate (H 3 L 2 ) substituents as well as the physico-chemical properties of the corresponding Mn 2+ and Zn 2+ complexes. The two complexes [Mn( L 1 )] 2- and [Mn( L 2 )] - have relatively moderate thermodynamic stability constants according to potentiometric titration data. However, they both display an exceptional kinetic inertness, as assessed by transmetallation experiments in the presence of 50 equiv excess of Zn 2+ , showing only ∼40 and 20% of dissociation for [Mn( L 1 )] 2 - and [Mn( L 2 )] - , respectively, after 150 days at pH 6 and 37 °C. Proton relaxivities amount to r 1 = 4.31 mM -1 s -1 ([Mn( L 1 )] 2 - ) and 3.64 mM -1 s -1 ([Mn( L 2 )] - ) at 20 MHz, 25 °C, and are remarkable for Mn 2+ complexes with one inner-sphere water molecule ( q = 1); they are comparable to that of the commercial contrast agent [Gd(DOTA)(H 2 O)] - . The presence of one inner-sphere water molecule and an associative water exchange mechanism was confirmed by temperature-dependent transverse 17 O relaxation rate measurements, which yielded k ex 298 = 0.12 × 10 7 and 5.5 × 10 7 s -1 for the water exchange rate of the phosphonate and the carboxylate complex, respectively. In addition, radiolabeling experiments with 52 Mn were also performed with H 2 ( L 1 ) 2- showing excellent radiolabeling properties and quantitative complexation at pH 7 in 15 min at room temperature as well as excellent stability of the complex in various biological media over 24 h.