Structural Variations in Carboxylated Bispidine Ligands: Influence of Positional Isomerism and Rigidity on the Conformation, Stability, Inertness and Relaxivity of their Mn2+ Complexes.

Mn2+ complexes of 2,4-pyridyl-disubstituted bispidine ligands have emerged as more biocompatible alternatives to Gd3+ -based MRI probes. They display relaxivities comparable to that of commercial contrast agents and high kinetic inertness, unprecedented for Mn2+ complexes. The chemical structure, in particular the substituents on the two macrocyclic nitrogens N3 and N7, are decisive for the conformation of the Mn2+ complexes, and this will in turn determine their thermodynamic, kinetic and relaxation properties. We describe the synthesis of four ligands with acetate substituents in positions N3, N7 or both. We evidence that the bispidine conformation is dependent on N3 substitution, with direct impact on the thermodynamic stability, kinetic inertness, hydration state and relaxivity of the Mn2+ complexes. These results unambiguously show that (i) solely a chair-chair conformation allows for favorable inertness and relaxivity, and (ii) in this family such chair-chair conformation is accessible only for ligands without N3-appended carboxylates.

55/52Mn2+ 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 (H4L1) and N-methanecarboxylate (H3L2) substituents as well as the physico-chemical properties of the corresponding Mn2+ and Zn2+ complexes. The two complexes [Mn(L1)]2- and [Mn(L2)]- 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 Zn2+, showing only ∼40 and 20% of dissociation for [Mn(L1)]2- and [Mn(L2)]-, respectively, after 150 days at pH 6 and 37 °C. Proton relaxivities amount to r1 = 4.31 mM-1 s-1 ([Mn(L1)]2-) and 3.64 mM-1 s-1 ([Mn(L2)]-) at 20 MHz, 25 °C, and are remarkable for Mn2+ complexes with one inner-sphere water molecule (q = 1); they are comparable to that of the commercial contrast agent [Gd(DOTA)(H2O)]-. The presence of one inner-sphere water molecule and an associative water exchange mechanism was confirmed by temperature-dependent transverse 17O relaxation rate measurements, which yielded kex298 = 0.12 × 107 and 5.5 × 107 s-1 for the water exchange rate of the phosphonate and the carboxylate complex, respectively. In addition, radiolabeling experiments with 52Mn were also performed with H2(L1)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.

Unprecedented Kinetic Inertness for a Mn2+ -Bispidine Chelate: A Novel Structural Entry for Mn2+ -Based Imaging Agents.

The search for more biocompatible alternatives to Gd3+ -based MRI agents, and the interest in 52 Mn for PET imaging call for ligands that form inert Mn2+ chelates. Given the labile nature of Mn2+ , high inertness is challenging to achieve. The strongly preorganized structure of the 2,4-pyridyl-disubstituted bispidol ligand L1 endows its Mn2+ complex with exceptional kinetic inertness. Indeed, MnL1 did not show any dissociation for 140 days in the presence of 50 equiv. of Zn2+ (37 °C, pH 6), while recently reported potential MRI agents MnPyC3A and MnPC2A-EA have dissociation half-lives of 0.285 h and 54.4 h under similar conditions. In addition, the relaxivity of MnL1 (4.28 mm-1 s-1 at 25 °C, 20 MHz) is remarkable for a monohydrated, small Mn2+ chelate. In vivo MRI experiments in mice and determination of the tissue Mn content evidence rapid renal clearance of MnL1 . Additionally, L1 could be radiolabeled with 52 Mn and the complex revealed good stability in biological media.

2,4-Substituted bispidines as rigid hosts for versatile applications: from κ-opioid receptor to metal coordination.

Bispidones (3,7-diazabicyclo[3.3.1]nonan-9-one) are bicyclic analogues of the natural antiarrhythmic agent, spartein. They can straightforwardly be obtained from two successive Mannich reactions. Reduction of the ketone gives the corresponding bispidol. Substituted bispidones and bispidols offer a large playground by varying the substituents, the configuration of the carbon atoms in position 2 and 4 as well as the conformation of the bicycle. While chair-boat conformers display a strong affinity for κ-opioid receptors, chair-chair bispidines provide adaptable coordination spheres for transition metal and rare-earth ions. Because of their very rich coordination chemistry, substituted bispidines have emerged in various applications of coordination chemistry, such as catalysis, magnetism and medical imaging.