The search for more biocompatible alternatives to Gd 3+-based MRI agents,a nd the interest in 52 Mn for PET imaging call for ligands that form inert Mn 2+ chelates.G iven the labile nature of Mn 2+ ,h igh inertness is challenging to achieve.The strongly preorganized structure of the 2,4-pyridyldisubstituted bispidol ligand L 1 endows its Mn 2+ complex with exceptional kinetic inertness.I ndeed, MnL 1 did not showa ny dissociation for 140 days in the presence of 50 equiv.o fZ n 2+ (37 8 8C, pH 6), while recently reported potential MRI agents MnPyC3A and MnPC2A-EA have dissociation half-lives of 0.285 ha nd 54.4 hu nder similar conditions.I na ddition, the relaxivity of MnL 1 (4.28 mm À1 s À1 at 25 8 8C, 20 MHz) is remarkable for am onohydrated, small Mn 2+ chelate.I nvivo MRI experiments in mice and determination of the tissue Mn content evidence rapid renal clearance of MnL 1 .Additionally, L 1 could be radiolabeled with 52 Mn and the complex revealed good stability in biological media.

While Mn II complexes meet increasing interest in biomedical applications, ligands are lacking that enable high Mn II complex stability and selectivity vs. Zn II , the most relevant biological competitor. We report here two new bispidine derivatives, which provide rigid and large coordination cavities that perfectly match the size of Mn II , yielding eight-coordinate Mn II complexes with record stabilities. In contrast, the smaller Zn II ion cannot accommodate all ligand donors, resulting in highly strained and less stable six-coordinate complexes. Combined theoretical and experimental data (X-ray crystallography, potentiometry, relaxometry and 1 H NMR spectroscopy) demonstrate unprecedented selectivity for Mn II vs. Zn II (K MnL / K ZnL of 10 8 -10 10 ), in sharp contrast to the usual Irving-Williams behavior, and record Mn II complex stabilities and inertness with logK MnL close to 25.

Bispidine (3,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.

As an essential metal ion and an efficient relaxation agent, Mn2+ holds a great promise to replace Gd3+ in magnetic resonance imaging (MRI) contrast agent applications, if its stable and inert complexation can be achieved. Toward this goal, four pyridine and one carboxylate pendants have been introduced in coordinating positions on the bispidine platform to yield ligand L3. Thanks to its rigid and preorganized structure and perfect size match for Mn2+, L3 provides remarkably high thermodynamic stability (log K MnL = 19.47), selectivity over the major biological competitor Zn2+ (log(K MnL/K ZnL) = 4.4), and kinetic inertness. Solid-state X-ray data show that [MnL3(MeOH)](OTf)2 has an unusual eight-coordinate structure with a coordinated solvent molecule, in contrast to the six-coordinate structure of [ZnL3](OTf), underlining that the coordination cavity is perfectly adapted for Mn2+, while it is too large for Zn2+. In aqueous solution, 17O NMR data evidence one inner sphere water and dissociatively activated water exchange (k ex 298 = 13.5 × 107 s–1) for MnL3. Its water proton relaxivity (r 1 = 4.44 mM–1 s–1 at 25 °C, 20 MHz) is about 30% higher than values for typical monohydrated Mn2+ complexes, which is related to its larger molecular size; its relaxation efficiency is similar to that of clinically used Gd3+-based agents. In vivo MRI experiments realized in control mice at 0.02 mmol/kg injected dose indicate good signal enhancement in the kidneys and fast renal clearance. Taken together, MnL3 is the first chelate that combines such excellent stability, selectivity, inertness and relaxation properties, all of primary importance for MRI use.

While MnII complexes meet increasing interest in biomedical applications, ligands are lacking that enable high MnII complex stability and selectivity vs. ZnII, the most relevant biological competitor. We report here two new bispidine derivatives, which provide rigid and large coordination cavities that perfectly match the size of MnII, yielding eight‐coordinate MnII complexes with record stabilities. In contrast, the smaller ZnII ion cannot accommodate all ligand donors, resulting in highly strained and less stable six‐coordinate complexes. Combined theoretical and experimental data (X‐ray crystallography, potentiometry, relaxometry and 1H NMR spectroscopy) demonstrate unprecedented selectivity for MnII vs. ZnII (KMnL/KZnL of 108–1010), in sharp contrast to the usual Irving–Williams behavior, and record MnII complex stabilities and inertness with logKMnL close to 25.

The development of efficient and low-cost catalytic systems is important for the replacement of robust noble metal complexes. The synthesis and application of a stable, phosphine-free, water-soluble cyclopentadienone iron tricarbonyl complex in the reduction of polarized double bonds in pure water is reported. In the presence of cationic bifunctional iron complexes, a variety of alcohols and amines were prepared in good yields under mild reaction conditions.

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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.