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.