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Cu chelation in biological systems is of interest as a tool to study the metabolism of this essential metal or for applications in the case of diseases with a systemic or local Cu overload, such as Wilson’s or Alzheimer’s disease. The choice of the chelating agent must meet several criteria. Among others, affinities and kinetics of metal binding and related metal selectivity are important parameters of the chelators to consider. Here, we report on the synthesis and characterization of Cu-binding properties of two ligands, L1 and L2, derivatives of the well-known peptidic CuII-binding motif Xxx-Zzz-His (also called ATCUN), where CuIIis bound to the N-terminal amine, two amidates, and the imidazole. In either L, the N-terminal amine was replaced with a pyridine, and for L2, one amide was replaced with an amine compared to Xxx-Zzz-His. In particular, L2 showed several interesting features, including a CuII-binding affinity with a log KDapp= −16.0 similar to that of EDTA and stronger than all reported ATCUN peptides. L2 showed high selectivity for CuIIover ZnIIand other essential metal ions, even under the challenging conditions of the presence of human serum albumin. Further, L2 showed fast and efficient CuIIredox silencing qualities and CuII-L2 was stable in the presence of mM GSH concentrations. Benefitting the fact that L2 can be easily elongated on its peptide part by standard SPPS to add other functions, L2 has attractive properties as a CuIIchelator for application in biological systems.

A DTPA-based chelate containing one phosphinate group was conjugated to a generation 5 polyamidoamine (PAMAM) dendrimer viaa benzylthiourea linkage. The Gd(iii) complex of this novel conjugate has potential as a contrast agent for magnetic resonance imaging (MRI). The chelates bind Gd3viathree nitrogen atoms, four carboxylates and one phosphinate oxygen, and one water molecule completes the inner coordination sphere. The monomer Gd(iii) chelates bearing nitrobenzyl and aminobenzyl groups ([Gd(DTTAP-bz-NO2)(H2O)]2−and [Gd(DTTAP-bz-NH2)(H2O)]2−) as well as the dendrimeric Gd(iii) complex G5-(Gd(DTTAP))63) were studied by multiple-field, variable temperature 17O and 1H NMR. The rate of water exchange is faster than that of [Gd(DTPA)(H2O)]2−and very similar on the two monomeric complexes (8.9 and 8.3 × 106s−1for [Gd(DTTAP-bz-NO2)(H2O)]2−and [Gd(DTTAP-bz-NH2)(H2O)]2−, respectively), while it is decreased on the dendrimeric conjugate (5.0 × 106s−1). The Gd(iii) complex of the dendrimer conjugate has a relaxivity of 26.8 mM−1s−1at 37 °C and 0.47 T (corresponding to 1H Larmor frequency of 20 MHz). Given the contribution of the second sphere water molecules to the overall relaxivity, this value is slightly higher than those reported for similar size dendrimers. The experimental 17O and 1H NMR data were fitted to the Solomon–Bloembergen–Morgan equations extended with a contribution from second coordination sphere water molecules. The rotational dynamics of the dendrimeric conjugate was described in terms of global and local motions with the Lipari–Szabo approach.

In the objective of optimizing water exchange rate on stable, nine-coordinate, monohydrated GdIIIpolyamino carboxylate complexes, we have prepared monopropionate derivatives of DOTA4−DO3A-Nprop4− and DTPA5−DTTA-Nprop5−. A novel ligand, EPTPA-BAA3−, the bisamylamide derivative of ethylenepropylenetriamine-pentaacetate EPTPA5− was also synthesized. A variable temperature 17O NMR study has been performed on their GdIIIcomplexes, which, for GdDTTA-NpropH2O2−and GdEPTPA-BAAH2O has been combined with multiple field EPR and NMRD measurements. The water exchange rates, kex298, are 8.0 × 107s−1, 6.1 × 107s−1and 5.7 × 107s−1for GdDTTA-NpropH2O2−, GdDO3A-NpropH2O−and GdEPTPA-BAAH2O, respectively, all in the narrow optimal range to attain maximum proton relaxivities, provided the other parameters electronic relaxation and rotation are also optimized. The substitution of an acetate with a propionate arm in DTPA5−or DOTA4−induces increased steric compression around the water binding site and thus leads to an accelerated water exchange on the GdIIIcomplex. The kexvalues on the propionate complexes are, however, lower than those obtained for GdEPTPAH2O2−and GdTRITAH2O−which contain one additional CH2unit in the amine backbone as compared to the parent GdDTPAH2O2−and GdDOTAH2O−. In addition to their optimal water exchange rate, GdDTTA-NpropH2O2−has, and GdDO3A-NpropH2O−is expected to have sufficient thermodynamic stability. These properties together make them prime candidates for the development of high relaxivity, macromolecular MRI contrast agents.

EuIIcomplexes are potential candidates for pO2‐responsive contrast agents in magnetic resonance imaging. In this regard, we have characterized two novel macrocyclic EuIIchelates, [EuII(DOTA)(H2O)]2−and [EuII(TETA)]2−(H4DOTA=1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid, H4TETA=1,4,8,11‐tetraazacyclotetradecane‐1,4,8,11‐tetraacetic acid) in terms of redox and thermodynamic complex stability, proton relaxivity, water exchange, rotation and electron spin relaxation. Additionally, solid‐state structures were determined for the SrIIanalogues. They revealed no inner‐sphere water in the TETA and one inner‐sphere water molecule in the DOTA complex. This hydration pattern is retained in solution, as the 17O chemical shifts and 1H relaxation rates proved for the corresponding EuIIcompounds. The thermodynamic complex stability, determined from the formal redox potential and by pH potentiometry, of [EuII(DOTA)(H2O)]2−(lg KEu(II)=16.75) is the highest among all known EuIIcomplexes, whereas the redox stabilities of both [EuII(DOTA)(H2O)]2−and [EuII(TETA)]2−are inferior to that of 18‐membered macrocyclic EuIIchelates. Variable‐temperature 17O NMR, NMRD and EPR studies yielded the rates of water exchange, rotation and electron spin relaxation. Water exchange on [EuII(DOTA)(H2O)]2−is remarkably fast (k$\rm{_{ex}^{298}}$=2.5×109s−1). The near zero activation volume (ΔV≠=+0.1±1.0 cm3mol−1), determined by variable‐pressure 17O NMR spectroscopy, points to an interchange mechanism. The fast water exchange can be related to the low charge density on EuII, to an unexpectedly long MOwaterdistance (2.85 Å) and to the consequent interchange mechanism. Electron spin relaxation is considerably slower on [EuII(DOTA)(H2O)]2−than on the linear [EuII(DTPA)(H2O)]3−(H5DTPA=diethylenetriaminepentaacetic acid), and this difference is responsible for its 25 % higher proton relaxivity (r1=4.32 mM−1s−1for [EuII(DOTA)(H2O)]2−versus 3.49 mM−1s−1for [EuII(DTPA)(H2O)]3−; 20 MHz, 298 K).