Magnetic resonance imaging is a commonly used diagnostic method in medicinal practice as well as in biological and preclinical research. Contrast agents (CAs), which are often applied are mostly based on Gd(III) complexes. In this paper, the ligand types and structures of their complexes on one side and a set of the physico-chemical parameters governing properties of the CAs on the other side are discussed. The solid-state structures of lanthanide(III) complexes of open-chain and macrocyclic ligands and their structural features are compared. Examples of tuning of ligand structures to alter the relaxometric properties of gadolinium(III) complexes as a number of coordinated water molecules, their residence time (exchange rate) or reorientation time of the complexes are given. Influence of the structural changes of the ligands on thermodynamic stability and kinetic inertness/lability of their lanthanide(III) complexes is discussed.

A monophosphonate analogue of H4dota, 1,4,7,10-tetraazacyclododecane-4,7,10-tris(carboxymethyl)-1-methylphosphonic acid (H5do3aP), and its complexes with lanthanides were synthesized. Multinuclear NMR studies reveal that, in aqueous solution, lanthanide(III) complexes of the ligand exhibit structures analogous to those of H4dota complexes. Thus, the central ion is nine-coordinate, surrounded by four nitrogen atoms, three acetate and one phosphonate oxygen atoms, and one water molecule in an apical position. For complexes of H5do3aP with Ln(III) ions in the middle of the series, the abundance of the desired twisted square-antiprismatic (TSAP) isomer is higher than for the corresponding H4dota complexes. The TSAP/square-antiprismatic (SAP) isomer ratio is highly sensitive to protonation of the phosphonate group: a higher abundance of the TSAP isomer was found in acidic solutions. The microscopic protonation constants of the TSAP isomers are higher than those of the SAP isomers. The presence of one water molecule in the first coordination sphere of the complexes in the pH region studied (pH 2.5-7.0) is confirmed by 17O NMR spectroscopy. The results of a simultaneous fit of variable-temperature 17O NMR relaxation data and 1H NMRD profiles show that the residence time of water (tauM) in the Gd(III) complex is much smaller than for [Gd(dota)(H2O)]-. The exchange rate appears to be dependent on the pH of the solution. The values of tauM are 37, 40, and 14 ns at pH 2.5, 4.7, and 7.0, respectively. These observations can be explained by an extensive second-sphere hydrogen-bonding network that varies with the state of protonation of the phosphonate moiety. Upon protonation of the complex, the second-sphere hydration probably becomes more ordered, which may result in a decrease in penetrability and an increase in tauM. The relaxivity of the Gd(III) complex is almost independent of the pH and is equal to 4.7 s(-1) mM(-1) (20 MHz, pH 7 and 37 degrees C). The solid-state structure was determined for the Nd(III) complex. It crystallizes as the TSAP isomer and the unit cell contains two independent molecules of the complex with different Nd-O(water) bond lengths of 2.499 and 2.591 A.

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For application in positron emission tomography (PET), PrP9, a N,N',N''-trisubstituted triazacyclononane with methyl(2-carboxyethyl)phosphinic acid pendant arms, was developed as (68)Ga(3+) complexing agent. The synthesis is short and inexpensive. Ga(III) and Fe(III) complexes of PrP9 were characterized by single-crystal X-ray diffraction. Stepwise protonation constants and thermodynamic stabilities of metal complexes were determined by potentiometry. The Ga(III) complex possesses a high thermodynamic stability (log K([GaL])=26.24) and a high degree of kinetic inertness. (68)Ga labeling of PrP9 is possible at ambient temperature and in a wide pH range, also at pH values as low as 1. This means that for the first time, the neat eluate of a TiO(2)-based (68)Ge/(68)Ga generator (typically consisting of 0.1 M HCl) can be directly used for labeling purposes. The rate of (68)Ga activity incorporation at pH 3.3 and 20 degrees C is higher than for the established chelators DOTA and NOTA. Tris-amides of PrP9 with amino acid esters were synthesized to act as models for multimeric peptide conjugates. These conjugates exhibit radiolabeling properties similar to those of unsubstituted PrP9.

Development of multifunctional nanoscale sensors working under physiological conditions enables monitoring of intracellular processes that are important for various biological and medical applications. By attaching paramagnetic gadolinium complexes to nanodiamonds (NDs) with nitrogen-vacancy (NV) centres through surface engineering, we developed a hybrid nanoscale sensor that can be adjusted to directly monitor physiological species through a proposed sensing scheme based on NV spin relaxometry. We adopt a single-step method to measure spin relaxation rates enabling time-dependent measurements on changes in pH or redox potential at a submicrometre-length scale in a microfluidic channel that mimics cellular environments. Our experimental data are reproduced by numerical simulations of the NV spin interaction with gadolinium complexes covering the NDs. Considering the versatile engineering options provided by polymer chemistry, the underlying mechanism can be expanded to detect a variety of physiologically relevant species and variables.