Twisted Square-antiprismatic Isomer Research Articles

Modifying LnHPDO3A Chelates for Improved T1 and CEST MRI Applications

The new ligand HPDO3MA [(R,R,R,R)-10-(2-hydroxypropyl)-α,α',α''-trimethyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid] was designed to combine and optimize the chemical properties of the macrocyclic ligands HPDO3A and DOTMA. The presence of the methyl groups on the acetic pendant arms of HPDO3A is expected to rigidify the structure of the ligand and favor an increase of the kinetic inertness of the Ln complexes. 1 H NMR spectra of Eu(HPDO3MA) displayed the presence of two pairs of diastereoisomers: SAP (square antiprismatic) and TSAP (twisted square antiprismatic) isomers (56 and 44 %, respectively). In addition, 1 H and 17 O relaxometric NMR studies of Gd(HPDO3MA) showed approximately a 10 % increase in relaxivity and a faster water exchange rate with respect to Gd(HPDO3A). Moreover, a detailed chemical exchange saturation transfer (CEST) characterization of Yb(HPDO3MA) displayed a sensitivity about two times larger than that of Yb(HPDO3A) both in phantom and in cell labeling experiments. Finally, the kinetic inertness of Yb(HPDO3MA) was measured to be twice as high as that of Yb(HPDO3A), with a dissociation half-life at physiological pH of about 2500 years.

Unexpected Changes in the Population of Coordination Isomers for the Lanthanide Ion Complexes of DOTMA-Tetraglycinate.

Lanthanide complexes with DOTA-tetraglycinate (DOTA-(gly)4) heavily favor the square antiprismatic (SAP) coordination isomer in aqueous solution, a structural feature that has made them useful as water-based paraCEST agents. In an effort to create amide-based paraCEST agents with rapid water exchange rates, we prepared the analogous tetraglycinate complexes with DOTMA, a ligand known to favor the twisted square antiprismatic (TSAP) coordination structures. Unexpectedly, NMR investigations show that the LnDOTMA-(gly)4 complexes, like the LnDOTA-(gly)4 complexes, also favor the SAP isomers in solution. This observation led to density functional theory (DFT) calculations in order to identify the energy terms that favor the SAP structures in lanthanide complexes formed with macrocyclic DOTA- and DOTMA-tetraamide ligands. The DFT calculations revealed that, regardless the nature of the ligand, the TSAP isomers present more negative hydration energies than the SAP counterparts. The extent to which the TSAP isomer is stabilized varies, however, depending on the ligand structure, resulting in different isomeric populations in solution.

The presence of fast-exchanging proton species in aqueous solutions of paraCEST agents can impact rate constants measured for slower exchanging species when fitting CEST spectra to the Bloch equations.

LnDOTA-tetraamide complexes typically exist in solution as a mixture of square-antiprismatic (SAP) and twisted square-antiprismatic (TSAP) coordination isomers. In most cases, the SAP isomer, which is preferred for CEST imaging, predominates, and the presence of the minor TSAP isomer is assumed to have little influence on quantitative measures of the water-exchange rate constant for the SAP isomer. Here, we sought to confirm the validity of this assumption by mixing two chelates with different SAP and TSAP isomer populations while measuring the water-exchange rate constant of the SAP isomer. The results show that an increase in the population of the TSAP isomer in solution results in as much as a 30% overestimation of the water-exchange rate constant for the SAP isomer when CEST spectra are fit to the Bloch equations. This effect was shown to be significant only when the TSAP isomer population exceeded 50%.

Tris(phosphonomethyl)cyclen Derivatives: Thermodynamic Stability, Kinetics, Solution Structure, and Relaxivity of Ln3+ Complexes

AbstractThe lanthanide (Ln3+) complexes of three cyclen‐based ligands containing three methylphosphonate pendant arms were studied, the ligands being 1,4,7,10‐tetraazacyclododecane‐1,4,7‐triyltris(methylphosphonic acid) (H6do3p), 3‐[4,7,10‐tris(phosphonomethyl)‐1,4,7,10‐tetraazacyclododec‐1‐yl]propanoic acid (H7do3p1pr), and 10‐(3‐hydroxypropyl)‐1,4,7,10‐tetraazacyclododecane‐1,4,7‐triyltris(methylphosphonic acid) (H6do3p1ol). The three macrocyclic ligands form complexes of very high thermodynamic stability with all studied Ln3+ ions. Kinetic studies showed that the acid‐assisted dissociation of Ce3+ complexes of these ligands is much faster than for the complex of the related ligand H8dotp [1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetrayltetrakis(methylphosphonic acid)]. The number of water molecules coordinated to the Eu3+ and Gd3+ complexes was estimated to be < 1 for the do3p1ol ligand but ca. 1 for the other two ligands, as obtained by time‐resolved luminescence spectroscopy and by 1H and 17O relaxometric measurements. The NMR spectroscopic data indicate the existence of a considerable contribution from second‐sphere water molecules to the relaxivity of all the Gd3+ complexes studied. The 1H and 31P NMR spectra of the Eu3+, Yb3+ and Lu3+ complexes showed that the propionate arm in the [Ln(do3p1pr)]4– complexes and the propanol arm in the [Ln(do3p1ol)]3– complexes are not bound to the Ln3+ ion. The [Ln(do3p)]3– and [Ln(do3p1pr)]4– complexes have a clear preference for the TSAP (twisted square antiprismatic) isomer, while both SAP (square antiprismatic) and TSAP isomers are present in solutions of the [Ln(do3p1ol)]3– complexes.

Properties, Solution State Behavior, and Crystal Structures of Chelates of DOTMA

The chemistry of polyamino carboxylates and their use as ligands for Ln(3+) ions is of considerable interest from the point of view of the development of new imaging agents. Of particular interest is the chemistry of the macrocyclic ligand 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and its derivatives. Herein we report that the tetramethylated DOTA derivative, DOTMA, possess several properties that, from an imaging agent development point of view, are more advantageous than those of the parent DOTA. In particular, the Ln(3+) chelates of DOTMA exhibit a marked preference for the monocapped twisted square antiprismatic coordination isomer which imparts more rapid water exchange kinetics on the chelates; τ(M)(298) was determined to be 85 ns for GdDOTMA. Differential analysis of the (17)O R(2ρ) temperature profiles of both GdDOTA and GdDOTMA afforded the τ(M)(298) values for the square (SAP) and twisted square antiprismatic (TSAP) isomers of each chelate that were almost identical: 365 ns (SAP) and 52 ns (TSAP). The origin of this accelerated water exchange in the TSAP isomer appears to be the slightly longer Gd-OH(2) bond distance (2.50 Å) that is observed in the crystal structure of GdDOTMA which crystallizes in the P(2) space group as a TSAP isomer. The Ln(3+) chelates of DOTMA also exhibit high thermodynamic stabilities ranging from log K(ML) = 20.5 for CeDOTMA, 23.5 for EuDOTMA and YbDOTMA comparable to, but a shade lower than, those of DOTA.

Towards Fluoride Sensing with Positively Charged Lanthanide Complexes

AbstractHerein we report a series of [LnL(H2O)]Cl3 complexes, in which L is a 1,4,7,10‐tetrazacyclododecane framework (cyclen) functionalized with 2‐methylpyridyl pendants on the nitrogen atoms at the 1‐ and 7‐positions and with N‐[2‐(2‐hydroxyethoxy)ethyl]acetamide groups on those at the 4‐ and 10‐positions, and Ln stands for Eu, La, and Tb. The complexes were isolated and characterized by elemental analysis, mass spectrometry, infrared spectroscopy, and 1H NMR spectroscopy for the La and Eu complexes. 1H NMR spectroscopy indicates that the complexes display a major twisted square antiprismatic (TSAP) geometry in solution, which was confirmed by using DFT calculations. 1H and 13C variable‐temperature NMR spectroscopic experiments on the La complex provided an activation free energy of ΔG≠ = (58 ± 3) kJ mol–1 for the enantiomerization process of the TSAP isomer, which requires both the inversion of the five‐membered chelate rings formed upon coordination of the cyclen moiety and the rotation of the pendant arms. The photophysical properties of the complexes were studied by means of absorption, steady‐state, and time‐resolved luminescence spectroscopy. Upon ligand excitation, the Eu and Tb complexes displayed the typical lanthanide‐centered emission spectra with weak emission efficiencies (Φov = 0.11 and 0.68 %, respectively, for Eu and Tb in H2O). Luminescence lifetime measurements in water and heavy water allowed the determination of the hydration number of the complexes; these were (1.0 ± 0.2) for Eu and Tb. Spectrophotometric titrations of the [LnL(H2O)]Cl3 complexes (Ln = Eu and Tb) with F–, Cl–, and Br– anions (in buffered water solutions, 0.01 M tris(hydroxymethyl)aminomethane (TRIS)/HClO4, pH = 7.0) showed the complexes to interact selectively with fluoride anions, whereas no interactions were observed with Cl– and Br–. The interaction with F– was monitored by luminescence spectroscopy with [EuL(H2O)], which evidenced dramatic changes in the shape of the luminescence spectra, and an association constant of (2.86 ± 0.06) log units was determined. In the case of the Eu complex, time‐resolved and high‐resolution emission spectroscopy showed that the interaction resulted in the displacement of the coordinated water molecule, which led to an increase of the overall luminescence quantum yield, with almost no impact on the ligand‐to‐metal sensitization efficiency. Investigation of the Eu and La complexes by potentiometry (0.1 M NaCl) allowed the determination of the protonation constants of the complexes as well as the association constants with fluoride anions. DFT calculations on the fluoride adduct of the Eu complex confirmed the higher stability of the TSAP isomer and evidenced large structural changes upon F– binding, in agreement with spectrophotometric observations in solution.

An NMR and DFT Investigation on the Conformational Properties of Lanthanide(III) 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetate Analogues Containing Methylenephosphonate Pendant Arms

The conformational properties of lanthanide(III) complexes with the mono- and biphosphonate analogues of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (DOTA) are investigated by means of density functional theory (DFT) calculations and NMR spectroscopy. Geometry optimizations performed at the B3LYP/6-31G(d) level and using a 46 + 4f(n) effective core potential for lanthanides provide two energy minima corresponding to the square-antiprismatic (SAP) and twisted square-antiprismatic (TSAP) geometries. Our calculations give relative free energies between the SAP and TSAP isomers in fairly good agreement with the experimental values. The SAP isomer presents the highest binding energy of the ligand to the metal ion, which further increases with respect to that of the TSAP isomer across the lanthanide series as the charge density of the metal ion increases. The stabilization of the TSAP isomer upon substitution of the acetate arms of DOTA by methylenephosphonate ones is attributed to the higher steric demand of the phosphonate groups and the higher strain of the ligand in the SAP isomer. A (1)H NMR band-shape analysis performed on the [Ln(DO2A2P)](3-) (Ln = La and Lu) complexes provided the activation parameters for enantiomerization of the TSAP form of the complexes. The TSAP isomerization process was also investigated by using DFT calculations on the [Lu(DOTA)](-) and [Ln(DO2A2P)](3-) (Ln = La and Lu) systems. Our results confirm that enantiomerization requires both rotation of the pendant arms and inversion of the four five-membered chelate rings formed upon coordination of the macrocyclic unit. According to our calculations, the arm rotation pathway in [Lu(DOTA)](-) is a one-step process involving the simultaneous rotation of the four acetate arms, while in the DO2A2P analogue, the arm-rotation process is a multistep path involving the stepwise rotation of each of the four pendant arms. The calculated activation free energies are in reasonably good agreement with the experimental data. A comparison of the experimental (13)C NMR shifts of [Ln(DO2A2P)](3-) (Ln = La and Lu) complexes and those calculated by using the GIAO method confirms that the major isomer observed in solution for these complexes corresponds to the TSAP isomer.

Gadolinium(iii) complexes of mono- and diethyl esters of monophosphonic acid analogue of DOTA as potential MRI contrast agents: solution structures and relaxometric studies

Two new macrocyclic DOTA-like chelates containing one phosphonate pendant arm were synthesised as potential contrast agents for MRI (magnetic resonance imaging). The chelates bind to the lanthanide(III) in an octadentate manner, via four nitrogen atoms, three carboxylate and one phosphonate oxygen atoms. Solution structures of [Ln(do3ap(OEt2))(H(2)O)] and [Ln(do3ap(OEt))(H(2)O)](-) were studied using (31)P and (1)H NMR spectroscopy and SAP (square-antiprismatic)/TSAP (twisted square-antiprismatic) isomerism was observed. Depending on the nature of the lanthanide(III) ion, the lanthanide(III) complexes of H(4)do3ap(OEt) are present in solution as up to four different diastereoisomers observable with NMR. The TSAP isomer is the most abundant at the beginning of the lanthanide series and, with a decrease of the ionic radius of lanthanide(III) ions, both TSAP and SAP forms were observed. A second interconversion (SAP<-->TSAP') becomes important at the end of the series (TSAP' means the TSAP species without a coordinated water molecule). The remaining axial coordination site is occupied by one water molecule for the Gd(3+)-complex. The calculated fraction of the TSAP isomer in the gadolinium(III) complexes increases in the order [Gd(DOTA)(H(2)O)](-) < [Gd(do3ap(OEt2))(H(2)O)] < [Gd(do3ap(OEt))(H(2)O)](-) < [Gd(do3ap)(H(2)O)](2-). Gadolinium(III) complexes of phosphorus-containing chelates, generally, have the advantage of a relatively fast water exchange rate due to a greater sterical demand of the phosphorus acid moiety and of the presence of the second-sphere water shell, which also contributes to the overall relaxivity. The [Gd(do3ap(OEt2))(H(2)O)] and [Gd(do3ap(OEt))(H(2)O)](-) complexes were studied by variable-temperature (17)O NMR and (1)H NMRD. The experimental data were evaluated simultaneously with commonly used equations based on Solomon-Bloembergen-Morgan approximation, extended by a contribution of the second coordination sphere. The water exchange rates were found to be strongly dependent on the TSAP/SAP isomeric ratio and the overall charge of the complex: the monoanionic [Gd(do3ap(OEt))(H(2)O)](-) complex with TSAP molar fraction equal to 0.36 has the water exchange rate of 20 x 10(6) s(-1) (tau(M) = 50 ns) while neutral [Gd(do3ap(OEt2))(H(2)O)] complex with TSAP molar fraction 0.28 has an exchange rate equal to 4.4 x 10(6) s(-1) (tau(M) = 227 ns).

Lanthanide(III) Complexes of a Mono(methylphosphonate) Analogue of H4dota: The Influence of Protonation of the Phosphonate Moiety on the TSAP/SAP Isomer Ratio and the Water Exchange Rate

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.