Acetate Pendant Arms Research Articles

Theoretical Study of Metal-Ligand Interactions in Lead Complexes with Radiopharmaceutical Interest.

The 203Pb and 212Pb lead radioisotopes are attracting growing interest as they can aid in the development of personalized, targeted radionuclide treatment for advanced and currently untreatable cancers. In the present study, the bonding interactions of Pb2+ with twelve macrocyclic ligands, having an octa and nona coordination, were assessed using Density Functional Theory (DFT) calculations. The molecular structures in an aqueous solution were computed utilizing the polarized continuum model. The preference for the twisted square antiprismatic (TSAP) structure was confirmed for ten out of the eleven cyclen-based complexes. The characteristics of the bonding were assessed using a Natural Energy Decomposition Analysis (NEDA). The analysis revealed a strong electrostatic character of the bonding in the complexes, with minor variations in electrical terms. The charge transfer (CT) had a comparable energetic contribution only in the case of neutral ligands, while in general, it showed notable variations regarding the various donor groups. Our data confirmed the general superiority of the carboxylate O and aromatic N donors. The combination of the selected efficient pendant arms pointed out the superiority of the acetate pendant arms and the lack of significant cooperation between the different pendant arms in the probed ligands. Altogether, the combination led only to a marginal enhancement in the total CTs in the complexes.

A seven-coordinate Mn(II) complex with a pyridine-based 15-membered macrocyclic ligand containing one acetate pendant arm: structure, stability and relaxation properties.

A new 15-membered pyridine-based macrocyclic ligand containing one acetate pendant arm (N-carboxymethyl-3,12,18-triaza-6,9-dioxabicyclo[12.3.1]octadeca-1(18),14,16-triene, L1) was synthesized and its Mn(II) complex MnL1 was investigated in the context of MRI contrast agent development. The X-ray molecular structure of MnL1 confirmed a coordination number of seven with an axially compressed pentagonal bipyramidal geometry and one coordination site available for an inner-sphere water molecule. The protonation constants of L1 and the stability constants of Mn(II), Zn(II), Cu(II) and Ca(II) complexes were determined by potentiometry, and revealed higher thermodynamic stabilities in comparison with complexes of 15-pyN3O2, the parent macrocycle without an acetate pendant arm. The MnL1 complex is fully formed at physiological pH 7.4, but it shows fast dissociation kinetics, as followed by relaxometry in the presence of an excess of Zn(II). The short dissociation half-life estimated for physiological pH (ca. 3 minutes) is related to fast spontaneous dissociation of the non-protonated complex. At lower pH values, the proton-assisted dissociation pathway becomes important, while the Zn(II) concentration has no effect on the dissociation rate. 17O NMR and 1H NMRD data indicated the presence of one inner-sphere water molecule with a rather slow exchange (k298ex = 4.5 × 106 s-1) and provided information about other microscopic parameters governing relaxation. The relaxivity (r1 = 2.45 mM-1 s-1 at 20 MHz, 25 °C) corresponds to typical values for monohydrated Mn(II) chelates. Overall, the acetate pendant arm in L1 has a beneficial effect with respect to 15-pyN3O2 in increasing the thermodynamic stability and kinetic inertness of its Mn(II) complex, but leads to a reduced number of inner-sphere water molecules and thus lower relaxivity.

Synthesis and Characterization of Late Transition Metal Complexes of Mono-Acetate Pendant Armed Ethylene Cross-Bridged Tetraazamacrocycles with Promise as Oxidation Catalysts for Dye Bleaching

Ethylene cross-bridged tetraazamacrocycles are known to produce kinetically stable transition metal complexes that can act as robust oxidation catalysts under harsh aqueous conditions. We have synthesized ligand analogs with single acetate pendant arms that act as pentadentate ligands to Mn, Fe, Co, Ni, Cu, and Zn. These complexes have been synthesized and characterized, including the structural characterization of four Co and Cu complexes. Cyclic voltammetry demonstrates that multiple oxidation states are stabilized by these rigid, bicyclic ligands. Yet, redox potentials of the metal complexes are modified compared to the "parent" ligands due to the pendant acetate arm. Similarly, gains in kinetic stability under harsh acidic conditions, compared to parent complexes without the pendant acetate arm, were demonstrated by a half-life seven times longer for the cyclam copper complex. Due to the reversible, high oxidation states available for the Mn and Fe complexes, the Mn and Fe complexes were examined as catalysts for the bleaching of three commonly used pollutant model dyes (methylene blue, methyl orange, and Rhodamine B) in water with hydrogen peroxide as oxidant. The efficient bleaching of these dyes was observed.

Versatile Macrocyclic Platform for the Complexation of [natY/90Y]Yttrium and Lanthanide Ions.

We report a macrocyclic ligand (H3L6) based on a 3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane platform containing three acetate pendant arms and a benzyl group attached to the fourth nitrogen atom of the macrocycle. The X-ray structures of the YL6 and TbL6 complexes reveal nine coordination of the ligand to the metal ions through the six nitrogen atoms of the macrocycle and three oxygen atoms of the carboxylate pendants. A combination of NMR spectroscopic studies (1H, 13C, and 89Y) and DFT calculations indicated that the structure of the YL6 complex in the solid state is maintained in an aqueous solution. The detailed study of the emission spectra of the EuL6 and TbL6 complexes revealed Ln3+-centered emission with quantum yields of 7.0 and 60%, respectively. Emission lifetime measurements indicate that the ligand offers good protection of the metal ions from surrounding water molecules, preventing the coordination of water molecules. The YL6 complex is remarkably inert with respect to complex dissociation, with a lifetime of 1.7 h in 1 M HCl. On the other hand, complex formation is fast (∼1 min at pH 5.4, 2 × 10–5 M). Studies using the 90Y-nuclide confirmed fast radiolabeling since [90Y]YL6 is nearly quantitatively formed (radiochemical yield (RCY) > 95) in a short time over a broad range of pH values from ca. 2.4 to 9.0. Challenging experiments in the presence of excess ethylenediaminetetraacetic acid (EDTA) and in human serum revealed good stability of the [90Y]YL6 complex. All of these experiments combined suggest the potential application of H3L6 derivatives as Y-based radiopharmaceuticals.

Complexation of Mn(II) by Rigid Pyclen Diacetates: Equilibrium, Kinetic, Relaxometric, Density Functional Theory, and Superoxide Dismutase Activity Studies.

We report the Mn(II) complexes with two pyclen-based ligands (pyclen = 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene) functionalized with acetate pendant arms at either positions 3,6 (3,6-PC2A) or 3,9 (3,9-PC2A) of the macrocyclic fragment. The 3,6-PC2A ligand was synthesized in five steps from pyclen oxalate by protecting one of the secondary amine groups of pyclen using Alloc protecting chemistry. The complex with 3,9-PC2A is characterized by a higher thermodynamic stability [log KMnL = 17.09(2)] than the 3,6-PC2A analogue [log KMnL = 15.53(1); 0.15 M NaCl]. Both complexes contain a water molecule coordinated to the metal ion, which results in relatively high 1H relaxivities (r1p = 2.72 and 2.91 mM-1 s-1 for the complexes with 3,6-PC2A and 3,9-PC2A, respectively, at 25 °C and 0.49 T). The coordinated water molecule displays fast exchange kinetics with the bulk in both cases; the rates (kex298) are 140 × 106 and 126 × 106 s-1 for [Mn(3,6-PC2A)(H2O)] and [Mn(3,9-PC2A)(H2O)], respectively. The two complexes were found to be remarkably inert with respect to their dissociation, with half-lives of 63 and 21 h, respectively, at pH = 7.4 in the presence of excess Cu(II). The r1p values recorded in blood serum remain constant at least over a period of 120 h. Cyclic voltammetry experiments show irreversible oxidation features shifted to higher potentials with respect to [Mn(EDTA)(H2O)]2- (H4EDTA = ethylenediaminetetraacetic acid) and [Mn(PhDTA)(H2O)]2- (H4PhDTA = phenylenediamine-N,N,N',N'-tetraacetic acid), indicating that the PC2A complexes reported here have a lower tendency to stabilize Mn(III). The superoxide dismutase activity of the Mn(II) complexes was tested using the xanthine/xanthine oxidase/p-nitro blue tetrazolium chloride assay at pH = 7.8. The Mn(II) complexes of 3,6-PC2A and 3,9-PC2A are capable of assisting decomposition of the superoxide anion radical. The kinetic rate constant of the complex of 3,9-PC2A is smaller by 1 order of magnitude than that of 3,6-PC2A.

Unexpected Trends in the Stability and Dissociation Kinetics of Lanthanide(III) Complexes with Cyclen-Based Ligands across the Lanthanide Series.

We report a detailed study of the thermodynamic stability and dissociation kinetics of lanthanide complexes with two ligands containing a cyclen unit, a methyl group, a picolinate arm, and two acetate pendant arms linked to two nitrogen atoms of the macrocycle in either cis (1,4-H3DO2APA) or trans (1,7-H3DO2APA) positions. The stability constants of the Gd3+ complexes with these two ligands are very similar, with log KGdL values of 16.98 and 16.33 for the complexes of 1,4-H3DO2APA and 1,7-H3DO2APA, respectively. The stability constants of complexes with 1,4-H3DO2APA follow the usual trend, increasing from log KLaL = 15.96 to log KLuL = 19.21. However, the stability of [Ln(1,7-DO2APA)] complexes decreases from log K = 16.33 for Gd3+ to 14.24 for Lu3+. The acid-catalyzed dissociation rates of the Gd3+ complexes differ by a factor of ∼15, with rate constants (k1) of 1.42 and 23.5 M-1 s-1 for [Gd(1,4-DO2APA)] and [Gd(1,7-DO2APA)], respectively. This difference is magnified across the lanthanide series to reach a 5 orders of magnitude higher k1 for [Yb(1,7-DO2APA)] (1475 M-1 s-1) than for [Yb(1,4-DO2APA)] (5.79 × 10-3 M-1 s-1). The acid-catalyzed mechanism involves the protonation of a carboxylate group, followed by a cascade of proton-transfer events that result in the protonation of a nitrogen atom of the cyclen unit. Density functional theory calculations suggest a correlation between the strength of the Ln-Ocarboxylate bonds and the kinetic inertness of the complex, with stronger bonds providing more inert complexes. The 1H NMR resonance of the coordinated water molecule in the [Yb(1,7-DO2APA)] complex at 176 ppm provides a sizable chemical exchange saturation transfer effect thanks to a slow water exchange rate of (15.9 ± 1.6) × 103 s-1.

Tripyridinophane Platform Containing Three Acetate Pendant Arms: An Attractive Structural Entry for the Development of Neutral Eu(III) and Tb(III) Complexes in Aqueous Solution.

We report a detailed characterization of Eu3+ and Tb3+ complexes derived from a tripyridinophane macrocycle bearing three acetate side arms (H3tpptac). Tpptac3- displays an overall basicity (∑ log KiH) of 24.5, provides the formation of mononuclear ML species, and shows a good binding affinity for Ln3+ (log KLnL = 17.5-18.7). These complexes are also thermodynamically stable at physiological pH (pEu = 18.6, pTb = 18.0). It should be noted that the pGd value of Gd-tpptac (18.4) is only slightly lower than that of commercially available MRI contrast agents such as Gd-dota (pGd = 19.2). Moreover, a very good selectivity for these ions over the endogenous cations (log KCuL = 14.4, log KZnL = 12.9, and log KCaL = 9.3) is observed. The X-ray structure of the terbium complex shows the metal coordinated by the nine N6O3 donor set of the ligand and one inner-sphere water molecule. DFT calculations result in two Eu-tpptac structures with similar bond energies (ΔE = 0.145 eV): one structure in which the water is coordinated to the metal ion and one structure in which the water molecule is farther away from the ion, bound to the ligand with an OH-π bond. By detailed luminescence experiments, we demonstrate that the europium complex in aqueous solution presents a hydration equilibrium between nine-coordinate, dehydrated [Eu-tpptac]0 and ten-coordinate, monohydrated [Eu-tpptac(H2O)]0 species. A similar trend is observed for the terbium complex. Despite the presence of this hydration equilibrium, the H3tpptac ligand sensitizes Eu3+ and Tb3+ luminescence efficiently in buffered water at physiological pH. Particularly, the terbium complex displays a long excited-state lifetime of 2.24 ms and an overall quantum yield of 33% with a brightness of 3600 M-1 cm-1. Such features of Ln3+ complexes of H3tpptac indicate that this platform appears to be particularly appealing for the further development of luminescent lanthanide labels.

Differences in the Relaxometric Properties of Regioisomeric Benzyl-DOTA Bifunctional Chelators: Implications for Molecular Imaging.

The bifunctional chelator S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane- N, N', N″, N‴-1,4,7,10-tetraacetate (IB-DOTA) is on paper the most attractive of the commercially available bifunctional chelators for magnetic resonance imaging (MRI) applications. The preserved DOTA scaffold is known to produce extremely kinetically and thermodynamically robust chelates with the Gd3+ ion. Also, ligation through four acetate pendant arms should ensure that the rapid water exchange kinetics so, crucial to the function of an MRI contrast agent are retained. However, upon ligation of the Gd3+ ion, IB-DOTA differentiates into two distinct isomers defined by the positions of the benzylic substituent (corner or side). A relaxometric analysis of these two isomers revealed marked differences in the property and behavior of the two chelates. Most notably the side isomer is found to be substantially more likely to aggregate in aqueous solution than its corner counterpart. This aggregation results in higher relaxivity for the side isomer versus the corner isomer, an observation that potentially obscures the impact of differences in water exchange kinetics between the two isomers. The side isomer is composed of a significant fraction of a twisted square antiprismatic coordination geometry that exchanges water more rapidly than optimal (τM = 7 ns) for maximizing relaxivity. The impact of this excessively fast exchange is not observed in the relaxivity of the side isomer only because in isolation this chelate tumbles much more slowly than the corner isomer. However, this situation is not expected to persist when the chelate is employed in a typical bioconjugate. These results imply that the corner isomer of IB-DOTA may represent a better choice of bifunctional chelator for bioconjugation applications in which a large macromolecule is to be tagged for MRI applications.

Efficient Synthesis of a Family of Bifunctional Chelators Based on the PCTA[12] Macrocycle Suitable for Bioconjugation

PCTA[12] is a 12‐membered tetraaza‐macrocyclic ligand that incorporates a pyridine unit within the macrocyclic ring and three acetate pendant arms. Unlike DOTA and NOTA chelators, PCTA is a recent entry to the field of macrocyclic polyaminocarboxylate ligands available to complex a variety of M2+/M3+ ions for biomedical applications such as diagnostic and radiotherapeutic. Despite the promising properties of its chelates, only a few of bifunctional chelating agents (BFCAs) derived from PCTA have been described so far. Based on our very recent methodology for the preparation of PCTA[12] itself, we report here the efficient synthesis of several BFCAs derived from PCTA bearing a free reactive function group, mainly devoted to conjugation purposes: ester, carboxylic acid, alcohol, aliphatic amine, aromatic amine, maleimide, bromo or azide functions. These functions were introduced either on the 4‐position of the pyridine ring or on the methylene carbon atom of the central acetate chelating arm, while keeping the three carboxylate groups available for metal chelation. Moreover, two of these BFCAs‐PCTA were used for conjugation with a tetrapeptide (cholecystokinin analogue), a bioactive molecule (biotin), or a solid support (silica gel).

Influence of a Pre-organized N-Donor Group on the Coordination of Trivalent Actinides and Lanthanides by an Aminopolycarboxylate Complexant.

The thermodynamic influence of a pre-organized N-donor group on the coordination of trivalent actinides and lanthanides by an aqueous aminopolycarboxylate complexant has been investigated. The synthesized reagent, N-2-methylpicolinate-ethylenediamine-N,N',N'-triacetic acid (EDTA-Mpic), resembles ethylenediamine-N,N,N',N'-tetraacetic acid (EDTA) with a single acetate pendant arm replaced by a 6-carboxypyridin-2-ylmethyl group. The rigid N-donor picolinate functionality has a profound impact on ligand protonation and trivalent f element complexation equilibria, as demonstrated by potentiometric, spectroscopic, and liquid/liquid metal-partitioning studies as well as by molecular dynamics calculations. Relative to diethylenetriamine-N,N,N',N'',N''-pentaacetic acid (DTPA), the ability to preferentially bind trivalent actinides over trivalent lanthanides was moderately lowered due to the presence of the N-(6-carboxypyridin-2-ylmethyl) substituent. The structural modification substantially amplifies the total ligand acidity of EDTA-Mpic. As a result the complexant sustains the metal complexation and efficient An3+ /Ln3+ differentiation in aqueous mixtures of unprecedented acidity for this class of reagents.

Structure and Magnetism of Seven‐Coordinate FeIII, FeII, CoII and NiII Complexes Containing a Heptadentate 15‐Membered Pyridine‐Based Macrocyclic Ligand

A heptadentate macrocyclic ligand, H2L (3,12,18‐triaza‐6,9‐dioxabicyclo[12.3.1]octadeca‐1,14,16‐triene‐3,12‐diacetic acid) with two acetate pendant arms, and its complexes [FeIIIL]ClO4 (1), [FeIIL]·H2O (2), [CoIIL]·H2O (3), and [NiIIL]·H2O (4) were synthesized. The complexes possess an axially compressed pentagonal bipyramidal geometry with the coordination numbers of 7 for 2 and 3, and 6 + 1 for 4. The magnetic susceptibility measurements revealed magnetic anisotropy for compounds 1–4 expressed by axial zero‐field splitting (ZFS) parameters (D = –1.3 cm–1 for 1, –9.6 cm–1 for 2, 29.1 cm–1 for 3, and –8.5 cm–1 for 4), with a rhombic ZFS (E/D = 0, 0.006, 0, and 0.193, respectively). Field‐induced slow relaxation of magnetization was observed for the CoII complex 3 only. The structural and magnetic features of 1–4 were compared with those of similar complexes containing ligand with two 2‐pyridylmethyl pendant arms. Magnetic features of the complexes were also evaluated using theoretical calculations (DFT, CASSCF/NEVPT2).

Effect of the Nature of Donor Atoms on the Thermodynamic, Kinetic and Relaxation Properties of Mn(II) Complexes Formed With Some Trisubstituted 12-Membered Macrocyclic Ligands.

During the past few years increasing attention has been devoted to Mn(II) complexes as possible substitutes for Gd(III) complexes as contrast agents in MRI. Equilibrium (log KMnL or pMn value), kinetic parameters (rates and half-lives of dissociation) and relaxivity of the Mn(II) complexes formed with 12-membered macrocyclic ligands were studied. The ligands were selected in a way to gain information on how the ligand rigidity, the nature of the donor atoms in the macrocycle (pyridine N, amine N, and etheric O atom), the nature of the pendant arms (carboxylates, phosphonates, primary, secondary and tertiary amides) affect the physicochemical parameters of the Mn(II) complexes. As expected, decreasing the denticity of DOTA (to afford DO3A) resulted in a drop in the stability and inertness of [Mn(DO3A)]− compared to [Mn(DOTA)]2−. This decrease can be compensated partially by incorporating the fourth nitrogen atom into a pyridine ring (e.g., PCTA) or by replacement with an etheric oxygen atom (ODO3A). Moreover, the substitution of primary amides for acetates resulted in a noticeable drop in the stability constant (PC3AMH), but it increased as the primary amides (PC3AMH) were replaced by secondary (PC3AMGly) or tertiary amide (PC3AMPip) pendants. The inertness of the Mn(II) complexes behaved alike as the rates of acid catalyzed dissociation increased going from DOTA (k1 = 0.040 M−1s−1) to DO3A (k1 = 0.45 M−1s−1). However, the rates of acid catalyzed dissociation decreased from 0.112 M−1s−1 observed for the anionic Mn(II) complex of PCTA to 0.0107 M−1s−1 and 0.00458 M−1s−1 for the cationic Mn(II) complexes of PC3AMH and PC3AMPip ligands, respectively. In spite of its lower denticity (as compared to DOTA) the sterically more hindered amide complex ([Mn(PC3AMPip)]2+) displays surprisingly high conditional stability (pMn = 8.86 vs. pMn = 9.74 for [Mn(PCTA)]−) and excellent kinetic inertness. The substitution of phosphonates for the acetate pendant arms (DOTP and DO3P), however, resulted in a noticeable drop in the conditional stability as well as dissociation kinetic parameters of the corresponding Mn(II) complexes ([Mn(DOTP)]6− and [Mn(DO3P)]4−) underlining that the phosphonate pedant should not be considered as a suitable building block for further ligand design while the tertiary amide moiety will likely have some implications in this respect in the future.

Expanding the Family of Pyclen-Based Ligands Bearing Pendant Picolinate Arms for Lanthanide Complexation.

We report a detailed characterization of lanthanide complexes with two azaligands based on the pyclen macrocycle containing two picolinate and one acetate pendant arms. The two picolinate arms are attached to either opposite (L3) or adjacent (L4) amine nitrogen atoms of the macrocyclic platform. The X-ray structures of the Yb3+ complexes show nine coordination of the ligand to the metal ion, a situation that is also observed for EuL4 in the solid state. The EuL3 complex forms centrosymmetric dimers in the solid state joined by μ2-η1:η1 carboxylate groups, which results in 10-coordinate Eu3+ ions. The emission spectra of EuL3 measured in H2O and D2O solution reveal the presence of a hydration equilibrium involving a nine-coordinate species lacking inner-sphere water molecules and a monohydrated 10-coordinate species. The Eu3+ complexes present modest emission quantum yields in buffered aqueous solution (Φ = 16 and 22% for EuL3 and EuL4, 0.1 M tris buffer, pH 7.4), while the corresponding Tb3+ complexes present very high emission quantum yields under the same conditions (∼90%). 1H NMR studies show that the complexes of L3 present a fluxional behavior in D2O solution, while those of L4 are more rigid. The analysis of the Yb3+-induced NMR shifts of YbL4 indicates that the complex presents a structure in solution similar to that observed in the solid state. The Gd3+ complexes present very high thermodynamic stability constants (log KGdL = 23.56(2) and 23.44(2) for GdL3 and GdL4, respectively). The corresponding pGd values (pGd = -log[Gd3+]free with cL = 1 × 10-5 M and cGd = 1 × 10-6 at pH 7.4) of 20.69 (GdL3) and 21.83 (GdL4) are higher than that of Gd(dota)- (pGd = 19.21). The Gd3+ complexes also show remarkable inertness with respect to their proton-assisted dissociation, with dissociation half-life times of 50 min (GdL3) and 20 h (GdL4) in 1 M HCl.

Crystal structures of two polymorphic forms of DOTAM-mono-acid dihydrate

The structural chemistry of 2-[4,7,10-tris(carbamoylmethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetic acid dihydrate, C16H31N7O5·2H2O, is described. The macrocyclic compound, also known by the abbreviation DOTAM-mono-acid, crystallized at room temperature and was isolated concomitantly as two polymorphic forms. The structures of both polymorphs were determined at 90 K. The first polymorph crystallized as a zwitterionic dihydrate [systematic name: 4,7,10-tris(carbamoylmethyl)-1-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-ium dihydrate] in the space group P21/n, with Z' = 1. The second polymorph crystallized as a zwitterionic dihydrate in the space group P21 at 90 K, with Z' = 2. The two independent molecules are related by a local center. In each polymorph, the zwitterion is formed between the negatively-charged carboxylate group and the ring N atom that bears the acetate pendant arm. Extensive inter- and intramolecular hydrogen bonding exists in both polymorphic structures. In polymorph 1, an intermolecular hydrogen-bonding network propagating parallel to the a direction creates an infinite chain. A second hydrogen-bonding network is observed through a water molecule of hydration in the b direction. Polymorph 2 also has two intermolecular hydrogen-bonding networks. One propagates parallel to the a direction, while the other propagates in the [-110] direction. Increasing the temperature of polymorph 2 yields the same structure at T = 180 K, but the pseudocenter becomes exact at 299 K. The higher-temperature structure has Z' = 1 in the space group P21/c.

Stable and Inert Yttrium(III) Complexes with Pyclen-Based Ligands Bearing Pendant Picolinate Arms: Toward New Pharmaceuticals for β-Radiotherapy.

We report the synthesis of two azaligands based on the pyclen macrocyclic platform containing two picolinate and one acetate pendant arms. The two ligands differ in the relative positions of the pendant functions, which are arranged either in a symmetrical (L3) or nonsymmetrical (L4) fashion. The complexation properties of the ligands toward natY3+ and 90Y3+ were investigated to assess their potential as chelating units for radiopharmaceutical applications. The X-ray structures of the YL3 and YL4 complexes show nonadentate binding of the ligand to the metal ions. A multinuclear 1H, 13C, and 89Y NMR study shows that the complexes present a structure in solution similar to that observed in the solid state. The two complexes present very high thermodynamic stability constants (log KYL = 23.36(2) and 23.07(2) for YL3 and YL4, respectively). The complexes also show a remarkable inertness with respect to their proton-assisted dissociation, especially YL4. 90Y radiolabeling was proved to be efficient under mild conditions. The 90YL3 and 90YL4 radiochelates were found to be more stable than 90Y(DOTA).

Synthesis and characterization of a novel aminopolycarboxylate complexant for efficient trivalent f-element differentiation: N-butyl-2-acetamide-diethylenetriamine-N,N',N'',N''-tetraacetic acid.

The novel metal ion complexant N-butyl-2-acetamide-diethylenetriamine-N,N',N'',N''-tetraacetic acid (DTTA-BuA) uses an amide functionalization to increase the total ligand acidity and attain efficient 4f/5f differentiation in low pH conditions. The amide, when located on the diethylenetriamine platform containing four acetate pendant arms maintains the octadentate coordination sphere for all investigated trivalent f-elements. This compact coordination environment inhibits the protonation of LnL- complexes, as indicated by lower K111 constants relative to the corresponding protonation site of the free ligand. For actinide ions, the enhanced stability of AnL- lowers the K111 for americium and curium beyond the aptitude of potentiometric detection. Density functional theory computations indicate the difference in the back-donation ability of Am3+ and Eu3+ f-orbitals is mainly responsible for stronger proton affinity of EuL- compared to AmL-. The measured stability constants for the formation of AmL- and CmL- complexes are consistently higher, relative to ML- complexes with lanthanides of similar charge density. When compared with the conventional aminopolycarboxylate diethylenetriamine pentaacetic acid (DTPA), the modified DTTA-BuA complexant features higher ligand acidity and the important An3+/Ln3+ differentiation when deployed on a liquid-liquid distribution platform.

Electrochemical investigation of the Eu3+/2+ redox couple in complexes with variable numbers of glycinamide and acetate pendant arms.

The Eu3+/2+ redox couple provides a convenient design platform for responsive pO2 sensors for magnetic resonance imaging (MRI). Specifically the Eu2+ ion provides T1w contrast enhancement under hypoxic conditions in tissues, whereas, under normoxia, the Eu3+ ion can produce contrast from chemical exchange saturation transfer in MRI. The oxidative stability of the Eu3+/2+ redox couple for a series of tetraaza macrocyclic complexes was investigated in this work using cyclic voltammetry. A series of Eu-containing cyclen-based macrocyclic complexes revealed positive shifts in the Eu3+/2+ redox potentials with each replacement of a carboxylate coordinating arm of the ligand scaffold with glycinamide pendant arms. The data obtained reveal that the complex containing four glycinamide coordinating pendant arms has the highest oxidative stability of the series investigated.

Thermodynamic, Spectroscopic, and Computational Studies of f-Element Complexation by N-Hydroxyethyl-diethylenetriamine-N,N',N″,N″-tetraacetic Acid.

Potentiometric and spectroscopic techniques were combined with DFT calculations to probe the coordination environment and determine thermodynamic features of trivalent f-element complexation by N-hydroxyethyl-diethylenetriamine-N,N',N″,N″-tetraacetic acid, HEDTTA. Ligand protonation constants and lanthanide stability constants were determined using potentiometry. Five protonation constants were accessible in I = 2.0 M (H+/Na+)ClO4. UV-vis spectroscopy was used to determine stability constants for Nd3+ and Am3+ complexation with HEDTTA. Luminescence spectroscopy indicates two water molecules in the inner coordination sphere of the Eu/HEDTTA complex, suggesting HEDTTA is heptadentate. Luminescence data was supported by DFT calculations, which demonstrate that substitution of the acetate pendant arm by a N-hydroxyethyl group weakens the metal-nitrogen bond. This bond elongation is reflected in HEDTTA's ability to differentiate trivalent actinides from trivalent lanthanides. The trans-lanthanide Ln/HEDTTA complex stability trend is analogous to Ln/DTPA complexation; however, the loss of one chelate ring resulting from structural substitution weakens the complexation by ∼3 orders of magnitude. Successful separation of trivalent americium from trivalent lanthanides was demonstrated when HEDTTA was utilized as aqueous holdback complexant in a liquid-liquid system. Time-dependent extraction studies for HEDTTA were compared to diethylenetriamine-N,N,N',N″,N″-pentaacetic acid (DTPA) and N-hydroxyethyl-ethylenediamine-N,N',N'-triacetic acid (HEDTA). The results indicate substantially enhanced phase-transfer kinetic rates for mixtures containing HEDTTA.

Definition of the Labile Capping Bond Effect in Lanthanide Complexes.

Two macrocyclic ligands containing a cyclen unit, a methyl group, a picolinate arm, and two acetate pendant arms attached to two nitrogen atoms of the macrocycle either in trans (1,7-H3 Medo2 ampa = 2,2'-(7-((6-carboxypyridin-2-yl)methyl)-10-methyl-1,4,7,10-tetraazacyclododecane-1,4-diyl)diacetic acid) or in cis (1,4-H3 Medo2 ampa) positions are reported. These ligands provide eight-coordination to the Ln3+ ions, leaving a coordination position available for a water molecule that occupies a capping position in the twisted square antiprismatic polyhedron (1,4-H3 Medo2 ampa) or one of the positions of the square antiprism (1,7-H3 Medo2 ampa). The charge neutral [Gd(1,7-Medo2 ampa)] complex presents an unprecedentedly low water-exchange rate (kex298 =8.8×103 s-1 ), whereas water exchange in [Gd(1,4-Medo2 ampa)] is three orders of magnitude faster (kex298 =6.6×106 s-1 ). These results showcase the labile capping bond phenomenon: A ligand occupying a capping position is hindered by the environment and thus is intrinsically labile.

Physico-chemical properties of MnII complexes formed with cis- and trans-DO2A: thermodynamic, electrochemical and kinetic studies

Synopsis: MnII complexes formed with cis- and trans-DO2A (DO2A=1,4,7,10-tetraazacyclododecane-1,4 (or 1,7) -diacetic acid) chelators were investigated by pH-potentiometry, 1H relaxometry, UV-vis spectrophotometry and cyclic voltammetry. The physico-chemical characteristics of MnII complexes of these structure isomers do not differ dramatically, however the cis-DO2A platform has better potential for further development.Manganese (MnII) is a promising alternative to gadolinium (GdIII) as a magnetic resonance imaging (MRI) agent. Unlike gadolinium, this biogenic metal might be better tolerated by the body, reducing the risk of toxicity associated with dissociation of the complex. Herein we report detailed equilibrium and kinetic studies performed with MnII complexes of 1,4,7,10-tetraazacyclododecane-1,4-diacetic acid (1,4-DO2A or cis-DO2A) and 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (1,7-DO2A or trans-DO2A). The protonation constants of the ligands as well as stability constants of their MnII complexes have been determined by pH-potentiometry. The stability constants of [Mn(cis-DO2A)] are slightly higher than those of [Mn(trans-DO2A)] (log KMnL=15.68 and 15.22, respectively). Cyclic voltammetric (CV) experiments performed on [Mn(cis-DO2A)] and [Mn(trans-DO2A)] revealed quasireversible systems with a half-wave potential of +636 and +705mV versus Ag/AgCl, respectively. These values indicate that the MnII ion in these complexes is more stabilized against the oxidation than in [Mn(EDTA)]2−. The kinetic inertness of the complexes has been studied in transmetallation reactions with CuII or ZnII ions. Kinetic measurements indicate that both MnII complexes primarily undergo acid catalyzed dissociation and positions of the acetate pendant arms do not influence kinetic inertness. The inertness of these complexes is comparable to that of [Mn(NOTA)]− (NOTA=1,4,7-triazacyclononane-1,4,7-triacetic acid) and about twenty times lower than that of [Mn(DOTA)]2− (DOTA=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). In conclusion, [Mn(cis-DO2A)] displays some very interesting features (thermodynamic and redox stability as well as kinetic inertness) which makes this complex a promising platform for the development of more efficient MnII complexes as alternatives to Gd-based MRI agents.