Phosphinate Analogues of Ida and Nta with Low Basicity of Nitrogen Atom: Acid-Base and Complexation Properties

<div><p></p><p>Analogues of iminodiacetic acid (H₂IDA) and nitrilotriacetic acid (H₃NTA) bearing two (hydroxomethyl)methylphosphinate or (2-carboxyethyl)methylphosphinate groups were synthesized. Their acid-base and coordination properties with divalent metal ions (Cu²⁺, Ni²⁺ and Zn²⁺) were studied by potentiometry. The compounds exhibit very low basicity of the amino groups (p<i>K</i>_a = 6.2–7.6) due to presence of two electron-withdrawing methylphosphinate groups and, consequently, a low stability of the complexes. In the case of IDA-analogues, the low complex stability results in precipitation of metal hydroxides in neutral region. As expected, NTA-analogues form more stable complexes and, thus, they were also studied in the alkaline region. Presence of additional carboxylate in the 2-carboxyethylphosphinic acid groups results in the formation of dinuclear complexes. Solid-state structures of two compounds were determined by X-ray diffraction analysis. The compounds are protonated on the nitrogen atom and the structures are stabilized by rich hydrogen bond network.</p></div

Eu(III) Complex with DO3A-amino-phosphonate Ligand as a Concentration-Independent pH-Responsive Contrast Agent for Magnetic Resonance Spectroscopy (MRS)

A new DOTA-like ligand H₅do3aNP with a 2-[amino­(methylphosphonic acid)]­ethyl-coordinating pendant arm was prepared, and its coordinating properties were studied by NMR spectroscopy and potentiometry. The study revealed a rare slow exchange (on the ¹H and ³¹P NMR time scale) between protonated and unprotonated complex species with a corresponding acidity constant p<i>K</i>_A ∼ 8.0. This unusually slow time scale associated with protonation is caused by a significant geometric change from square-antiprismatic (SA) arrangement observed for protonated complex SA-[Eu­(Hdo3aNP)]⁻ to twisted-square-antiprismatic (TSA) arrangement found for deprotonated complex TSA-[Eu­(do3aNP)]^2–. This behavior results in simultaneous occurrence of the signals of both species in the ³¹P NMR spectra at approximately −118 and +70 ppm, respectively. Such an unprecedented difference in the chemical shifts between species differing by a proton is caused by a significant movement of the principal magnetic axis and by a change of phosphorus atom position in the coordination sphere of the central Eu­(III) ion (i.e., by relative movement of the phosphorus atom with respect to the principal magnetic axis). It changes the sign of the paramagnetic contribution to the ³¹P NMR chemical shift. The properties discovered can be employed in the measurement of pH by MRS techniques as presented by proof-of-principle experiments on phantoms

Complexation of Metal Ions with TRAP (1,4,7-Triazacyclononane Phosphinic Acid) Ligands and 1,4,7-Triazacyclononane-1,4,7-triacetic Acid: Phosphinate-Containing Ligands as Unique Chelators for Trivalent Gallium

Three phosphinic acid 1,4,7-triazacyclononane (TACN) derivatives bearing methylphosphinic (TRAP-H), methyl­(phenyl)­phosphinic (TRAP-Ph), or methyl­(hydroxymethyl)­phosphinic acid (TRAP-OH) pendant arms were investigated as members of a new family of efficient Ga³⁺ chelators, TRAP ligands (triazacyclononane phosphinic acids). Stepwise protonation constants of ligands and stability constants of their complexes with Ga³⁺, selected divalent metal, and Ln³⁺ ions were determined by potentiometry. For comparison, equilibrium data for the metal ion–NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) systems were redetermined. These ligands exhibit high thermodynamic selectivity for Ga³⁺ over the other metal ions (log <i>K</i>_GaL – log <i>K</i>_ML = 7–9) and a selective complexation of smaller Mg²⁺ over Ca²⁺. Stabilities of the Ga³⁺ complexes are dependent on the basicity of the donor atoms: [Ga­(NOTA)] (log <i>K</i>_GaL = 29.6) > [Ga­(TRAP-OH)] (log <i>K</i>_GaL = 23.3) > [Ga­(TRAP-H)] (log <i>K</i>_GaL = 21.9). The [Ga­(TRAP-OH)] complex exhibits unusual reversible rearrangement of the “in-cage” N₃O₃ complex to the “out-of-cage” O₆ complex. The in-cage complex is present in acidic solutions, and at neutral pH, Ga³⁺ ion binds hydroxide anion, induces deprotonation and coordination of the <i>P</i>-hydroxymethyl group­(s), and moves out of the macrocyclic cavity; the hypothesis is supported by a combination of results from potentiometry, multinuclear nuclear magnetic resonance spectrometry, and density functional theory calculations. Isomerism of the phosphinate Ga³⁺ complexes caused by a combination of the chelate ring conformation, the helicity of coordinated pendant arms, and the chirality of the coordinated phosphinate groups was observed. All Ga³⁺ complexes are kinetically inert in both acidic and alkaline solutions. Complex formation studies in acidic solutions indicate that Ga³⁺ complexes of the phosphinate ligands are formed quickly (minutes) and quantitatively even at pH <2. Compared to common Ga³⁺ chelators (e.g., 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) derivatives), these novel ligands show fast complexation of Ga³⁺ over a broad pH range. The discussed TRAP ligands are suitable alternatives for the development of ⁶⁸Ga radiopharmaceuticals

Cyclam Derivatives with a Bis(phosphinate) or a Phosphinato–Phosphonate Pendant Arm: Ligands for Fast and Efficient Copper(II) Complexation for Nuclear Medical Applications

Cyclam derivatives bearing one geminal bis­(phosphinic acid), −CH₂PO₂HCH₂PO₂H₂ (H₂<b>L</b>^<b>1</b>), or phosphinic–phosphonic acid, −CH₂PO₂HCH₂PO₃H₂ (H₃<b>L</b>^<b>2</b>), pendant arm were synthesized and studied as potential copper­(II) chelators for nuclear medical applications. The ligands showed good selectivity for copper­(II) over zinc­(II) and nickel­(II) ions (log <i>K</i>_CuL = 25.8 and 27.7 for H₂<b>L</b>^<b>1</b> and H₃<b>L</b>^<b>2</b>, respectively). Kinetic study revealed an unusual three-step complex formation mechanism. The initial equilibrium step leads to <i>out-of-cage</i> complexes with Cu²⁺ bound by the phosphorus-containing pendant arm. These species quickly rearrange to an <i>in-cage</i> complex with cyclam conformation <b>II</b>, which isomerizes to another <i>in-cage</i> complex with cyclam conformation <b>I</b>. The first <i>in-cage</i> complex is quantitatively formed in seconds (pH ≈5, 25 °C, Cu:L = 1:1, <i>c</i>_M ≈ 1 mM). At pH >12, <b>I</b> isomers undergo nitrogen atom inversion, leading to <b>III</b> isomers; the structure of the <b>III</b>-[Cu­(H<b>L</b>^<b>2</b>)] complex in the solid state was confirmed by X-ray diffraction analysis. In an alkaline solution, interconversion of the <b>I</b> and <b>III</b> isomers is mutual, leading to the same equilibrium isomeric mixture; such behavior has been observed here for the first time for copper­(II) complexes of cyclam derivatives. Quantum-chemical calculations showed small energetic differences between the isomeric complexes of H₃<b>L</b>^<b>2</b> compared with analogous data for isomeric complexes of cyclam derivatives with one or two methylphosphonic acid pendant arm(s). Acid-assisted dissociation proved the kinetic inertness of the complexes. Preliminary radiolabeling of H₂<b>L</b>^<b>1</b> and H₃<b>L</b>^<b>2</b> with ⁶⁴Cu was fast and efficient, even at room temperature, giving specific activities of around 70 GBq of ⁶⁴Cu per 1 μmol of the ligand (pH 6.2, 10 min, ca. 90 equiv of the ligand). These specific activities were much higher than those of H₃<b>nota</b> and H₄<b>dota</b> complexes prepared under identical conditions. The rare combination of simple ligand synthesis, very fast copper­(II) complex formation, high thermodynamic stability, kinetic inertness, efficient radiolabeling, and expected low bone tissue affinity makes such ligands suitably predisposed to serve as chelators of copper radioisotopes in nuclear medicine

NOTA Complexes with Copper(II) and Divalent Metal Ions: Kinetic and Thermodynamic Studies

H₃nota derivatives are among the most studied macrocyclic ligands and are widely used for metal ion binding in biology and medicine. Despite more than 40 years of chemical research on H₃nota, the comprehensive study of its solution chemistry has been overlooked. Thus, the coordination behavior of H₃nota with several divalent metal ions was studied in detail with respect to its application as a chelator for copper radioisotopes in medical imaging and therapy. In the solid-state structure of the free ligand in zwitterionic form, one proton is bound in the macrocyclic cavity through a strong intramolecular hydrogen-bond system supporting the high basicity of the ring amine groups (log <i>K</i>_a = 13.17). The high stability of the [Cu­(nota)]⁻ complex (log <i>K</i>_ML = 23.33) results in quantitative complex formation, even at pH <1.5. The ligand is moderately selective for Cu­(II) over other metal ions (e.g., log <i>K</i>_ML(Zn) = 22.32 and log <i>K</i>_ML(Ni) = 19.24). This ligand forms a more stable complex with Mg­(II) than with Ca­(II) and forms surprisingly stable complexes with alkali-metal ions (stability order Li­(I) > Na­(I) > K­(I)). Thus, H₃nota shows high selectivity for small metal ions. The [Cu­(nota)]⁻ complex is hexacoordinated at neutral pH, and the equatorial N₂O₂ interaction is strengthened by complex protonation. Detailed kinetic studies showed that the Cu­(II) complex is formed quickly (millisecond time scale at <i>c</i>_Cu ≈ 0.1 mM) through an <i>out-of-cage</i> intermediate. Conversely, conductivity measurements revealed that the Zn­(II) complex is formed much more slowly than the Cu­(II) complex. The Cu­(II) complex has medium kinetic inertness (τ_1/2 46 s; pH 0, 25 °C) and is less resistant to acid-assisted decomplexation than Cu­(II) complexes with H₄dota and H₄teta. Surprisingly, [Cu­(nota)]⁻ decomplexation is decelerated in the presence of Zn­(II) ions due to the formation of a stable dinuclear complex. In conclusion, H₃nota is a good carrier of copper radionuclides because the [Cu­(nota)]⁻ complex is predominantly formed over complexes with common impurities in radiochemical formulations, Zn­(II) and Ni­(II), for thermodynamic and, primarily, for kinetic reasons. Furthermore, the in vivo stability of the [Cu­(nota)]⁻ complex may be increased due to the formation of dinuclear complexes when it interacts with biometals

Paramagnetic ¹⁹F Relaxation Enhancement in Nickel(II) Complexes of <i>N</i>‑Trifluoroethyl Cyclam Derivatives and Cell Labeling for ¹⁹F MRI

1,8-Bis­(2,2,2-trifluoroethyl)­cyclam (<b>te2f</b>) derivatives with two coordinating pendant arms involving methylenecarboxylic acid (H₂<b>te2f2a</b>), methylenephosphonic acid (H₄<b>te2f2p</b>), (2-pyridyl)­methyl (<b>te2f2py</b>), and 2-aminoethyl arms (<b>te2f2ae</b>) in 4,11-positions were prepared, and their nickel­(II) complexes were investigated as possible ¹⁹F MR tracers. The solid-state structures of several synthetic intermediates, ligands, and all complexes were confirmed by X-ray diffraction analysis. The average Ni···F distances were determined to be about 5.2 Å. All complexes exhibit a <i>trans</i>-III cyclam conformation with pendant arms bound in the apical positions. Kinetic inertness of the complexes is increased in the ligand order <b>te2f2ae</b> ≪ <b>te2f</b> < <b>te2f2py</b> ≈ H₄<b>te2f2p</b> ≪ H₂<b>te2f2a.</b> The [Ni­(<b>te2f2a</b>)] complex is the most kinetically inert Ni­(II) complex reported so far. Paramagnetic divalent nickel caused a shortening of ¹⁹F NMR relaxation time down to the millisecond range. Solubility, stability, and cell toxicity were only satisfactory for the [Ni­(<b>te2f2p</b>)]^2– complex. This complex was visualized by ¹⁹F MRI utilizing an ultrashort echo time (UTE) imaging pulse sequence, which led to an increase in sensitivity gain. Mesenchymal stem cells were successfully loaded with the complex (up to 0.925/5.55 pg Ni/F per cell).¹⁹F MRI using a UTE pulse sequence provided images with a good signal-to-noise ratio within the measurement time, as short as tens of minutes. The data thus proved a major sensitivity gain in ¹⁹F MRI achieved by utilization of the paramagnetic (transition) metal complex as ¹⁹F MR tracers coupled with the optimal fast imaging protocol