Search

A new efficient and easy method to anchor Gd(III) chelates onto a TiO2 surface in order to prepare a nanoparticulate T1MRI contrast agent is reported. For this purpose, a new ligand, DOTAPP, a DOTA-monoamide derivative containing a phenylphosphonic acid function in the amide side chain, was synthesized. As expected, its Ln(III) complexes exhibit structure analogy to the Ln(III) complexes of DOTA with one water molecule bound in the apical position. The Gd(III)-DOTAPP complex shows similar relaxometric properties as Gd(III) complexes of other DOTA-monoamides. Gd(III)-DOTAPP was anchored onto the surface of nanocrystalline TiO2via its phosphonate moiety. The oxide surface is completely covered by the complexes and a strong interaction between the TiO2 surface and the phosphonate group results in stable chemisorption. The millimolar relaxivity (r1) of the Gd(III)-DOTAPP complex adsorbed on the surface is substantially higher than that of the free (non-anchored) complex.

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 large number of macrocycles is derived from 12 or 14-membered tetraazamacrocycles i.c. “cyclen” and “cyclen” respectively. Here we report synthesis, structure and soluction properties of two polyazamacrocycle ligards 1,4,7,10-tetraazacyclotera decane 1,4,8,11-tetrayl-tetra-methylene tetrakia(phenylphoshinic acid) II.

We have recently described a technique for the generation of alkyl metaphosphates, ROPO2, by thermolysis of phosphoramidic acids of structure ROP(O)(OH)NHR (1) [1]. We have now successfully shown that alkyl metathiophosphates, ROP(S)(O), which have received but little previous consideration [2], can be generated by the same approach. Compounds 2 (Ad = 1-adamantyl) and 3 were synthesized for this study. Both were easily fragmented on heating in an inert solvent. When an alcohol trapping agent was present each gave EtO-P(S)(OR)(OH) consistent with EtOP(S)(O) as an intermediate. In the absence of a trap, 2 was cleanly converted to the pyrophosphate derivative 4 in a process established to follow first-order kinetics, thus proving that decomposition of 2 proceeded by elimination of EtOP(S)(O). Compound 3 decomposed by mixed first and second order kinetics, and gave a more complex mixture of products. EtOP(S)(O) generated from 2 phosphorylated the OH groups on the surface of silica gel, a process prev...

Ethylenediamine-tetrakis- [methylene(phenylphosphinic)] acid, piperidine [methylenephosphinio] acid and piperasine-bis- thylenephoaphinic] acid have been prepared by the method of Plaza and Grim1 and Meier2. Their dissociation constants and stability constants with Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Fe2+, Co2+ and Ni2+ have been determined. Study of the dependence of the 1H, 31P and 13C NMR spectra of solutions of the acids mentioned above on the pH indicates similarity to amino acids than to analogous phosphonic acids.

The dissociation constants of ethylenediamine-tetrakis-[methylene(phenylphosphinic)] acid (H4edtmpPh) and its stability constants with Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Fe2+, Co2+ and Ni2+ have been determined. Study of the dependence of the 1H, 31P and 13C NMR spectra of H4edtmpPh solutions on the pH indicates that it is more similar to H4edta than to analogous phosphonic acids.

Cyclam derivatives bearing one geminal bis-(phosphinic acid), −CH2PO2HCH2PO2H2 (H2L1), or phosphinic−phosphonic acid, −CH2PO2HCH2PO3H2 (H3L2), 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 KCuL = 25.8 and 27.7 for H2L1 and H3L2, respectively). Kinetic study revealed an unusual threestep complex formation mechanism. The initial equilibrium step leads to out-of-cage complexes with Cu2+ bound by the phosphorus-containing pendant arm. These species quickly rearrange to an in-cage complex with cyclam conformation II, which isomerizes to another in-cage complex with cyclam conformation I. The first in-cage complex is quantitatively formed in seconds (pH ≈5, 25 °C, Cu:L = 1:1, cM ≈ 1 mM). At pH >12, I isomers undergo nitrogen atom inversion, leading to III isomers; the structure of the III-[Cu(HL2)] complex in the solid state was confirmed by X-ray diffraction analysis. In an alkaline solution, interconversion of the I and III 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 H3L2 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 H2L1 and H3L2 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 H3nota and H4dota 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.

A series of aminomethylphosphinic acids H2NCH2PRO2H (R = H, Me, But or Ph) was synthesized and the acid–base and complexing properties with CoII, NiII and CuII were determined pH-metrically (25 °C, 0.1 mol dm–3 KNO3). The pKa values were found to increase from R = H to Ph, Me and But, as the –I effect decreases. The complex stability constants lie in the same order, except for R = H. The compound H2NCH2PHO2H (HL1) exhibits higher values than the ligands with methyl or phenyl substituents, probably due to better deformability of the PHO2– group and its better ability to form chelate rings. The complexes of H2NCH2P(Ph)O2H (HL4), H2NCH2P(Me)O2H (HL2) and H2NCH2P(But)O2H (HL3) with several transition metals were prepared and the crystal structures of [CuL42]1 and [Cu3L24][ClO4]22 were determined. The formation of chelate rings was observed in both structures; 1 forms dimers and 2 polymeric layers via the phosphinates.

Complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayltetramethylenetetrakis(phenylphosphinic acid) H4L1 with yttrium and a number of lanthanides were synthesized and the crystal structures of Li[LaL1(H2O)]·10H2O and Li[CeL1(H2O)]·10H2O determined. The complexes are isostructural with RSRS configurations at the phosphorus atoms. The ligand is co-ordinated by four nitrogen atoms in a plane and by four phosphinate oxygen atoms in a parallel plane. The planes form a twisted square prismatic co-ordination sphere. A molecule of water capping the O4 plane completes the co-ordination sphere of both ions. Solution properties of the complexes were investigated by 1H and 31P NMR. In solution six possible isomers with different configurations on phosphorus atoms are in equilibrium. The most abundant shows the RRRS configuration. A dynamic behavior similar to lanthanide complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid is not observed. The NMR as well as luminescence measurements show that no water molecule is co-ordinated directly to the lanthanide ions in solution. The ions Li+and Na+ form stable ion pairs with the complexes in methanol-d4 solution as confirmed by the lanthanide induced shift of 7Li and 23Na resonances in the presence of paramagnetic lanthanide ions. The ion pairs are not stable in aqueous solution. The alkali metal ion is located close to fourfold magnetic axes of the complexes above the oxygen atoms and between the phenyl rings. Luminescence spectra of [LnL1]–, Ln = Eu or Tb, indicate low symmetry of the species and co-ordination number 8.

A novel bimodal fluorescence/MRI probe based on a cyclodextrin scaffold has been synthesized and characterized. The final agent employs the fluorescein (F) functionality as a fluorescence marker and the Gd(III) complex of a macrocyclic DOTA-based ligand (GdL) having one aminobenzyl-phosphinic acid pendant arm as an MRI probe, and has a statistical composition of (GdL)(6.9)-F(0.1)-beta-CD. Slow rotational dynamics (governed by a very rigid cyclodextrin scaffold) combined with fast water exchange (ensured by the chosen macrocyclic ligand) resulted in a high relaxivity of approximately 22 s(-1) mM(-1) per Gd(III) or approximately 150 s(-1) mM(-1) per molecule of the final conjugate (20 MHz, 25 degrees C). In vitro labelling of pancreatic islets (PIs) and rat mesenchymal stem cells has been successfully performed. The agent is not cytotoxic and is easily internalized into cells. The labelled cells can be visualized by MRI, as proved by the detection of individual labelled PIs. A fluorescence study performed on mesenchymal stem cells showed that the agent stays in the intracellular space for a long time.

A study of the dependence of the 1H, 31P and 13C NMR spectra of D2O solutions of piperidinomethylphosphinic acid (HL1) and piperazine-1,4-diylbis(methylene)bis(phosphinic acid)(H2L2) on the pH has indicated a strong acidity of the phosphinic groups and a low basicity of the nitrogen atoms. It is confirmed that the acids from zwitterions in aqueous solution and that the HL1 ring behaves similarly to the N-methylpiperidine ring. The stability constants of complexes formed with Mg2+, Ca2+, Pb2+, Co2+, Ni2+, Cu2+, Cd2+ and Zn2+ are lower than those of their acetic or phosphonic acid analogues. In the solid state, HL1·H2O exists as a zwitterion, monoclinic, space group P21/n, a= 6.884(2), b= 11.485(2), c= 11.994(2)A and β= 97.87(2)°. Two molecules are linked by hydrogen bonds into dimers which are connected by water molecules to form endless chains.

International audience; Mn(2+) complexes represent an alternative to Gd(3+) chelates which are widely used contrast agents in magnetic resonance imaging. In this perspective, we investigated the Mn(2+) complexes of two 12-membered, pyridine-containing macrocyclic ligands bearing one pendant arm with a carboxylic acid (HL(1), 6-carboxymethyl-3,6,9,15-tetraazabicyclo[9.3.1] pentadeca-1(15),11,13-triene) or a phosphonic acid function (H(2)L(2), 6-dihydroxyphosphorylmethyl-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene). Both ligands were synthesized using nosyl or tosyl amino-protecting groups (starting from diethylenetriamine or tosylaziridine). The X-ray crystal structures confirmed a coordination number of 6 for Mn(2+) in their complexes. In aqueous solution, these pentadentate ligands allow one free coordination site for a water molecule. Potentiometric titration data indicated a higher basicity for H(2)L(2) than that for HL(1), related to the electron-donating effect of the negatively charged phosphonate group. According to the protonation sequence determined by (1)H and (31)P pH-NMR titrations, the first two protons are attached to macrocyclic amino groups whereas the subsequent protonation steps occur on the pendant arm. Both ligands form thermodynamically stable complexes with Mn(2+), with full complexation at physiological pH and 1:1 metal to ligand ratio. The kinetic inertness was studied via reaction with excess of Zn(2+) under various pHs. The dissociation of MnL(2) is instantaneous (at pH 6). For MnL(1), the dissociation is very fast (k(obs) = 1-12 × 10(3) s(-1)), much faster than that for MnDOTA, MnNOTA, or the Mn(2+) complex of the 15-membered analogue. It proceeds exclusively via the dissociation of the monoprotonated complex, without any influence of Zn(2+). In aqueous solution, both complexes are air-sensitive leading to Mn(3+) species, as evidenced by UV-vis and (1)H NMRD measurements and X-ray crystallography. Cyclic voltammetry gave low oxidation peak potentials (E(ox) = 0.73 V for MnL(1) and E(ox) = 0.68 V for MnL(2)), in accordance with air-oxidation. The parameters governing the relaxivity of the Mn(2+) complexes were determined from variable-temperature (17)O NMR and (1)H NMRD data. The water exchange is extremely fast, k(ex) = 3.03 and 1.77 × 10(9) s(-1) for MnL(1) and MnL(2), respectively. Variable-pressure (17)O NMR measurements have been performed to assess the water exchange mechanism on MnL(1) and MnL(2) as well as on other Mn(2+) complexes. The negative activation volumes for both MnL(1) and MnL(2) complexes confirmed an associative mechanism of the water exchange as expected for a hexacoordinated Mn(2+) ion. The hydration number of q = 1 was confirmed for both complexes by (17)O chemical shifts. A relaxometric titration with phosphate, carbonate or citrate excluded the replacement of the coordinated water molecule by these small endogenous anions.

A series of phosphonodipeptides containing glycyl, L-alanyl, L-leucyl, or L-phenylalanyl and a terminal aminomethylphosphonic acid residue was studied pH-metrically at 25 °C and at an ionic strength of 0.1 mol dm–3(KNO3), and their protonation and complex-formation stability constants with Co2+, Ni2+, Cu2+ and Zn2+ were determined. The protonation constants show the same dependence on the side chain as those of common dipeptides but the differences are not as large. The stability constants point to the formation of protonated, non-protonated and deprotonated complexes with a metal:ligand molar ratio of 1:1 and, except for zinc, to the formation of 1:2 complexes. Simultaneous deprotonation and co-ordination of the peptide amide bond was confirmed only for Cu2+. The same influence of the size of the amino acid side chain as found for common dipeptides was observed but the differences are smaller due to the stronger complexing ability of the phosphonic group.

1-Alkyl and 1,8-dialkyl-1,4,8,11-tetraazacyclotetradecanes (alkyl = benzyl or methyl) were synthesised through cis-aminal of cyclam which was obtained by reaction of glyoxal and cyclam. The corresponding trans-aminal was synthesised from the respective linear tetraamine and glyoxal followed by cyclisation using 1,2-dibromoethane. The trans-aminal derivatives cannot be used for preparation of cyclam or its derivatives due to exceptional stability of the aminal bridge. The different reactivity of both cis- and trans-aminals is discussed on the basis of the X-ray structures determined for a series of the cyclam derivatives and could be explained by steric hindrance in the trans-aminals.

Phosphinic acid analogues of Gly-Gly, NH2CH2CONHCH2-P(R)O2H (R = Me, Ph, t-Bu), were synthesised by the active ester method from free aminomethylphosphinic acids purified on cation exchange resins. The crystal and molecular structure was determined for Gly–Gly(PPh)·H2O (R = Ph). The results point to similar bond parameters as were found for Gly–Gly and its phosphonic analogue Gly–Gly(P).

The complexing properties of aminomethylphosphonic acid, Gly-(P), and glycylaminomethylphosphonic acid, Gly-Gly-(P), with Pt II and Pd II were investigated pH-metrically at 25 °C and at an ionic strength of 0.1 mol dm -3 (KNO 3 ) using ‘out of cell’ titrations. The stability constants calculated indicate formation of complexes with a metal∶ligand molar ratio of 1∶1 and 1∶2. The species and their distribution determined pH-metrically were confirmed by 31 P and 1 H NMR titrations. Comparison of our results for Gly-(P) and Gly-Gly-(P) with those for glycine and glycylglycine and other common dipeptides shows that the complexing properties of Pd II and Pt II towards both types are very similar.