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Effect of reaction conditions on preparations of rhenium-188 hydroxyethylidene diphosphonate complexes.

Rhenium-186 (Re-186) hydroxyethylidene diphosphonate (HEDP) has been shown to localize in metastatic foci within bone in a manner similar to Tc-99m bone-seeking agents. Usually, in the preparation of diagnostic Tc-99m radiopharmaceuticals, the concentration of Tc is at trace level (10(-8) M). However, large amounts of carrier are included in the preparation of Re-186 radiopharmaceuticals (10(-4) M), which may significantly affect the preparation of Re-HEDP. In this study, Re-188 was used as an Re tracer. The effects of pH and concentrations of Re carrier on the preparation of Re-HEDP were investigated. Re-188-Sn-HEDP was prepared by reconstitution of a kit of lyophilized HEDP mixture, and tin chloride with a radioactive solution of perrhenate in saline. The total concentration of Re present in this work ranged from 10(-8) to 10(-3) M. The results showed that high labeling efficiency was obtained for each preparation. Although the chemical behaviors of the Re-188 HEDP complexes, with and without carrier, were similar, the biodistribution patterns of carrier free Re-188 HEDP in rats were found to differ from the biodistribution patterns of carrier-added Re-188 HEDP.

Animals↗

Zinc diphosphonates templated by organic amines: syntheses and characterizations of [NH3(CH2)2NH3]Zn(hedpH2)2*2H2O and [NH3(CH2)nNH3(CH2)nNH3]Zn2(hedpH)2*2H2O (n=4,5,6) (hedp=1-hydroxyethylidenediphophonate).

Four new zinc diphosphonate compounds with formulas [NH(3)(CH(2))(2)NH(3)]Zn(hedpH(2))(2).2H(2)O, 1, [NH(3)(CH(2))(n)()NH(3)]Zn(2)(hedpH)(2).2H(2)O, (n = 4, 2; n = 5, 3; n = 6, 4) (hedp = 1-hydroxyethylidenediphosphonate) have been synthesized under hydrothermal conditions at 110 degrees C and in the presence of alkylenediamines NH(2)(CH(2))(n)()NH(2) (n = 2, 4, 5, 6). Crystallographic data for 1: monoclinic, space group C2/c, a = 24.7422(15), b = 5.2889(2), c = 16.0338(2) A, beta = 117.903(1) degrees, V = 1856.17(18) A(3), Z = 4; 2: monoclinic, space group P2(1)/n, a = 5.4970(3), b = 12.1041(6), c = 16.2814(12) A, beta = 98.619(5) degrees, V = 1071.07(11) A(3), Z = 2; 3: monoclinic, space group P2(1)/n, a = 5.5251(2), b = 12.5968(3), c = 16.1705(5) A, beta = 99.182(1) degrees, V = 1111.02(6) A(3), Z = 2; 4: triclinic, space group P-1, a = 5.4785(2), b = 14.1940(5), c = 16.0682(6) A, alpha = 81.982(2) degrees, beta = 89.435(2) degrees, gamma = 79.679(2) degrees, V = 1217.11(8) A(3), Z = 2. In compound 1, two of the phosphonate oxygens are protonated. The metal ions are bridged by the hedpH(2)(2-) groups through three of the remaining four phosphonate oxygens, forming a one-dimensional infinite chain. The protonated ethylenediamines locate between the chains in the lattice. In compounds 2-4, only one phosphonate oxygen is protonated. Compounds 2 and 3 have a similar three-dimensional open-network structure composed of [Zn(2)(hedpH)(2)](n) double chains with strong hydrogen bonding interactions between them, thus generating channels along the [100] direction. The protonated diamines and water molecules reside in the channels. Compound 4 contains two types of [Zn(2)(hedpH)(2)](n) double chains which are held together by strong hydrogen bonds, forming a two-dimensional network. The interlayer spaces are occupied by the [NH(3)(CH(2))(6)NH(3)](2+) cations and water molecules. The significant difference between structures 2-4 is also featured by the coordination geometries of the zinc atoms. The geometries of those in 2 can be described as distorted octahedral, and those in 3 as distorted square pyramidal. In 4, two independent zinc atoms are found, each with a distorted octahedral and a tetrahedral geometry, respectively.

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Hydrothermal synthesis and structure determination from powder data of new three-dimensional titanium(IV) diphosphonates Ti(O(3)P-(CH(2))(n)-PO(3)) or MIL-25(n) (n = 2, 3).

Ti(O(3)P-(CH(2))(n)-PO(3)) or MIL-25(n) (n = 2, 3) were prepared under hydrothermal conditions (4 days, 463 K, autogenous pressure). Their structures were determined ab initio from X-ray diffraction powder data. MIL-25(2) is triclinic (space group P-1 (no. 2)), with a = 5.033(1), b = 5.092(1), c = 6.859(1) A, alpha = 95.860(1) degrees, beta = 99.994(1) degrees, gamma = 118.217(1) degrees, and Z = 2. MIL-25(3) exhibits an orthorhombic symmetry (space group Cm2m (no. 38)), with a = 5.230(1), b = 8.451(1), c = 17.400(2) A, and Z = 4. Their three-dimensional structures are built up from TiO(6) titanium(IV) octahedra linked together via diphosphonate groups. This leads to pillared structures whose inorganic sheets are closely related to those of the alphaTiP titanium phosphate structure.

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Synthesis, characterization, and crystal structures of two divalent metal diphosphonates with a layered and a 3D network structure.

Reactions of N-methyliminobis(methylenephosphonic acid), CH(3)N(CH(2)PO(3)H(2))(2) (H(4)L), with divalent metal acetates under different conditions result in metal diphosphonates with different structures. Mn(H(3)L)(2).2H(2)O (complex 1) with a layer structure was prepared by a layering technique. It is triclinic, P1 macro with a = 9.224(3) A, b = 9.780(3) A, c = 10.554(3) A, alpha = 82.009(6) degrees, beta = 74.356(6) degrees, gamma = 89.853(6) degrees, Z = 2. The Mn(II) ion is octahedrally coordinated by six phosphonate oxygen atoms from four ligands, two of them in a bidentate and two in a unidentate fashion. Each MnO(6) octahedron is further linked to four neighboring MnO(6) octahedra through four bridging phosphonate groups, resulting in a two-dimensional metal phosphonate (002) layer. These layers are held together by strong hydrogen bonds between uncoordinated phosphonate oxygen atoms. The zinc complex Zn(3)(HL)(2) (complex 2) was synthesized by hydrothermal reactions (4 days, 438 K, autogenous pressure). It is monoclinic, P2(1)/n with a = 7.7788(9) A, b = 17.025(2) A, c = 13.041(2) A, beta = 94.597(2) degrees, Z = 4. The structure of complex 2 features a 3D network built from ZnO(4) tetrahedra linked together by bridging phosphonate groups. Each zinc cation is tetrahedrally coordinated by four phosphonate oxygen atoms from four ligands, each of which connects with six zinc atoms, resulting in voids of various sizes. Magnetic measurements for the manganese complex shows an antiferromagnetic interaction at low temperature. The effect of the extent of deprotonation of phosphonic acids on the type of complex formed is discussed.

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Synthesis and characterization of [Mo(7)O(16)(O(3)PCH(2)PO(3))(3)]:(8-) a mixed-valent polyoxomolybdenum diphosphonate anion with octahedrally and tetrahedrally coordinated molybdenum.

Two new compounds containing the title diphosphono-polyoxometalate anion and diprotonated ethylenediamine (enH(2)) or piperazine (ppzH(2)) countercations have been hydrothermally synthesized and structurally characterized ((enH(2))(4)[Mo(7)O(16)(O(3)PCH(2)PO(3))(3)].7H(2)O, triclinic, P(-)1, Z = 2, a = 10.3455(7) A, b = 13.136(1) A, and c = 20.216(3) A, alpha = 93.247(6) degrees, beta = 96.434(6) degrees, and gamma = 111.900(6) degrees; (ppzH(2))(4)[Mo(7)O(16)(O(3)PCH(2)PO(3))(3)].8H(2)O, triclinic, P(-)1, Z = 2, a = 13.255(2) A, b = 13.638(2) A, and c = 16.874(4) A, alpha = 93.20(2) degrees, beta = 101.27(2) degrees, and gamma = 105.87(1) degrees). The anion is a ring of three pairs of edge-sharing octahedra of Mo(V)O(6) (with Mo(V)-Mo(V) bonds) that share corners with each other. The diphosphonate groups connect the pairs at the periphery. The ring is "capped" by a tetrahedron of Mo(VI)O(4). According to magnetic measurements, the compounds are diamagnetic.

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Investigation of the interaction between 1-hydroxyethane-1,1'-diphosphonic acid (HEDP) and uranium(VI).

A detailed study, using a panel of spectroscopic analytical methods, of the complexation between 1-hydroxyethane-1,1'-diphosphonic acid (HEDP) and uranyl ion (UO(2)(2+)) is reported. Results suggest that the metal complex is present as only 1:1 (metal/ligand) species at low concentration (<10(-)(4) M). The conditional constants of this complex were determined at various pH using time-resolved laser-induced fluorescence (TRLIF) and electrospray ionization mass spectrometry (ESI-MS). Further investigations indicate the presence of a 1:2 (metal/ligand) complex at higher concentrations ( approximately 10(-)(2) M). Selectivity studies as well as structural aspects are presented.

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Novel mixed-valence heteropolyoxometalates: a molybdenum diphosphonate anion [MoV7MoVIO16(O3PPhPO3H)4]3- and its one- and two-dimensional assemblies.

A novel mixed-valence polyoxomolybdenum anion, [Mo(V)(7)Mo(VI)O(16)(O(3)PPhPO(3)H)(4)](3)(-), was synthesized hydrothermally from molybdenum oxide, molybdenum metal, boric and phosphoric acids, 1,2-phenyldiphosphonic acid, and imidazole (ImH) and was structurally characterized as an imidazolium salt (orthorhombic, Aba2; a = 16.674(4), b = 17.238(1), and c = 24.81(2) A). One- and two-dimensional structures of this anion and additional molybdenum diphosphonate linkers were assembled as well. They were structurally characterized as their pyridinium (pyH) salts (pyH)(4)[[Mo(V)(7)Mo(VI)O(16)(O(3)PPhPO(3))(2)(O(3)PPhPO(3)H)(2)][Mo(2)O(4)(OH)(HO(3)PPhPO(3)H)]].5H(2)O (monoclinic, P2(1)/c; a = 20.8506(9), b = 22.866(1), and c = 21.1403(9) A; beta = 118.7087(8) degrees ) and (pyH)(3)[[Mo(V)(7)Mo(VI)O(16)(O(3)PPhPO(3))(4)][Mo(2)O(2)(OH)(2)(HO(3)PPhPO(3)H)]].3H(2)O (orthorhombic, Pca2(1); a = 19.057(1), b = 20.402(2), and c = 20.660(2) A). The compounds were also characterized by IR spectroscopy and magnetic measurements.

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One-dimensional cobalt diphosphonates exhibiting weak ferromagnetism and field-induced magnetic transitions.

This paper reports two new cobalt phosphonate compounds [NH3(CH2)nNH3]Co2(hedpH)2.2H2O [n = 4 (1), 5 (2)], where hedp is (1-hydroxyethylidene)diphosphonate [CH3C(OH)(PO3)2]. Both contain ladderlike chains with the same composition [Co2(hedpH)2](n)(2n-), where edge-shared [CoO6] octahedra are each bridged by O-P-O units. The chains are linked by very strong hydrogen bonds to form a three-dimensional open network with channels in which the diammonium counterions and lattice water reside. Magnetic studies reveal dominant antiferromagnetic interactions between the Co centers within the chain in both compounds. The field dependent magnetization confirms the occurrence of the field-induced magnetic transitions, with the critical fields ca. 25 kOe for 1 and 27.5 kOe for 2, respectively. In the case of compound 2, weak ferromagnetism is also observed at very low temperatures, possibly arising from spin canting of the antiferromagnetically coupled Co(II) ions in the chain. Crystal data: 1, monoclinic, P2(1)/c, a = 5.4868(8), b = 12.9116(18), and c = 15.251(2) A, beta = 98.843(2) degrees, V = 1067.6(3) A(3), Z = 2; 2, monoclinic, P2(1)/c, a = 5.4757(7), b = 12.7740(16), and c = 15.794(2) A, beta = 98.797(2) degrees, V = 1091.7(2) A(3), Z = 2.

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Syntheses, structures, and magnetic properties of mixed-valent diruthenium(II,III) diphosphonates with discrete and one-dimensional structures.

Four mixed-valent ruthenium diphosphonates, namely, Na(4)[Ru(2)(hedp)(2)X]x16H(2)O [X = Cl (1), Br (2)], K(3)[Ru(2)(hedp)(2)(H(2)O)(2)]x6H(2)O (3), and Na(7)[Ru(2)(hedp)(2)Fe(CN)(6)]x24H(2)O (4), where hedp represents 1-hydroxyethylidenediphosphonate [CH(3)C(OH)(PO(3))(2)](4-), were synthesized and structurally characterized. Compounds 1, 2, and 4 show linear chain structures in which the mixed-valent [Ru(2)(hedp)(2)](3-) dimers are linked by X(-) or [Fe(CN)(6)](4-) bridges. Compound 3 contains discrete species of [Ru(2)(hedp)(2)(H(2)O)(2)](3-) where the axial positions of [Ru(2)(hedp)(2)](3-) paddlewheel are terminated by water molecules. Magnetic studies show that significant antiferromagnetic exchanges are mediated between the [Ru(2)(hedp)(2)](3-) (S = 3/2) units through halide bridges in compounds 1 and 2.

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Template- and pH-directed assembly of diruthenium diphosphonates with different topologies and oxidation states.

In the presence of organic templates, six diruthenium diphosphonates, namely, [H3N(CH2)3NH3]2[Ru2(hedp)2] (1), [H3N(CH2)4NH3]2[Ru2(hedp)2].4H2O (2), [H3N(CH2)5NH3]2[Ru2(hedp)2].4H2O (3), [H3N(CH2)3NH3][Ru2(hedp)(hedpH)].H2O (4), [H3N(CH2)4NH3][Ru2(hedpH(0.5))2].2H2O (5), and [H3N(CH2)5NH3]2[Ru2(hedp)2][Ru2(hedpH)2]] (6) [hedp = 1-hydroxyethylidenediphosphonate, CH3C(OH)(PO3)2] have been synthesized under hydrothermal conditions. Compounds 1-3 contain homovalent paddlewheel cores of Ru2(II,II)(hedp)2(4-) that are connected through edge-sharing of the [RuO5Ru] octahedra, resulting in infinite linear chains. Compounds 4-6 contain mixed-valent diruthenium(II,III) phosphonate paddlewheel cores of Ru2(II,III)(hedpH(n))2(3-2n)- that are connected by phosphonate oxygen atoms, forming distorted square-grid layers in 4 and 6 or a kagomé lattice in 5. Both the templates and the pH values are found to play important roles in directing the final products with particular topologies and oxidation states of the diruthenium unit. The magnetic studies show that weak antiferromagentic interactions are propagated between the homovalent diruthenium units in compounds 1-3. For compounds 4-6, weak ferromagnetic interactions are observed.

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Mechanism of the Topotactic Formation of gamma-Zirconium Phosphate Covalently Pillared with Diphosphonate Groups.

The topotactic reaction of gamma-ZrPO(4)[O(2)P(OH)(2)].2H(2)O (gamma-ZrP) with benzenediphosphonic acid was examined in water and in acetone-water mixtures. This reaction was found to take place in water only on the external surface of the microcrystals, and pillared compounds were never obtained, even after very long reaction times. On the contrary, covalently pillared compounds were quickly obtained in acetone-water mixtures. The mechanism of the latter topotactic reaction was investigated by determining the rate of the phosphate groups released and the rate of the benzenediphosphonates taken up by gamma-ZrP over a long time (50 days). These data showed that pillared derivatives of gamma-ZrP can be obtained because colloidal dispersions of exfoliated lamellae are formed in acetone-water mixtures. The diphosphonate group acts initially as a monovalent species, replacing only one dihydrogen phosphate group on the surface of the exfoliated gamma-lamellae. The colloidal and partially derivatized lamellae thus formed can interact with each other by forming polylamellar pillared systems. When the number of pillared lamellae exceeds a given value (usually 5-6), flocculation of the colloidal gamma-ZrP takes place. Topotactic reactions between packets of pillared lamellae may also continue in the flocculated system. Therefore, the average number of the pillared lamellae slowly increases over time.

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Template-Directed One- and Two-Dimensional Copper(II) Diphosphonates: Structures and Characterizations of (NH(4))(2)Cu(3)(hedp)(2)(H(2)O)(4), [NH(3)(CH(2))(4)NH(3)]Cu(3)(hedp)(2).2H(2)O, and [NH(2)(C(2)H(4))(2)NH(2)]Cu(3)(hedp)(2) (hedp = 1-Hydroxyethylidenediphosphonate).

Three new copper(II) diphosphonates, (NH(4))(2)Cu(3)(hedp)(2)(H(2)O)(4) (1), [NH(3)(CH(2))(4)NH(3)]Cu(3)(hedp)(2).2H(2)O (2), and [NH(2)(C(2)H(4))(2)NH(2)]Cu(3)(hedp)(2) (3), where hedp = 1-hydroxyethylidenediphosphonate, have been synthesized and characterized by single-crystal structural analysis. Crystal data: 1, monoclinic, P2(1)/n, a = 6.2137(13) Å, b = 14.747(2) Å, c = 11.1802(12) Å, beta = 105.83(2) degrees, Z = 2; 2, triclinic, P&onemacr;, a = 7.4840(12) Å, b = 8.032(3) Å, c = 10.007(2) Å, alpha = 111.68(2) degrees, beta = 96.188(14) degrees, gamma = 96.97(2) degrees, Z = 1; 3, triclinic, P&onemacr;, a = 7.0155(6) Å, b = 8.0904(9) Å, c = 9.2644(11) Å, alpha = 112.611(13) degrees, beta = 90.819(8) degrees, gamma = 92.824(7) degrees, Z = 1. The compound 1 is composed of infinite chains with a ladder-type motif. The compounds 2 and 3 adopt a two-dimensional layer structure which contains four- and eight-membered rings assembled from vertex-sharing {CuO(4)} units and {CPO(3)} tetrahedra. The magnetic properties of 3 have been investigated.

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Self-assembled monolayers of alpha,omega-diphosphonic acids on Ti enable complete or spatially controlled surface derivatization.

Alpha,omega-diphosphonic acids self-assemble on the native oxide surfaces of Ti or Ti-6Al-4V. Heating gives strongly bonded phosphonate monolayers. Infrared and X-ray spectroscopic and water contact angle data show that the films are bonded to the surface by one phosphonate unit; the other remains a phosphonic acid. Surface loadings were measured by quartz crystal microbalance procedures. Mechanical shear strengths for the films were also measured; these do not correlate simply with surface loadings. Films formed from 1,12-diphosphonododecane were treated with zirconium tetra(tert-butoxide) to give surface Zr complex species; derivatives of these surface complexes are stable to hydrolysis under physiological conditions and are mechanically strong. The complexation reaction can be accomplished over the entire surface; alternatively, dropwise application of the alkoxide to the surface enables spatial control of deposition. The cell attractive peptide derivative RGDC can be bound to these surface Zr alkoxide complexes through (maleimido)-alkylcarboxylate intermediates. Surfaces modified with RGDC were shown to be effective for osteoblast binding and proliferation.

Cell Adhesion↗

The interaction of diphosphonates with calcitic surfaces: understanding the inhibition activity in marble dissolution.

The rates of dissolution of calcitic Carrara marble have been reported to be significantly reduced in alkaline pH (pH 8.25) at 25 degrees C in the presence of (1-hydroxyethylidene)-1,1 diphosphonic acid (HEDP). The adsorption takes place at the calcite/water interface at the double layer through the interaction of charged surface species with the charged solution species of the adsorbate. The present work focused on obtaining a better understanding of the interaction of the calcite surface with HEDP. Calculations were performed according to the triple layer model, assuming the formation of surface complexes between the charged surface species of calcite and the species of HEDP dominant at pH 8.25. According to the model, the adsorbed species are located at the inner Helmholtz plane of the electrical double layer. Strong lateral interactions between the adsorbed species were suggested and were corroborated from the calculation of the respective energy, which was equal to 69 kJ mol(-1). The adsorption isotherm was consistent with the proposed model at low surface coverage values, while discrepancies between the values experimentally measured and the predicted were found at higher adsorbate concentrations. The deviations from the predicted values were attributed to the fact that HEDP adsorption on calcite resulted in the formation of multiple layers. The model explained adequately the changes in the zeta-potential values of calcite in the presence of HEDP in the solution which resulted in charge reversal upon adsorption.

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Changes in murine bone marrow macrophages and erythroid burst-forming cells following the intravenous injection of liposome-encapsulated dichloromethylene diphosphonate (Cl2MDP).

In order to explore the effect on bone marrow macrophages of liposome-encapsulated dichloromethylene diphosphonate (Cl2MDP), mice were injected intravenously with a preparation of such liposomes at a dose known to deplete spleen and liver macrophages. Two days later, the macrophages in the marrow of the femoral bones were quantified by flow cytometry using a macrophage-specific monoclonal antibody (F4/80), and their ultrastructure and phagocytic activity towards zymosan particles was assessed. To determine the effect on erythropoiesis of liposome-encapsulated Cl2MDP-induced changes in bone marrow macrophages, red blood cell parameters and the formation of erythroid burst-forming unit (BFU-E)-derived colonies in vitro were evaluated. In mice injected with liposome-encapsulated Cl2MDP, there was a 54% and 67% decrease in the total number of bone marrow macrophages as compared to uninjected controls and mice treated with empty liposomes, respectively. Moreover, residual macrophages showed an abnormal ultrastructure, with reduced numbers of crystalloid inclusions and increased numbers of large myelin figures. However, the phagocytic activity of these cells was unimpaired or slightly enhanced. In mice injected with liposome-encapsulated Cl2MDP there was an approximately 60% decrease in the percentage and total number of circulating reticulocytes and a 54% reduction in the BFU-E number, demonstrating deregulation of erythropoiesis under conditions of macrophage loss and impairment. The results suggest that mice treated with liposome-encapsulated Cl2MDP are a model for studying the role of macrophages in erythropoiesis.

Animals↗

Effect of diphosphonate on crystallization of calcium oxalate in vitro.

Reliable techniques for the calculation of activity product (state of saturation), formation product (limit of metastability) and crystal growth of calcium oxalate were devised. The activity product at saturation was 2.53 times 10 minus 9 M2, and was independent of duration of incubation, solid-to-solution ratio, pH, calcium concentration or ionic strength. These tehcniques were utilized to assess the effect of disodium ethane-1-hydroxy-1, 1-diphosphonate (EHDP) on crystallization of calcium oxalate in an aqueous salt solution in vitro. EHDP increased the formation product of calcium oxalate, indicating an inhibition of nucleation of calcium oxalate. Further, it inhibited the crystal growth of calcium oxalate.

Calcium↗

Value of the 99mTc-methylene diphosphonate bone scan in renal osteodystrophy.

The value of radionuclide bone scanning in the diagnosis of renal osteodystrophy is still debated. In order to re-examine this issue, 25 uremic patients treated by intermittent hemodialysis underwent 99m-Technetium Methylene Diphosphonate (99mTc-MDP) bone scan. They were subdivided into three groups according to quantitative bone histology. Group 1 (N = 8) had pure dialysis osteomalacia, group 2 (N = 7) mixed lesions, and group 3 (N = 10) pure osteitis fibrosa. The scintigraphic studies were interpreted by means of a five point semi-quantitative scale. Using this quantification, all but one group 1 patients had decreased bone tracer uptake, and all patients of group 3 had an increased uptake (chi square test of Yates, P less than 0.001). Among patients of group 2, bone uptake was decreased in the three patients with clearly reduced mineralization front and moderate osteitis fibrosa, but it was increased in all patients with severe osteitis fibrosa and subnormal mineralization front. A quantitative analysis of regional tracer uptake into bone was performed in two patients: one of group 2 and one of group 3. The results obtained clearly corroborated the semi-quantitative findings. Thus, in hemodialysis patients with symptomatic bone disease, the 99mTc-MDP bone scan provides useful information for the differential diagnosis between dialysis-related osteomalacia and secondary hyperparathyroidism. In patients with mixed lesions, the importance of bone tracer uptake appears to depend on the extent of the mineralization front and on the intensity of osteitis fibrosa.

Adult↗