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Three compounds that are based on cyclen and contain three methylphosphonate pendant arms ? (1,4,7,10-tetraazacyclododecane-1,4,7-triyl)tris(methylene)trip hosphonic acid (H6do3p), 3-{4,7,10-tris[(dihydroxyphosphoryl)methyl]-1,4,7,10-tetraazacy clododecan-1-yl}propanoic acid (H7do3p1pr) and [10-(3-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triy l]tris(methylene)triphosphonic acid (H6do3p1ol) ? were synthesized and characterized. X-ray crystal structures were determined for H6do3p and for the complex [Cu(H2O)6]2+[Cu(H2O)(H4dotp)]2 of a related ligand H8dotp [H8dotp = (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrakis(methy lene)tetraphosphonic acid]. They show the copper(II) centre coordinated only to the four amines of the macrocycle and one water molecule in the apical position. The acidbase properties of the three compounds were studied in aqueous solution by potentiometry and 31P NMR spectroscopy. All ligands exhibit very high basicity and their protonation schemes are dominated by proton relocations between the basic sites and intramolecular hydrogen bonding. The thermodynamic stability constants for complexes of the three ligands with Cu2+ and Zn2+ metal ions were determined by potentiometry and exhibit very high values for the complexes of Cu2+. UV/Vis spectroscopy was used to assess the acid-assisted dissociation of the Cu2+ complexes and showed that the dissociation rates are faster than for the corresponding complex of H8dotp, whereas the [Cu(do3p1ol)]4 complex is the most inert one in this series.

Polyamidoamine dendrimers (PAMAMs) of generations 1 (G1) and 4 (G4) were conjugated with a bifunctional pyridine- N -oxide DOTA analog, 10-[(4-carboxy-1-oxidopyridin-2-yl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (H 4 do3a-py NO−C ), through the pyridine-4-carboxylic acid group, and the conjugates were radiolabeled with indium-111. Reaction conditions for the radiolabelling were optimized. Both radiolabeled conjugates, G1-[ 111 In(do3a-py NO−C )] and G4-[ 111 In(do3a-py NO−C )], were kinetically stable for at least 48 h after preparation; in the presence of competitive ligands, the radiochemical purity of the conjugates slightly decreased (4–7%) over the same time period. The preclinical pharmacokinetics of both agents were evaluated. Biodistribution and elimination in rats were more favorable for the G1-[ 111 In(do3a-py NO−C )] conjugate than G4-[ 111 In(do3a-py NO−C )] conjugate. However, the G1-[ 111 In(do3a-py NO−C )] conjugate was rapidly eliminated from the body, mainly through urine, while, significant and long-term radioactivity uptake in the liver and kidney was observed for the G4-[ 111 In(do3a-py NO−C )] conjugate.

Multimodal imaging-therapeutic nanoprobe TiO(2)@RhdGd was prepared and successfully used for in vitro and in vivo cell tracking as well as for killing of cancer cells in vitro. TiO(2) nanoparticles were used as a core for phosphonic acid modified functionalities, responsible for contrast in MRI and optical imaging. The probe shows high (1)H relaxivity and relaxivity density values. Presence of fluorescent dye allows for visualization by means of fluorescence microscopy. The applicability of the probe was studied, using mesenchymal stem cells, cancer HeLa cells, and T-lymphocytes. The probe did not exhibit toxicity in any of these systems. Labeled cells were successfully visualized in vitro by means of fluorescence microscopy and MRI. Furthermore, it was shown that the probe TiO(2)@RhdGd can be changed into a cancer cell killer upon UV light irradiation. The above stated results represent a valuable proof of a principle showing applicability of the probe design for diagnosis and therapy.

The first systematic study of chemical adsorption/desorption of phosphonic acid and geminal bis(phosphonic acid) on/from the surface of anatase nanoparticles is reported. Stable TiO2 colloidal nanodispersions were used in the study. The colloidal stability is preserved upon nanoparticle modification. A macrocyclic lanthanide(III) complex, attached through a phosphonic/bis(phosphonic) group to the TiO2 surface allowed precise quantification of sorption parameters by means of inductively coupled plasma atomic emission spectroscopy (ICP-AES). Results show different behavior of phosphonate and bis(phosphonate) groups. For phosphonate, a monomolecular layer formation was observed, and the desorption rate depends on the sorption conditions. It is probably caused by different phosphonate binding modes on the surface. Excess amounts of phosphate in the washing media accelerates the desorption rate of the phosphonate. The bis(phosphonate) is adsorbed on the surface in large quantities forming multilayers that resist desorption even in the presence of phosphate ions and, thus, the bis(phosphonate) moiety is a suitable group for anchoring other molecules on the TiO2 particle surface.

Potentiometric titrations and 1H NMR spectroscopic studies of amino acids binding to the [ZnL]2+-complex where L = cyclen in aqueous solution provide information concerning complexing species identity, their stability, and coordination mode declaration. The amino acids form stable ternary [ZnL(HLn)]2+ and [ZnL(Ln)]+ complexes. The observations indicate bidentate coordination mode of the deprotonated amino acids, involving both the amine and the carboxylate functions to the [ZnL]2+ complex in pH region of about 7.5–9.5. The determined stability constants indicate that [ZnL]2+ complex is a very efficient receptor for simple amino acids such as glycine and alanine. Copyright © 2010 John Wiley & Sons, Ltd.

A new cyclam-based ligand, [4,8,11-tris(phosphonomethyl)-1,4,8,11-tetraazacyclotetradec-1-yl]acetic acid (H7te3p1a) was synthesised and characterised. The potentiometricand 31P NMR spectroscopic titrations of the complexes inan aqueous solution at an ionic strength of 0.10 or0.50 mol dm–3 in [N(CH3)4]NO3, respectively, indicated that the ligand is highly basic. The stepwise protonations were dominated by extensive proton relocations and were influenced by the intramolecular hydrogen bonds. The thermodynamic stability constants for the complexes formed by H7te3p1a in the presence of metal ions were determined by potentiometric titrations. The Cu2+ complexes exhibited very high stability, those of Zn2+, Cd2+, Pb2+, La3+, Sm3+, Gd3+, Ho3+ and Lu3+ presented high stability while that of Ca2+ had lower stability, as expected. The ligand and its complexes behaviour is similar to that of the tetrakis(phosphonomethyl)cyclam derivative, H8tetp. The NMR spectroscopic studies of the Zn2+ and Cd2+ complexes pointed to the involvement of the three phosphonate moieties in the coordination of the latter ion, while several isomer species were generally present in solution for the Zn2+ complex. A major isomer was stabilised in solution upon heating. In this isomer only one of the methylphosphonate arms was coordinated to the metal centre and this isomer probably adopts a distorted square pyramidal geometry with the macrocyclic ring in the type I conformation.

International audience; This work intends to investigate samarium and holmium complexes with a set of H4dota-analogues bearing methylphosphonate/methylphosphinic acid pendant arms (H5do3ap, H5do3apPrA and H4do3apABn) as new bifunctional ligands for radiolanthanide targeted therapy. Radiolanthanide complexes of these ligands were prepared and evaluated and thermodynamic solution studies were also performed to get a better insight on the radiochemical results. The radiocomplexes were quantitatively prepared, are hydrophilic and negatively charged. They present a high in vitro and in vivo stability, a low plasma protein binding and a rapid clearance from the main organs with a high rate of whole body radioactivity excretion. Stability constants with Sm(III) and Ho(III) were determined by potentiometry and the values found are very high for all the ligands. Actually, they are similar to those of H4dota for the phosphinate analogues and even higher for the phosphonate ligand, being the constants similar to those with other lanthanide(III) ions. The effect of methylphosphorus acid pendant arms functionalization and the use of these ligands as bifunctional chelate agents are discussed. Copyright © 2009 John Wiley & Sons, Ltd.

Synthesis and characterization of a series of novel Zn–cyclen–aminoacid complexes are reported and non-covalent interactions were used for the conformation changes description. In addition to the TRANS-I ++++ (same position of NH hydrogen atoms in both isomers) configuration we observed two different isomers in the case of the [{Zn(Δ-cyclen)(HGly)}{Zn(Λ-cyclen)(HGly)}](ClO4)4 · 2H2O (1), [{Zn(Δ-cyclen)(S-HPhe)}{Zn(Λ-cyclen)(S-HPhe)}](ClO4)4 (2) and [Zn(Δ-cyclen)(S-HAla)](ClO4)2 (3) complexes with pentacoordinated zinc atom. Moreover, work also deals with the correlation between spectral and structural properties of the prepared complexes and their thermal stability.

Bis(phosphonic) acid derivative of cyclam was synthesized by an improved synthesis. Thermodynamic stability of divalent metal complexes was determined. Formation and decomplexation kinetics of complexes with divalent copper, zinc and cadmium was investigated.

A bifunctional ligand, DO3A-py(NO-C) (DO3A-py(NO-C) = 10-[(4-carboxy-1-oxidopyridin-2-yl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid), was attached to different generations (G0, G1, G2, and G4) of ethylenediamine-cored PAMAM dendrimers (PAMAM = polyamidoamine). The gadolinium(III) complex of this ligand possesses one molecule of water in its first coordination sphere and has a unique combination of a short water residence lifetime (tau(M) = 34 ns), a neutral overall charge, and a possibility for rigid attachment to molecules bearing primary amino groups. These favorable properties predestine the ligand for constructions of highly efficient nanosized contrast agents for magnetic resonance imaging (MRI). The coupling reaction between the carboxylic group on the pyridine-N-oxide moiety of the protected ligand molecule and primary amines in the dendrimers was achieved by an active ester method under nonaqueous conditions using the coupling agent TBTU. This reaction afforded conjugates with high loadings (80-100% of the theoretically available primary amines) and of high purity. The gadolinium(III) complexes of the conjugates were studied by variable-temperature 17O NMR and 1H NMRD measurements. The water residence lifetime (tau(M) = 55 ns) found in the largest conjugate G4-[Gd(H2O)(do3a-py(NO-C))]57, though somewhat longer compared to the "monomeric" complex, is still short enough not to limit the relaxivity. Surprisingly, compared with analogous conjugates with negatively charged chelates, the prepared uncharged compounds displayed much faster global rotational correlation times (tau(g)) and lower relaxivities. This phenomenon can be explained on the basis of Coulomb interactions. The motion of the charged chelates is restrained due to interactions with their counterions and the chelates themselves, while the uncharged chelates are not affected. Comparison of the PAMAM-based conjugates bearing uncharged and (1-)-charged chelates based on relaxometric data, 1H DOSY spectra, and SAXS measurements reveals that tau(g) reflects the rotational motion of large segments (dendrons) of the conjugates rather than that of the whole macromolecule.

In this study, the complexation rates of two new phosphinate H 4 dota (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) analogs, H 5 do3ap PrA and H 4 do3ap ABn , and H 4 dota itself were compared under identical conditions (H 5 do3ap PrA =10-{[(2-carboxyethyl)hydroxyphosphoryl]methyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid; H 4 do3ap ABn =10-{[(4-aminophenyl)hydroxyphosphoryl]methyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid). The biodistribution of their 111 In and 90 Y complexes in healthy rats was also studied. Unlike the observation obtained under “chemical” conditions where differences between the ligands were observed no such differences in complexation rates were found under radiochemical conditions. The ligands bind the radiometals similarly to H 4 dota. So, “chemical” formation kinetic data should be transferred into radiochemical conditions only with high care and “radiochemical” complexation experiments should be run as part of standard in vitro studies with new ligands considered as potential radiopharmaceuticals. Pharmacokinetic studies in rats showed similar distribution characteristics for both phosphinate H 4 dota analogs radiolabelled with 111 In and 90 Y when compared with that of the 111 In–H 4 dota complex. No specific uptake in any organ and tissue of rats was determined. The phosphinate complexes are not accumulated in calcified tissues.

Five DOTA-like ligands lacking a water molecule in the first coordination sphere of their Gd III complexes, namely the phosphinates H 4 DOTP H , H 4 DOTP hm and H 4 DOTP Et , and the phosphonate monoesters H 4 DOTP OEt and H 4 DOTP OBu , were synthesized with the aim of exploring the influence of the second hydration sphere on the relaxivity of Gd III complexes. The H 4 DOTP H , H 4 DOTP hm and H 4 DOTP OEt ligands and their Ln III complexes were characterized by potentiometry and time-resolved luminescence; the Gd III complexes are thermodynamically much less stable than that of H 4 DOTA, and no water is coordinated in the inner sphere. The crystal structures of the free ligand H 4 DOTP OEt and of the Gd III complexes of H 4 DOTP H and H 4 DOTP OEt were determined by X-ray diffraction. The complexes have the expected octadentate coordination mode with an N 4 O 4 arrangement; no water molecule is bound to the Gd III ion. Information on the structures of the Ln III complexes of all five ligands in aqueous solution were obtained from 1 H and 31 P NMR spectra. The NMR spectra of the [Ln(DOTP hm )]- and [Ln(DOTP Et )]- complexes show that these compounds have a clear preference for a specific arrangement of phosphorus atoms which gives rise to the symmetrical RRRR (or SSSS) isomer. However, many diastereoisomers were observed for all other complexes. Ln III -induced 17 O NMR shift data reveal that the spatial location of the second-sphere water molecules for the two groups of complexes differs. The parameters governing the effect of the second hydration sphere on the relaxivity of the Gd III complexes of all ligands were evaluated by EPR, variable-temperature 17 O NMR spectroscopy and 1 H NMRD re-laxometry. The presence of second-sphere water molecules is clearly confirmed, depending on the character of the pendant arms. As the relaxivity does not depend significantly on the nature of the phosphorus substituents and/or on the isomerism present in solution, the second-sphere water molecules should be located close to the phosphorus-oxygen atoms.

A new bifunctional cyclen-based ligand, 3-[hydroxy({4,7,10-tris[( TERT-butoxycarbonyl)methyl]-1,4,7,10-tetraazacyclododecan-1-yl}methyl)phosphoryl]propanoic acid, was synthe-sized by alkylation of tri- TERT-butyl 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate ( T-Bu 3 DO3A) by ethyl 3-{ethoxy[(mesyloxy)methyl]phosphoryl}propanoate [MsOCH 2 P(O)(OEt)CH 2 CH 2 CO 2 Et]. The ethyl carboxylate group in the side chain was selectively deprotected to obtain the esterified bifunctional ligand. More efficient syntheses of some phosphinopropanoic acid derivatives were devised and the phosphorus alkylation reagent was prepared starting from hypophosphorus acid or its salt.

The dissociation kinetics of cerium(III) complexes with H 8 dotp ( I = 3.0 mol dm −3 (Na,H)ClO 4 , t = 25–60 °C) was studied by means of molecular absorption spectroscopy in the UV region. The mechanism of the proton-assisted reaction was proposed, and the activation parameters ( E a = 111 ± 20 kJ mol −1 , Δ H ≠ = 108 ± 20 kJ mol −1 , Δ S ≠ = 32 ± 62 J K −1 mol −1 ) for the rate-determining step were calculated.

The adsorption on hydroxyapatite of three conjugates of a bisphosphonate and a macrocycle having C1, C2, and C3 spacers and their terbium complexes was studied by the radiotracer method using 160Tb as the label. The radiotracer-containing complex of the conjugate with the C3 spacer was used as a probe for the determination of the adsorption parameters of other bisphosphonates that lack a DOTA unit. A physicochemical model describing the competitive adsorption was successfully applied in the fitting of the obtained data. The maximum adsorption capacity of bisphosphonates containing bulky substituents is determined mainly by their size. For bisphosphonates having no DOTA moiety, the maximum adsorption capacity is determined by the electrostatic repulsion between negatively charged bisphosphonate groups. Compounds with a hydroxy or amino group attached to the alpha-carbon atom show higher affinities. Macrocyclic compounds containing a short spacer between the different bisphosphonic acid groups and the macrocyclic unit exhibit high affinities, indicating a synergic effect of the bisphosphonic and the macrocyclic groups during adsorption. The competition method described uses a well-characterized complex and allows a simple evaluation of the adsorption behavior of bisphosphonates. The application of the macrocycle-bisphosphonate conjugates allows easy radiolabeling via complexation of a suitable metal isotope.

A series of new compounds built up on the skeleton of 1,5,8,12-tetraazabicyclo[10.2.2]hexadecane (1,4-ethylene-bridged cyclam, 1,4-en-cyclam) were synthesized and characterized by means of NMR and MS spectroscopy and a single-crystal X-ray structure determination. The attempts to substitute the secondary amino group of the p-nitrobenzyl-1,4-en-cyclam 3, using acetic acid derivatives as the alkylating agents, led to unexpected substitution of one of the piperazine ring nitrogen atoms, yielding the monoquaternary derivatives 4BrBr and 5BrBr, respectively. In order to explain this reaction behaviour, the solution structure of the starting compound 3 was established using 2D-NMR techniques. The acid–base behaviour of the ligands and thermodynamic stability constants of their copper(II) and zinc(II) complexes were determined using potentiometric titrations. Stability constants of the investigated metal complexes are significantly lower than those of the cyclam complexes and comparable to those of the Me4cyclam complexes. A copper(II) complex of amine 3 was prepared and characterized. In the solid state, this complex has the central copper atom surrounded by five donor atoms forming a coordination sphere with geometry between trigonal bipyramid and square pyramid.

International audience; The complexation ability of DOTA analogs bearing one methylenephosphonic (DO3AP) or methylene-phosphinic (DO3AP PrA and DO3AP ABn) acid pendant arm toward scandium was evaluated. Stability constants of their scandium(III) complexes were determined by potentiometry combined with 45 Sc NMR spectroscopy. The stability constants of the monophosphinate analogues are somewhat lower than that of the Sc–DOTA complex. The phosphorus acid moiety interacts with trivalent scandium even in very acidic solutions forming out-of-cage complexes; the strong affinity of the phosphonate group to Sc(III) precludes stability constant determination of the Sc–DO3AP complex. These results were compared with those obtained by the free-ion selective radiotracer extraction (FISRE) method which is suitable for trace concentrations. FISRE underestimated the stability constants but their relative order was preserved. Nonetheless , as this method is experimentally simple, it is suitable for a quick relative comparison of stability constant values under trace concentrations. Radiolabelling of the ligands with 44 Sc was performed using the radioisotope from two sources, a 44 Ti/ 44 Sc generator and 44m Sc/ 44 Sc from a cyclotron. The best radio-labelling conditions for the ligands were pH = 4, 70 °C and 20 min which were, however, not superior to those of the parent DOTA. Nonetheless, in vitro behaviour of the Sc(III) complexes in the presence of hydroxyapatite and rat serum showed sufficient stability of 44 Sc complexes of these ligands for in vivo applications. PET images and ex vivo biodistribution of the 44 Sc–DO3AP complex performed on healthy Wistar male rats showed no specific bone uptake and rapid clearance through urine.

The dissociation kinetics of the europium(III) complex with H8dotp ligand was studied by means of molecular absorption spectroscopy in UV region at ionic strength 3.0 mol dm-3 (Na,H)ClO4 and in temperature region 25-60 degrees C. Time-resolved laser-induced fluorescence spectroscopy (TRLIFS) was employed in order to determine the number of water molecules in the first coordination sphere of the europium(III) reaction intermediates and the final products. This technique was also utilized to deduce the composition of reaction intermediates in course of dissociation reaction simultaneously with calculation of rate constants and it demonstrates the elucidation of intimate reaction mechanism. The thermodynamic parameters for the formation of kinetic intermediate and the activation parameters for the rate-determining step describing the complex dissociation were determined. The mechanism of proton-assisted reaction was proposed on the basis of the experimental data.

Complexation kinetics of the europium(III)-H5do3ap complex (1,4,7,10-tetraazacyclododecane-1,4,7-triacetic-10-(methylphosp honic acid)) was studied at 25 degrees C and I= 0.1 M KCI and compared with the analogous H4dota-like ligands. The mechanism of the formation reactions between the europium(III) ion and H3do3a, H4dota and H4dota analogs having one methylphosphonic (H5do3ap) or phosphinic acid pendant arms with a propionate side chain (H5do3apPrA) was proposed on the basis of TRLIFS measurements. The experimental data of the dissociation kinetics of the europium(III) complexes with H5do3ap and H5do3apPrA ligands show that there is no change in reactivity of the complexes due to the side chain of the phosphinic acid bifunctional chelate. The TRLIFS study of the proton-assisted decomplexation reaction of the europium(III) complexes with H3do3a, H4dota, H5do3ap and H5do3ap-PrA demonstrates different behaviour influenced by a change in the number of water molecules during the reaction.

Binary and ternary systems containing Zn2+, cyclen and/or pyridinecarboxylic acids and amides [picolinic (HL1), nicotinic (HL2) and dipicolinic (H2L3) acids and nicotinamide (L4)] have been investigated in solution and in the solid state. Dissociation and stability constants for the ligands and binary systems, respectively, are in accordance with literature results. Both picolinic and dipicolinic acids form stable ternary complexes with the [Zn(cyclen)]2+ species; a weak interaction is observed for nicotinic acid and nicotinamide. The formation of ternary complexes stabilizes the products of protonation at the cyclen nitrogen atom, and these protonated complexes are found even up to pH = 7. The structures of the complexes in solution correlate well with those found in the solid state and by molecular modelling calculations. The solid-state structures of several complexes are determined. The zinc atom in the [Zn(cyclen)(NO3)]+ complex is bound in an N4O tetragonal-pyramidal environment. The nicotinic acid anion forms a bridge in the [{Zn(cyclen)}2(μ-L2-N,O)]3+ cation, and both [Zn(cyclen)]2+ units exhibit tetragonal-pyramidal arrangements. An unusual coordination mode is found in the [{Zn(cyclen)}2(μ-L1-O:N,O′)]3+ cation, where the picolinic acid anion also bridges two [Zn(cyclen)]2+ units but is coordinated monodentately through one oxygen atom to one unit (N4O tetragonal pyramid) and chelates through the other pyridine nitrogen and carboxylate oxygen atoms. Nicotinamide in the [Zn(cyclen)(L4-N)]2+ cation is bound to the [Zn(cyclen)]2+ unit through the pyridine nitrogen atom in the axial position of the tetragonal pyramid. This is the first fully quantitative assessment of Zn2+-cyclen-ligand ternary systems, and the results, namely the presence of protonated cyclen in the ternary species even at high pH, are relevant for evaluation of the [Zn(cyclen)]2+ unit as a model complex for zinc-containing enzymes.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Two new tetraamine ligands, bis[N-(2-aminoethyl)aminomethyl]phosphinic acid (Hen2p) and bis[N-(3-aminopropyl)aminomethyl]phosphinic acid (Hpn2p), were synthesized from the corresponding diaminoalkanes and bis(chloromethyl)phosphinic acid. Their acid–base properties and complexation with Cu2+, Ni2+, and Zn2+ ions were studied by potentiometric titrations. Different chain lengths of the ligands result in significantly different coordination abilities. The five-membered chelate ring of Hen2p leads to a higher stability of its complexes. In comparison with tetraamines having the same number of the bridging atoms separating the amino groups, the presence of the phosphinic acid moiety decreases the basicity of the amine groups, and consequently, the stability of their complexes. Several solid-state structures were determined by X-ray diffraction analysis. Four nitrogen atoms coordinate the Cu2+ or Zn2+ ion in a square-planar fashion, whereas the phosphinic acid group is not coordinated or acts as a bridging unit between neighboring metal ions. The unexpectedly high stability of the Ni2+/Hpn2p complex can be explained by the possible presence of a tetramer in solution as was found in the solid state.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

The complex formation of the bifunctional monophosphinic acid DOTA analogue DO3APABn (1,4,7,10-tetraazacyclododecane-4,7,10-triacetic-1-{methyl[(4-aminophenyl)methyl] phosphinic acid}) with 111In at a tracer level was analyzed. Formation of a complex between 111In and DO3APABn was very rapid even at room temperature and high radiolabeling yields were achieved. As introducing the methylphosphinic acid arm to the DOTA structure generated a chiral centre, more than one peak (probably corresponding to various diastereoisomers) of 111In-DO3APABn were separated on HPLC. Four peaks were separated by HPLC, they probably correspond to four diastereoisomers of 111In-DO3APABn originating from combination of chirality of complexes of DOTA-like ligands with chirality of coordinated phosphorus atom. Studies in rats showed rapid elimination of radioactivity from the blood and other organs and tissues. The results indicate that DO3APABn represents a promising ligand for radiolabeling of target-specific biomolecules with radiometals.

Five geminal bis(phosphonates) containing an amino group in the α, γ or δ position of the carbon chain have been synthesised and their acid–base and complexation properties with Cu2+, Zn2+, Ca2+, Mg2+ and Na+ ions studied by potentiometry. Determination of the stability constants of the complexes with divalent metal ions is complicated by the formation of precipitates. The results of these studies show a negligible effect of the hydroxo group in the α position on the acid–base and complexation properties of the ligands. The presence of an amino group in the α position, however, decreases the basicity, which results in a lower complexation ability of the bis(phosphonates). The crystal structures of the three ligands with different degrees of protonation have also been determined. The structure of the triammonium salt of aminomethylbis(phosphonic acid) shows that the proton is bound to the nitrogen atom in monoprotonated species. The structure of the Cu2+ complex of pamidronate [{Cu2(H2pam)2}·H2O]n shows the presence of dimeric units with a relatively short distance (2.99 A) between the metal centres. These units form a coordination polymeric chain. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Kinetically inert Ni(ii) complexes of N(1),N(8)-bis(2,2,2-trifluoroethyl)cyclams with hydrogen atoms or phosphonic acid groups in the N(4),N(11)-positions show significant (19)F NMR relaxation rate enhancement useful for 19-fluorine MRI imaging.

Background Metastatic bone lesion is a common syndrome of many cancer diseases in an advanced state. The major symptom is severe pain, spinal cord compression, and pathological fracture, associated with an obvious morbidity. Common treatments including systemic application of bisphosphonate drugs aim on pain reduction and on improving the quality of life of the patient. Particularly, patients with multiple metastatic lesions benefit from bone-targeting therapeutic radiopharmaceuticals. Agents utilizing beta-emitting radionuclides in routine clinical praxis are, for example, [89Sr]SrCl2 and [153Sm]Sm-EDTMP. No-carrier-added (n.c.a.) 177Lu is remarkably suitable for an application in this scope. Methods Five 1,4,7,10-tetraazacyclododecane N,N′,N′′,N′′-tetra-acetic acid (DOTA)- and DO2A-based bisphosphonates, including monomeric and dimeric structures and one 1,4,7-triazacyclononane-1,4-diacetic acid (NO2A) derivative, were synthesized and labelled with n.c.a. 177Lu. Radio-TLC and high-performance liquid chromatography (HPLC) methods were successfully established for determining radiochemical yields and for quality control. Their binding to hydroxyapatite was measured in vitro. Ex vivo biodistribution experiments and dynamic in vivo single photon computed tomography (SPECT)/CT measurements were performed in healthy rats for 5 min and 1 h periods. Data on %ID/g or standard uptake value (SUV) for femur, blood, and soft-tissue organs were analyzed and compared with [177Lu]citrate. Results Radiolabelling yields for [177Lu]Lu-DOTA and [177Lu]Lu-NO2A monomeric bisphosphonate complexes were >98 % within 15 min. The dimeric macrocyclic bisphosphonates showed a decelerated labelling kinetics, reaching a plateau after 30 min of 60 to 90 % radiolabelling yields. All 177Lu-bisphosphonate complexes showed exclusive accumulation in the skeleton. Blood clearance and renal elimination were fast. SUV data (all for 1 h p.i.) in the femur ranged from 3.34 to 5.67. The bone/blood ratios were between 3.6 and 135.6, correspondingly. 177Lu-bisphosphonate dimers showed a slightly higher bone accumulation (SUVfemur = 4.48 ± 0.38 for [177Lu]Lu-DO2A(PBP)2; SUVfemur = 5.41 ± 0.46 for [177Lu]Lu-DOTA(MBP)2) but a slower blood clearance (SUVblood = 1.25 ± 0.09 for [177Lu]Lu-DO2A(PBP)2; SUVblood = 1.43 ± 0.32 for [177Lu]Lu-DOTA(MBP)2). Conclusions Lu-complexes of macrocyclic bisphosphonates might become options for the therapy of skeletal metastases in the near future, since they show high uptake in bone together with a very low soft-tissue accumulation.

The behaviour of two structural isomers of the copper(II) complex of 1,4,8,11-tetraazacyclotetradecane-1,8-bis(methylphosphonic acid) (H(4)dipon), penta- and hexacoordinated species, was studied by capillary electrophoresis. The separation and determination of both the isomers with the same molecular weight and charge and the free H(4)dipon ligand were achieved in 75 mM disodium tetraborate aqueous solution (pH 9.5) as background electrolyte and, simultaneously, magnitudes of their effective mobilities were determined. The influence of both variables (pH and buffer composition/concentration) on the separation was established and the principle of the separation was proposed. The method of separation was applied to the study of the reaction mechanism of the isomerization. It was proved that the reaction can be explained by several mechanisms with the same fit through experimental data. The first step of the isomerization reaction proceeds relatively slowly and is the rate-determining step of reaction.

The thermodynamic and kinetic stabilities of the complexes of phosphonate and phenylphosphinate analogues of H5dtpa with selected transition- and lanthanide-metal ions are presented. Both phosphorus-containing ligands form thermodynamically very stable complexes, with stability constants comparable with or even higher than those reported for the parent H5dtpa. However, the kinetic inertness of their gadolinium(III) complexes against acid- and metal-assisted decomplexations is surprisingly much lower. The half-life times of gadolinium(III) complexes of the new ligands in the pres

Two triphenylphosphine derivatives, diethyl [4-(diphenylphosphanyl)benzyl]phosphonate (3a) and tetraethyl {[5-(diphenylphosphanyl)-1,3-phenylene]dimethylene}bis(phosphonate) (3b), and also the corresponding free acids 4a and 4b were prepared. These ligands were characterized by 1H, 13C and 31P NMR spectroscopy and mass spectrometry. A full set of their Pd(II) and Pt(II) complexes of the general formula [MCl2L2] and one dinuclear complex trans-[Pd2Cl4(3a)2] were synthesized and their isomerization behaviour in solution was studied. The complexes were characterized by 1H, 13C, 31P and 195Pt NMR spectroscopy, mass spectrometry and far-IR spectroscopy. The X-ray structures of all complexes with 3a or 3b have usual slightly distorted square-planar geometry on the metal ion. Salts of phosphonic acids 4a and 4b and their complexes are freely soluble in aqueous solution; therefore, they can be potentially useful in aqueous or biphasic catalysis.

Compound [Y(Hdo3aP(ABn))(H2O)][Y(Hdo3aP(ABn))].6H2O.iPrOH, where H4do3aP(ABn) is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic-10-methyl(4-aminobenzylphosphinic) acid, a monophosphinate analogue of H4dota, was prepared in the solid state and studied using X-ray crystallography. In contrast to all single-crystal structures of complexes of H4dota-like ligands published before, three distinct units were found in one cell: two species adopting a twisted-square-antiprismatic configuration with (TSA) and without (TSA') a coordinated water molecule and one isomer with a square-antiprismatic configuration (SA). In addition, this is the first complex with the H4dota-like ligand for which the structures of three possible species were determined in the solid state.

A new cyclam-based ligand, 1,4,8,11-tetraazacyclotetradecane-1,4-bis(methylphosphonic acid) (1,4-H4te2p), was synthesized. Cyclam was protected by the reaction with PhP(S)Cl2 to form exclusively five-membered cyclic phenylphosphonothioic diamide 2 in a moderate yield. The solid-state structures of 2 and several by-products were determined. Compound 2 was isolated as two stable conformers differing in a mutual position of benzene ring and sulfur atom with respect to the cyclam ring. Compound 2 was used for the synthesis of 1,4-dibenzylcyclam. However, the deprotection of the thiophosphoryl-protected bis(methylphosphonate diester) with aqueous HCl under non-optimized conditions led to a mixture of cyclam derivatives differently substituted with methylphosphonic acid groups. The crystal structures of the target product, 1,4-H4te2p, and also 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrakis(methylphosphonic acid) (H8tetp) were determined. A similar reaction with cyclen (1,4,7,10-tetraazacyclododecane) led only to hardly purifiable mixtures.

The luminescence lifetimes of europium(III) complexes with new monophosphorus acid derivatives of H(4)dota were measured by means of time-resolved laser-induced luminescence spectroscopy in H(2)O and D(2)O. The hydration numbers of these complexes were estimated using different empirical equations [Horrocks and Sudnick (1979) J. Am. Chem. Soc. 101 (1979) 334; Choppin and Barthelemy(1989) Inorg. Chem. 28, 3354-3357; Choppin and Bünzli Lanthanide probes in life, chemical and earth sciences. Theory and practice (1989); Kimura and Kato J. Alloys Comp. 275-277 (1998) 806; Parker (1999) J. Chem. Soc., Perkin Trans. 2, 493-503; Supkowski and Horroks (2002) Inorg. Chim. Acta. 340, 44-48]. It was shown that all the relationships gave similar results with a satisfactory precision. The hydration numbers of complexes of H(3)do3a and H(4)dota agreed with the literature values. One water molecule is coordinated in complexes of the new ligands. The results showed that the Choppin formula based on measurements only in H(2)O can be satisfactorily used for estimation of the hydration numbers.

Solution properties of complexes of a new H4dota-like ligand containing three acetate and one methylphosphonate pendant arms (H5do3ap, H5L) were studied. The ligand exhibits a high last dissociation constant (pKA = 13.83) as a consequence of the presence of phosphonate moiety. In solution, successive attachment of protons leads to several reorganizations of protonation sites and the neutral zwitterionic species H5do3ap has the same solution structure as in the solid state, where the nitrogen atom binding methylphosphonate and the opposite nitrogen atoms are protonated. Stability constants with Na+ and trivalent lanthanide ions (La3+, Ce3+, Eu3+, Gd3+, Lu3+) and Y3+ have been determined. The constants are comparable or higher than those of H4dota due to the higher overall basicity of H5do3ap. Formation of the stable protonated complexes, as well as complexes with the L:M = 1:2 stoichiometry, was proved. Formation and decomplexation kinetics of the Ce3+ and Gd3+ complexes were investigated. The mechanism of formation of the H5do3ap complexes is similar to that observed for H4dota complexes and the complex species with mono- or diprotonated ligand on the cyclen ring are considered as the reaction intermediates. Acid-assisted decomplexation of H5do3ap complexes is faster in comparison with those of H4dota. This is caused by higher basicity of the phosphonate pendant arm and the ring nitrogen atoms, which facilitates the proton transfer from the bulk solution to the nitrogen atoms of cyclen ring.

A new macrocyclic ligand, 1,4,8,11-tetraazacyclotetradecane-1,8-bis(methylphosphonic acid)(dipon), is selective complexing agent for copper(II) over other transition metal ions. The ligand was tested for analytical applications of copper(II) determination. Spectrophotometric determination under optimal experimental conditions (−log [H+]= 5.5, cL≈ 5 × 10−4 mol L−1, λ= 310 nm) is valid in dynamic range (5–200)× 10−6 mol L−1 with detection limit 2.2 × 10−6 mol L−1, i.e. 0.14 μg ml−1. Volumetric determination of copper(II) with standardized dipon solution was used for copper(II) determination at micromolar concentration level without any necessity to sequester interfering metal ions. A sharp end point of titration was detected by UV/VIS spectrophotometry. Both methods were tested on artificial and real samples (spiked mineral water, alloys) and gave satisfactory results without any systematic error. The advantage of both methods is their simplicity, rapidity and no sensitivity to the presence of other metal ions.

A novel conjugate of a polysaccharide and a Gd(III) chelate with potential as contrast agent for magnetic resonance imaging (MRI) was synthesized. The structure of the chelate was derived from H5DTPA by replacing the central pendant arm by a phosphinic acid functional group, which was covalently bound to the polysaccharide inulin. On the average, each monosaccharide unit of the inulin was attached to approximately one (0.9) chelate moiety. The average molecular weight is 23110 and the average number of Gd3+ ions per molecule is 24. The ligand binds the Gd3+ ion in an octadentate fashion via three nitrogen atoms, four carboxylate oxygen atoms, and one P-O oxygen atom, and its first coordination sphere is completed by a water molecule. This compound shows promising properties for application as a contrast agent for MRI thanks to a favorable residence lifetime of this water molecule (170 ns at 298 K), a relatively long rotational correlation time (866 ps at 298 K), and the presence of two water molecules in the second coordination sphere of the Gd3+ ion. Furthermore, its stability toward transmetalation with Zn(II) is as high as that of the clinically used [Gd(DTPA)(H2O)]2-.

In an aqueous solution at room temperature, 1,4,8,11-tetraazacyclotetradecane-1,8-bis(methylphosphonic acid) (H(4)L(1)) and Cu(I) (I) form a pentacoordinated (pc) complex, pc-[Cu(L(1))](2-), exhibiting conformation I of the cyclam ring. At high temperature, the complex isomerises to a hexacoordinated isomer, trans-O,O-[Cu(L(1))](2-), with a trans-III conformation of the cyclam ring. In pc-[Cu(L(1))](2-), four ring nitrogen atoms and one phosphonate oxygen atom are arranged around Cu(I) (I) in a structure that is half-way between a trigonal bipyramid and a tetragonal pyramid, with one phosphonic acid group uncoordinated. In the trans-O,O-[Cu(L(1))](2-) isomer, the nitrogen atoms form a plane and the phosphonic acid groups are in a mutually trans configuration. A structurally very similar ligand, 4-methyl-1,4,8,11-tetraazacyclotetradecane-1,8-bis(methylphosphonic acid) (H(4)L(2)), forms an analogous pentacoordinated complex, pc-[Cu(L(2))](2-), at room temperature. However, the complex does not isomerise to the octahedral complex analogous to trans-O,O-[Cu(L(1))](2-). Because of the high thermodynamic stability of pc-[Cu(L(1))](2-), (logbeta=25.40(4), 25 degrees C, I=0.1 mol dm(-3) KNO(3)) and the formation of protonated species, Cu(I) (I) is fully complexed in acidic solution (-log [H(+)] approximately 3). Acid-assisted decomplexation of both of the isomers of [Cu(H(2)L(1))] takes place only after protonation of both uncoordinated oxygen atoms of each phosphonate moiety and at least one nitrogen atom of the cycle. The exceptional kinetic inertness of both isomers is illustrated by their half-lives tau(1/2)=19.7 min for pc-[Cu(H(2)L(1))] and tau(1/2) about seven months for trans-O,O-[Cu(H(2)L(1))] for decomplexation in 5 M HClO(4) at 25 degrees C. The mechanism of formation of pc-[Cu(L(1))](2-) is similar to those observed for other macrocyclic complexes.

Bis(aminomethyl)phosphinic acid, (NH2CH2)2PO2H (HL), was synthesized using a new procedure. Its coordination ability towards Co(II)/(III), Ni(II), Cu(II) and Zn(II) was studied both in solution and in the solid state. Because of the presence of two nitrogen atoms the ligand exhibits a higher overall basicity than common (aminoalkyl)phosphinic acids. Consequently, the values of the determined stability constants are comparable with those found for (aminoalkyl)phosphonic acids. NMR titrations of Zn(II) point to the interaction of phosphinate with the metal ion in a strong acid solution. The X-ray structures show several coordination modes in the solid state. All-trans-[MCl2(H2L-O)2(H2O)2]Cl2, where M(II) are Mn(II), Co(II), Ni(II), Cu(II), Zn(II), Ca(II), and Cd(II), crystallized from acid solutions. The central ion is octahedrally coordinated with two phosphinate oxygen atoms, two molecules of water and two chlorides in all-trans arrangement. Amine groups are protonated and non-coordinated. Participation of the donor groups in crystals isolated from neutral solutions depends on the metal ion. All donor atoms are coordinated in monomeric fac-N,N,O-trans-O,O′-[Co(L-N,N,O)2]+. On the other hand, in the zinc(II) complex, two phosphinate oxygen atoms and two amine nitrogen atoms (trans to each other) of two different ligand molecules are coordinated in an equatorial plane and two amino groups of the two other ligand molecules are bound in axial positions. Thus, each molecule of the amino acid forms a five-membered N,O-chelate to one zinc(II) ion and the other amino group is bound to the neighbouring ion creating an infinite chain. Nickel(II) forms a trans-O,O′-[Ni(H2O)2(L-N,N)2] complex in which the metal ion is chelated by four amine nitrogen atoms forming two six-membered chelates in an equatorial plane and the octahedron is completed with two water molecules at the apical positions. The phosphinate group is not coordinated. The above results point to a relatively low coordination ability of the phosphinate group; however, due to its low pKA, it is able to bind metal ions at lower pH than other coordinating groups do.

Two novel macrocyclic ligands based on trans-substituted cyclam with N-methyl and N-(4-aminobenzyl) groups as well as with two methylphosphinic (H2L1) or methylphosphonic (H4L2) acid pendant arms were synthesised and investigated in solutions. The ligands form stable complexes with transition metal ions. Both ligands show a high thermodynamic selectivity for divalent copper over nickel(II) and zinc(II) (K(CuL) is higher than K(Ni/ZnL) by about 7 orders of magnitude). Complexation is significantly faster for the phosphonate ligand H4L2 probably due to stronger coordination ability of more basic phosphonate groups, which efficiently bind the metal ion in the out-of-cage complex and helps its in-cage binding. The rate of complexation of Cu(II) by the phosphinate ligand H2L1 is comparable to that of cyclam itself and it derivatives with non-coordinating substituents. Acid-assisted decomplexation of the copper(II) complexes is relatively fast (½ 44 and 42 s in 1 M aq. HCl at 25 °C for H2L1 and H4L2, respectively). Combination of the properties is convenient for selective copper removal/purification. Thus, the title ligands were employed in preparation of ion-selective resins for radiocopper(II) separation. Glycidyl-methacrylate copolymer beads were modified with the ligands through diazotation reaction. The separation ability of the modified polymers was tested with cold copper(II) or non-carrier-added (NCA) 64Cu in the presence of a high excess of both nickel(II) and zinc(II). The experiments exhibited high overall separation efficiency leading to 60–70 % recovery of radiocopper with high selectivity over the other metal ions originally present in 900-times molar excess. The results showed the concept of chelating resins with properly tuned selectivity of complexing moieties can be employed for radiocopper separation.

International audience; We report the synthesis of a cyclen-based ligand (4,10-bis[(1-oxidopyridin-2-yl)methyl]-1,4,7,10-tetraazacyclododecane-1,7-diacetic acid=L1) containing two acetate and two 2-methylpyridine N-oxide arms anchored on the nitrogen atoms of the cyclen platform, which has been designed for stable complexation of lanthanide(III) ions in aqueous solution. Relaxometric studies suggest that the thermodynamic stability and kinetic inertness of the Gd(III) complex may be sufficient for biological applications. A detailed structural study of the complexes by (1) H NMR spectroscopy and DFT calculations indicates that they adopt an anti-Δ(λλλλ) conformation in aqueous solution, that is, an anti-square antiprismatic (anti-SAP) isomeric form, as demonstrated by analysis of the (1) H NMR paramagnetic shifts induced by Yb(III) . The water-exchange rate of the Gd(III) complex is ${k{{298\hfill \atop {\rm ex}\hfill}}}$=6.7×10(6) s(-1) , about a quarter of that for the mono-oxidopyridine analogue, but still about 50 % higher than the ${k{{298\hfill \atop {\rm ex}\hfill}}}$ of GdDOTA (DOTA=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). The 2-methylpyridine N-oxide chromophores can be used to sensitize a wide range of Ln(III) ions emitting in both the visible (Eu(III) and Tb(III) ) and NIR (Pr(III) , Nd(III) , Ho(III) , Yb(III) ) spectral regions. The emission quantum yield determined for the Yb(III) complex (${Q{{{\rm L}\hfill \atop {\rm Yb}\hfill}}}$=7.3(1)×10(-3) ) is among the highest ever reported for complexes of this metal ion in aqueous solution. The sensitization ability of the ligand, together with the spectroscopic and relaxometric properties of its complexes, constitute a useful step forward on the way to efficient dual probes for optical imaging (OI) and MRI.

A comparison of complexing properties of cyclen and cyclam derivatives containing acetic acid pendant arms on one hand and their methylphosphonic or methylphosphinic acid analogues on the other is made mainly with complexes of copper and lanthanides due to their applications in medicine. The stability constant values of Cu(II) complexes are determined mainly by the basicity of amine groups. The influence of other possible effects, such as the macrocyclic effect in tetraazacycle in contrast to linear amines or the number of additional donor atoms in or outside of pendant arms and their basicity, seems to be very small. The stability constants for Gd(III), in addition to the basicity of amines, are also influenced by the basicity of the pendants and their number. The values of cyclam derivatives are lower than those of cyclen and it corresponds to the ring size effect as was found for zinc(II) complexes. In contrast to Cu(II), the Gd(III) stability constants of the phosphonic acid ligands are also lower than those with H4dota derivatives. A comparison of co-ordination polyhedra of the carboxylic and phosphonic or phosphinic derivatives shows similar motifs that are more determined by the macrocyclic effect than by the kind of donor groups in pendant arms. The differences between the polyhedra observed result from longer C–P(O) bond in the phosphorus derivatives than that C–C(O) in the acetate pendants. Consequently, the lanthanide(III) complexes with phosphorus acid derivatives are more sterically hindered; oxygen atoms in the O4 plane are close to one another and there is insufficient room for co-ordination of a water molecule, which is crucial in MRI applications.

The X-ray structure determinations show that 1,4,8,11-tetraazacyclotetradecane-1,8-bis(methylphosphonic) acid H4L forms both cis- and trans-O,O isomeric complexes with Co(III). Orientation of the other donor atoms indicates the formation of cis-O1,O2-trans-N1,N8-cis-O1,N4-[Co(HL)]. The kinetically preferred cis-isomer is easily formed due to the strong hydrogen bond between the neighboring phosphonic acid groups. The presence of the hydrogen bond in aqueous solution is confirmed by the value of pKa which increases by four orders of magnitude in comparison with the trans-isomer. Formation of the trans-[Co(HL)] occurs only after long heating of a Co(II) solution with the ligand under inert atmosphere before oxidation, which is explained by insertion of the Co(II) ion in the plane of nitrogen atoms of 1,4,8,11-tetraazacyclotetradecane.

Nickel(II) ion reacts with 1,4,8,11-tetraazacyclotetradecane-1,8-bis(methylphosphonic acid) (H4L1) at room temperature with formation of cis-[Ni(L1)]2- complex. The complex was crystallised in several forms in dependence on conditions of isolation (temperature, pH, solvent mixture). Crystal structures of cis-O,O-[Ni(H2L1)] (1), cis-O,O-[Ni(H2L1)]·2H2O (2), cis-O,O-[Ni(H3L1)]Cl·H2O (3) and cis-O,O-[Ni(H4L1)]Cl2·2H2O (4) were determined by X-ray diffraction. In all the compounds, Ni2+ is in octahedral cis-O1,O2-trans-N1,N8-cis-O1,N4-[Ni(L1)]2- (hereafter abbreviated as cis-O,O-[Ni(L1)]2-) arrangement with V conformation of the cyclam ring. Complexes 3 and 4 exhibit very unusual coordination through the phosphoryl group of double-protonated phosphonate moiety. Tetraethylester of H4L1 having only poorly coordinating phosphoryl oxygen atoms also forms nickel(II) complex 5 with cis arrangement. Corresponding trans-O,O-[Ni(L1)]2- complex is formed only in strongly acidic medium through conversion of the cis complex; it was characterised by X-ray diffraction as dihydrochloride dihydrate, trans-O,O-[Ni(H4L1)]Cl2·2H2O (6). The analogous compound (NH4)2(trans-O,O-[Ni(L2)])·H2O (7) is obtained quantitatively by reaction of Ni2+ with 4,11-dibenzyl-1,4,8,11-tetraazacyclotetradecane-1,8-bis(methylphosphonic acid) (H4L2). Formation of this complex 7 in the III cyclam ring conformation is preferred to the cis complex due to steric hindrance of bulky benzyl groups in cis-[Ni(L2)]2- complex with the V cyclam ring conformation.

In magnetic resonance imaging (MRI), paramagnetic complexes are utilized as contrast agents. Much attention has been paid to the development of new contrast agents responsive to pH, temperature or concentration of various components of body liquids. We report a new type of MRI probe sensing the concentrations of calcium and magnesium in biological media. The ligand do3apBP combines a dota-like chelator with a bisphosphonate group. In the complex, the Gd(III) ion is entrapped in the macrocyclic cavity whereas the bisphosphonate group is not coordinated and therefore is available for coordination with endogenous metal ions. In the presence of metal ions, Gd–do3apBP appears to show formation of coordination oligomers leading to an unprecedented increase in r1 up to 200–500%. The extremely high relaxivity response makes this type of compound interesting for further studies as MRI ion-responsive probes for biomedical research. Copyright © 2010 John Wiley & Sons, Ltd.

Cyclam derivatives with methylphosphonic acid arms in position 1,8 and substituent R = H, Me, CH2Ph in positions 4 and 11 are synthesised by Mannich reaction of an appropriate cyclam derivative, formaldehyde and phosphonic acid/diethyl phosphite followed by removal of protecting benzyl groups from nitrogen atoms. Mono(methylphosphonic acid) derivative of cyclam can be obtained by a similar route. Crystal structures of four phosphonic acid derivatives show the same ring conformation and orientation pendants due to strong intramolecular hydrogen bonds between phosphonate oxygen atoms and protonated nitrogen atoms adjacent over ethylene chains. The hydrogen bonds are stable even in aqueous solution. Activation parameters for destabilisation of the conformation are estimated from temperature-dependent NMR measurement. The protonation constants determined confirm the expected high basicity of the compounds and its dependence on the nitrogen atom substituents. The enhanced basicity of the nitrogen atoms non-bonded to methylenephosphonic acid moiety, is explained by the presence of the strong hydrogen bonds.

A new macrocyclic ligand 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraylmethyltrimethylenetris(phenylphosphinic acid) H3L1 was synthesised and its complexes with lanthanides were prepared. X-Ray analysis of seven Ln complexes (Ln = La, Ce, Nd, Eu, Tb, Er, Yb) shows a formation of dimers [LnL1]2 with phosphinic acid bridges in the solid state. All complexes are isostructural and the coordination polyhedra are formed by four N atoms and four O atoms of phosphinic acid groups. A water molecule is placed near the O4 base. The LnOw distance is strongly dependent on Ln(III), it varies from 2.815(6) A in the La complex to 4.448(10) A in the Yb complex. The 31P NMR studies show formation of a rather complex mixture of isomers in solution. The dimer stability in solution is verified by reaction with triphenylphosphine oxide (tppo) and with pyridine N-oxide and by cyclic voltammetry.

Lanthanide complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis[methylene(phenylphosphinic) acid] (H4L) were found to give a linear correlation of 1H and 31P NMR chemical shifts to temperature in the physiologically relevant temperature range, with dependencies comparable or better than those found for existing complexes; due to the greater hydrophobic character of the ligand the complexes may exhibit a different biodistribution in the body.

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 (pKa = 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.Graphical abstract

The acid–base and complexing properties of (S,S) and (S,R) diastereoisomers of 1-(methionylamino)ethylphosphonic acid were studied pH-metrically (25 °C, 0.1 mol dm -3 KNO 3 ). The protonation and stability constants for complex formation with Co 2+ , Ni 2+ and Zn 2+ indicate co-ordination only via the amine, carbonyl peptide and phosphonic groups and, for Cu 2+ , also via nitrogen of the deprotonated peptide amide group. The presence of the same types of complexes as in phosphonodipeptide series which do not contain sulfur in the amino acid side chain was observed. Similarly, the differences found between diastereoisomers correspond to the interaction of the hydrophobic and/or hydrophilic parts of the molecule. Co-ordination via sulfur has not been observed. The species determined by ‘out of cell’ titrations of the platinum(II) and palladium(II) systems depend on the initial metal∶phosphonic acid molar ratio. A 1∶2 ratio indicates the co-ordination of amine and sulfur in a wide pH region; in the alkaline region, sulfur atoms are replaced by the peptide amide group. A 1∶1 ratio indicates the formation of dimers with co-ordinated phosphonic groups. The pH-metrically determined species were confirmed by 31 P-{ 1 H} and 1 H NMR titrations of the systems involving Pd II and Pt II .

Ligands with geminal bis(phosphonic acid) appended to 1,4,7-triazacyclonone-1,4-diacetic acid fragment through acetamide (NOTAM(BP) ) or methylenephosphinate (NO2AP(BP) ) spacers designed for (68) Ga were prepared. Ga(III) complexation is much faster for ligand with methylenephosphinate spacer than that with acetamide one, in both chemical (high reactant concentrations) and radiolabeling studies with no-carrier-added (68) Ga. For both ligands, formation of Ga(III) complex was slower than that with NOTA owing to the strong out-of-cage binding of bis(phosphonate) group. Radiolabeling was efficient and fast only above 60 °C and in a narrow acidity region (pH ~3). At higher temperature, hydrolysis of amide bond of the carboxamide-bis(phosphonate) conjugate was observed during complexation reaction leading to Ga-NOTA complex. In vitro sorption studies confirmed effective binding of the (68) Ga complexes to hydroxyapatite being comparable with that found for common bis(phosphonate) drugs such as pamindronate. Selective bone uptake was confirmed in healthy rats by biodistribution studies ex vivo and by positron emission tomography imaging in vivo. Bone uptake was very high, with SUV (standardized uptake value) of 6.19 ± 1.27 for [(68) Ga]NO2AP(BP) ) at 60 min p.i., which is superior to uptake of (68) Ga-DOTA-based bis(phosphonates) and [(18) F]NaF reported earlier (SUV of 4.63 ± 0.38 and SUV of 4.87 ± 0.32 for [(68) Ga]DO3AP(BP) and [(18) F]NaF, respectively, at 60 min p.i.). Coincidently, accumulation in soft tissue is generally low (e.g. for kidneys SUV of 0.26 ± 0.09 for [(68) Ga]NO2AP(BP) at 60 min p.i.), revealing the new (68) Ga complexes as ideal tracers for noninvasive, fast and quantitative imaging of calcified tissue and for metastatic lesions using PET or PET/CT.

Complexing properties of aminomethylenephosphonic acid and dipeptides glycyl-aminomethylenephosphonic acid and both diastereoisomers of (S)-methionyl-1-aminoethylphosphonic acid with Pt(II) and Pd(II) were investigated pH-metrically at 25 °C and at ionic strength of 0.1 mol dm−3 (KNO3). The stability constants calculated indicate formation of the complexes with a metal: ligand molar ratio of 1 : 1 and 1 : 2. The differences found for diastereoisomers are much higher than for systems with common dipeptides. Distribution of all species found by potentiometry were confirmed by 31P and 1H NMR titrations.

O-Ethyl N-1-adamantylphosphoramidothioate was synthesized and found to fragment on heating in inert solvents to form the pyrophosphate AdNHP(S)(OEt)OP(S)(OEt)OH. The proposed mechanism involves an elimination of the amine portion with release of ethyl metathiophosphate (EtOP(S)O), as was confirmed in previous work for the comparable structure with oxygen. This transient compound then phosphorylates the starting phosphoramidothioate. O-Ethyl N,N-diethylphosphoramidothioate was also synthesized, and while it gave a similar pyro compound on heating, the reaction mixture was more complex. Both phosphoramidothioates, however, served effectively as thiophosphorylating agents toward alcohols, a silanol, and the silanol groups on the surface of silica gel. Exploratory experiments showed that these phosphoramidothioates also could thiophosphorylate the OH group of a monoester of phosphoric acid, as well as that of phosphinic acids, forming anhydrides with the partial structure