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A new facile synthetic strategy was developed to prepare bifunctional monophosphinic acid Ln-DOTA derivatives, Gd-DO2AGAPNBn and Gd- DO2AGAPABn. The relaxivities of the Gd-complexes are enhanced compared to Gd-DOTA. Monophosphinic acid arm of these Gd-complexes affords enhancement of inner sphere water exchange rate due to its steric bulkiness. The different functionalities of DO2AGAPNBn were appended in trans positions and are designed to conjugate identical or different vectors according to the potential applications. The conjugation of Gd-DO2AGAPABn with E3 peptide known to target apoptosis was successfully performed and in vivo MRI allowed cell death detection in a mouse model.

Preparation of two benzylic bis(phosphonic acids) modified with primary amine or carboxylic acid groups on the benzene ring is described. These compounds were prepared and characterized in the form of both bis(phosphonate) tetraesters and corresponding free acids. The phosphonic acid esters are suitable for further derivation, mainly for conjugation through the amide bond. Mild conversion of the bis(phosphonate) esters to free acids using trimethylsilylbromide allowed to work with functional groups sensitive to conditions of acidic and/or alkaline hydrolysis. Three bis(phosphonate)-containing fluorescent probes were prepared from the building blocks, utilizing amide and sulfamide bonds as spacers. Dyes containing the dansyl group, rhodamine B, and fluorescein were chosen due to their common availability and low cost. The prepared bis(phosphonate)-building blocks and modified fluorescent probes were used for adsorption studies with hydroxyapatite, the commonly used model of bone tissue. Sorption ability of the prepared bis(phosphonate) compounds was similar to that of pamidronate.

Three magnetic resonance (MR)/fluorescence imaging probes were tested for visualization, cellular distribution, and survival of labeled pancreatic islets in vitro and following transplantation. As T(1) contrast agents (CAs), gadolinium(III) complexes linked to β-cyclodextrin (Gd-F-βCD) or bound to titanium dioxide (TiO2 @RhdGd) were tested. As a T(2) CA, perovskite manganite nanoparticles (LSMO@siF@si) were examined. Fluorescein or rhodamine was incorporated as a fluorescent marker in all probes. Islets labeled with gadolinium(III) CAs were visible as hyperintense spots on MR in vitro, but detection in vivo was inconclusive. Islets labeled with LSMO@siF@si CA were clearly visible as hypointense spots or areas on MR scans in vitro as well as in vivo. All CAs were detected inside the islet cells by fluorescence. Although the vitality and function of the labeled islets was not impaired by any of the tested CAs, results indicate that LSMO@siF@si CA is a superior marker for islet labeling, as it provides better contrast enhancement within a shorter scan time.

A synthesis of 1-hydroxy-1,1-bis(H-phosphinates) from acylchlorides is described. Solid-state structures of two bis(phosphinates) determined by X-ray diffraction showed variations in the PC distances. The compounds show negligible sorption on hydroxyapatite and an intermediate chemical stability in aqueous solution. The hydrolysis occurs in acidic as well as alkaline media. Hydrolysis rates of four derivatives show the lowest stability for aromatic derivatives as a result of the electron-withdrawing effect. Main products of hydrolysis are 1-hydroxy-(H-phosphinates) and phosphorous acid. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 23:195–201, 2012; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.21003

99mTc-phosphonate structures are well established tracers for bone tumour imaging. Our objective was to investigate different 68Ga-labelled phosphonate ligands concerning labelling kinetics, binding to hydroxyapatite and bone imaging using μ-PET. Seven macrocyclic phosphorus-containing ligands and EDTMP were labelled in nanomolar scale with n.c.a. 68Ga in Na-HEPES buffer at pH∼4. Except for DOTP, all ligands were labelled with >92% yield. Binding of the 68Ga-ligand complexes on hydroxyapatite was analysed to evaluate the effect of the number of the phosphorus acid groups on adsorption parameters. Adsorption of 68Ga-EDTMP and 68Ga-DOTP was >83%. For the 68Ga-NOTA-phosphonates an increasing binding with increasing number of phosphonate groups was observed but was still lower than 68Ga-DOTP and 68Ga-EDTMP. μ-PET studies in vivo were performed with 68Ga-EDTMP and 68Ga-DOTP with Wistar rats. While 68Ga-EDTMP-PET showed uptake on bone structures, an excess amount of the ligand (>1.5 mg EDTMP/kg body weight) had to be used, otherwise the 68Ga3+ is released from the complex and forms gallium hydroxide or it is transchelated to 68Ga-transferrin. As a result, the main focus of further phosphonate structures has to be on complex formation in high radiochemical yields with macrocyclic ligands with phosphonate groups that are not required for complexing 68Ga.

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.

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 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.

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.

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.

Three new bis(phosphonic) acids were prepared by derivatization of p-tert-butylcalix[4]arene on the lower rim by –(CH2)xPO3H2 groups and were fully characterized by NMR spectroscopy; some of them were further investigated by X-ray analysis. The compounds obtained were tested as extractants for La3+, Eu3+, Yb3+ and Th4+ in 0.1–1 M HNO3. Structural details of the complex HLn(H2L1)2 where Ln = Y, La, Eu were elucidated by NMR techniques in solution. The extraction efficiencies decrease with increasing length of the CH2 spacer; the dependence is not monotonic, and an extraordinary selectivity was observed for Yb. The extraction efficiency of Ln3+ for all of the ligands studied increased significantly with decreasing ionic radius.

Perhydro-3,6,9,12-tetraazacyclopenteno[1,3- f,g ]acenaphthylene is readily mono- and dialkylated on nitrogen with alkyl bromides and iodides giving mono- and bis-quarternary ammonium salts. The title compound is a unified starting material for the preparation of cyclene based chelators.

Addition of compounds with a P-H bond to Schiff bases of both simple and macrocyclic compounds proceeds smoothly as a non catalysed thermally initialised reaction in an inert solvent. For macrocyclic systems and bulky phosphorus substituents a stereoselective formation of the trans isomer was confirmed by X ray analysis. The addition is reversible, and the reverse reaction is catalysed by Lewis acids. The trans orientation of phosphorus substituents on the macrocycle ring, the stereochemical rigidity of molecules and reversibility of the addition limit the use of the compounds formed in such manner as ligands.

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

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.

Several phosphorus acids (methyl- and phenylphosphonic, diphenylphosphinic, and ethyl phosphoric acids) were round to give inters on reaction with tert-butyldimethylsilanol. The reactions occurred simply on beating the reactants in an inert solvent (hexane or toluene). The reaction is reversible, and yields or inters were improved by continuous water removal. The dibasic acids gave either mono- or disilyl inters; the latter were more easily purified and characterized. The OH groups on the surface or silica gel were also round to react with various phosphorus acids under similar conditions to give surface-bonded esters. Products were characterized by CP/MAS 31 P and 28 Si NMR

Precursors for the generation of neopentyl and 1-adamantyl metaphosphates were prepared by the insertion of oxygen into a ring carbon-phosphorus bond of some 7-phosphanorbornene derivatives. The stereochemistry of the resulting products, which possess the 2,3-oxaphosphabicyclo[2.2.2]octene ring system, was established by NMR spectroscopy, and by X-ray analysis in one case. The O-insertion (by MCPBA) generally proceed with retention of phosphorus configuration, but in one precursor with a syn-neopentoxy group a minor product from an inversion process was isolated. The 7-phosphanorbornene isomer with the uncommon anti neopentoxy structure was synthesized by rearrangement of the syn isomer; O-insertion gave exclusively the product of retention, identical to the minor product from the syn isomer. Conditions were developed for the photochemical fragmentation of the precursors at room temperature to release the metaphosphates; these highly reactive species were trapped as phosphates when alcohols were inclued in the medium. Thermal fragmentation also was effective for generating the neopentyl ester. Irridiation was also performed at -75°C in an attempt to stabilize the metaphosphates so as to allow their spectral characterization, but a rearrangement occured to give a novel tricyclic compound. In this rearrangement, the ring oxygen shifted stereospecifically to the adjacent sp 2 carbon, and a cyclopropane ring was formed

Phosphonodipeptides containing aminomethylphosphonic and 1-aminoethylphosphonic acids were synthesized by the active ester method using N-hydroxybenztriazole and DCC. Fragmentation in electron ionization mass spectra (EI/MS) of protected phosphonodipeptides has been proposed. Results from 1H NMR have shown slightly larger magnetic nonequivalence of—CH2—protons and larger differences in NMR parameters between diastereoisomers than in common dipeptides.

For application in positron emission tomography (PET), PrP9 ,a N,N',N''-trisubstituted triazacyclono- nane with methyl(2-carboxyethyl)phos- phinic acid pendant arms, was devel- oped as 68 Ga 3 + complexing agent. The synthesis is short and inexpensive. Ga III and Fe III complexes of PrP9 were char- acterized by single-crystal X-ray dif- fraction. Stepwise protonation con- stants and thermodynamic stabilities of metal complexes were determined by potentiometry. The Ga III complex pos- sesses a high thermodynamic stability (log K(GaL) = 26.24) and a high degree of kinetic inertness. 68 Ga labeling of PrP9 is possible at ambient temperature and in a wide pH range, also at pH values as low as 1. This means that for the first time, the neat eluate of a TiO2- based 68 Ge/ 68 Ga generator (typically consisting of 0.1 m HCl) can be directly used for labeling purposes. The rate of 68 Ga activity incorporation at pH 3.3 and 208C is higher than for the estab- lished chelators DOTA and NOTA. Tris-amides of PrP9 with amino acid esters were synthesized to act as models for multimeric peptide conju- gates. These conjugates exhibit radio- labeling properties similar to those of unsubstituted PrP9.

On photolysis in propionitrile or THF solution at −75°, three phosphonates (1-adamantyl, neopentyl, and ethyl as O-substituents) with the 2,3-oxaphosphabicyclo[2,2,2] octene ring system underwent extensive rearrangement accompanying the usual result at room temperature of metaphosphate extrusion. The rearrangement product contains a cyclopropane ring, arising from detachment of the bridgehead-bound oxygen followed by attack on the double bond and subsequent ring closure. The rearrangement does not occur with related phosphonamides but has been detected with a phosphine oxide.

A series of dendrimeric conjugates based on a PAMAM (polyamidoamine) backbone with macrocyclic Gd-DO3A-P(ABn) complexes (monophosphinated analogue of DOTA) was prepared. The chelates were covalently attached to the G1-, G2-, and G4-PAMAM dendrimers through a thiourea linker in high loads (90%). The prepared conjugates G1-(Gd-DO3A-P(BnN{CS}))(8), G2-(Gd-DO3A-P(BnN{CS}))(16), and G4-(Gd-DO3A-P(BnN{CS}))(59) showed relaxivities of 10.1, 14.1, and 18.6 s(-)(1) mM(-)(1) at 20 MHz and 37 degrees C and pH = 7.5, respectively. A variable-pH study (range 2-12) revealed up to 30% increase in the relaxivity at low pH for the G2-(Gd-DO3A-P(BnN{CS}))(16) conjugate. As confirmed by (1)H NMR titration of the unmodified G2 dendrimer, this is due to protonation of core tertiary amines leading to a more open and rigid structure. The variable-temperature (17)O NMR and (1)H NMRD relaxometric studies confirmed that the relaxivity is not controlled by water exchange but by rotational dynamics. A multiparametrical data evaluation using the Lipari-Szabo approach revealed that the water residence lifetime, (298)tau(M), for the conjugates studied was ca. 45-70 ns, which is longer than the value found for the monomeric model compound Gd-DO3A-P(ABn) (16 ns) but short enough so as not to limit the relaxivity. The global rotational correlation time, (298)tau(Rg), varied from 1.5 to 3.1 ns and seemed to indicate a sufficiently slow molecular tumbling to achieve the high relaxivities measured; however, the rigidity factor S(2) (approximately 0.26), describing the internal flexibility, was far from optimum. The overall relaxivity was significantly increased (e.g. by a factor of 1.8 for the G1-(Gd-DO3A-P(BnN{CS}))(8) conjugate) when a positively charged polyaminoacid like poly(Arg) or poly(Lys) was added to the conjugate solutions. The electrostatic interactions partially "freeze" the internal mobility of the conjugate and also slow down global motion. This assumption was confirmed by an evaluation of (1)H relaxometric data obtained for the G2-(Gd-DO3A-P(BnN{CS}))(16)-poly(Lys)(59) adduct. Importantly, it was proved that the adduct formation did not hamper the water exchange process.

A monophosphonate analogue of H4dota, 1,4,7,10-tetraazacyclododecane-4,7,10-tris(carboxymethyl)-1-methylphosphonic acid (H5do3aP), and its complexes with lanthanides were synthesized. Multinuclear NMR studies reveal that, in aqueous solution, lanthanide(III) complexes of the ligand exhibit structures analogous to those of H4dota complexes. Thus, the central ion is nine-coordinate, surrounded by four nitrogen atoms, three acetate and one phosphonate oxygen atoms, and one water molecule in an apical position. For complexes of H5do3aP with Ln(III) ions in the middle of the series, the abundance of the desired twisted square-antiprismatic (TSAP) isomer is higher than for the corresponding H4dota complexes. The TSAP/square-antiprismatic (SAP) isomer ratio is highly sensitive to protonation of the phosphonate group: a higher abundance of the TSAP isomer was found in acidic solutions. The microscopic protonation constants of the TSAP isomers are higher than those of the SAP isomers. The presence of one water molecule in the first coordination sphere of the complexes in the pH region studied (pH 2.5-7.0) is confirmed by 17O NMR spectroscopy. The results of a simultaneous fit of variable-temperature 17O NMR relaxation data and 1H NMRD profiles show that the residence time of water (tauM) in the Gd(III) complex is much smaller than for [Gd(dota)(H2O)]-. The exchange rate appears to be dependent on the pH of the solution. The values of tauM are 37, 40, and 14 ns at pH 2.5, 4.7, and 7.0, respectively. These observations can be explained by an extensive second-sphere hydrogen-bonding network that varies with the state of protonation of the phosphonate moiety. Upon protonation of the complex, the second-sphere hydration probably becomes more ordered, which may result in a decrease in penetrability and an increase in tauM. The relaxivity of the Gd(III) complex is almost independent of the pH and is equal to 4.7 s(-1) mM(-1) (20 MHz, pH 7 and 37 degrees C). The solid-state structure was determined for the Nd(III) complex. It crystallizes as the TSAP isomer and the unit cell contains two independent molecules of the complex with different Nd-O(water) bond lengths of 2.499 and 2.591 A.

A new bifunctional octa-coordinating ligand containing an aminobenzyl moiety, DO3APABn (H4DO3APABn = 1,4,7,10-tetraazacyclododecane-4,7,10-triacetic-1-{methyl[(4-aminophenyl)methyl]phosphinic acid}), has been synthesized. Its lanthanide(III) complexes contain one water molecule in the first coordination sphere. The high-resolution 1H and 31P spectra of [Eu(H2O) (DO3APABn)]- show that the twisted square-antiprismatic form of the complexes is more abundant in respect to the corresponding Eu(III)-DOTA complex. The 1H NMRD and variable-temperature 17O relaxation measurements of [Gd(H2O)(DO3APABn)]- show that the water residence time is short (298tauM = 16 ns) and falls into the optimal range predicted by theory for the attainment of high relaxivities once this complex would be endowed by a slow tumbling rate. The relaxivity (298r1 = 6.7 mM(-1) s(-1) at 10 MHz) is higher than expected as a consequence of a significant contribution from the second hydration sphere. These results prompt the use of [Gd(H2O)(DO3APABn)]- as a building block for the set-up of highly efficient macromolecular MRI contrast agents.

Three novel phosphorus-con- taining analogues of H5DTPA (DTPA = diethylenetriaminepentaacetate) were synthesised (H6L 1 ,H 5L 2 ,H 5L 3 ). These compounds have a -CH2- P(O)(OH)-R function (R = OH, Ph, CH2NBn2) attached to the central ni- trogen atom of the diethylenetriamine backbone. An NMR study reveals that these ligands bind to lanthanide(iii) ions in an octadentate fashion through the three nitrogen atoms, a PO oxygen atom and four carboxylate oxygen atoms. The complexed ligand occurs in several enantiomeric forms due to the chirality of the central nitro- gen atom and the phosphorus atom upon coordination. All lanthanide com- plexes studied have one coordinated water molecule. The residence times (t 298 ) of the coordinated water mole- cules in the gadolinium(iii) complexes of H6L 1 and H5L 2 are 88 and 92 ns, re- spectively, which are close to the opti- mum. This is particularly important upon covalent and noncovalent attach- ment of these Gd 3 + chelates to poly- mers. The relaxivity of the complexes studied is further enhanced by the presence of at least two water mole- cules in the second coordination sphere of the Gd 3 + ion, which are probably bound to the phosphonate/phosphinate moiety by hydrogen bonds. The com- plex (Gd(L 3 )(H2O)) 2� shows strong binding ability to HSA, and the adduct has a relaxivity comparable to MS-325 (40 s � 1 mm � 1 at 40 MHz, 378C) even though it has a less favourable tM value (685 ns). Transmetallation experiments with Zn 2 + indicate that the complexes have a kinetic stability that is compara- ble to-or better than-those of (Gd(dtpa)(H2O)) 2� and (Gd(dtpa

The phosphinic dipeptides of the general formula H2NCH2CONHCH2P(R)(O)(OH) where R˭Me, Ph and t-Bu has been synthetized from the free phosphinic acids and N-hydroxnunimide esters of the N-protected glycine. The deprotected dipeptida were purified by combination of the column chromato graphy on strong and week cation exchange resins by elution with diluted aqueous ammonia (0.1–3%)

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.

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.

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.

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).