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In order to develop novel, more efficient, and/or selective contrast agents for magnetic resonance imaging (MRI), different modi operandiare explored as alternatives to water-relaxation enhancement. In this work, cobalt(II/III) complexes of bis(N-trifluoroethyl)cyclam derivatives with two acetate or two phosphonate pendant arms, H2te2f2aand H4te2f2p, were prepared and investigated. X-ray diffraction structures confirmed octahedral coordination with a very stable trans-IIIcyclam conformation and with fluorine atoms located about 5.3 Å from the metal center. The Co(II) complexes are kinetically inert, decomposing slowly even in 1 M aqueous HCl at 80 °C. The Co(II) complexes exhibited well-resolved paramagnetically shifted NMR spectra. These were interpreted with the help of quantum chemistry calculations. The 13C NMR shifts of the trans-[CoII(te2f2p)]2−complex were successfully assigned based on spin density delocalization within the ligand molecule. The obtained spin density also helps to describe d-metal-induced NMR relaxation properties of 19F nuclei, including the contribution of a Fermi contact relaxation mechanism. The paramagnetic complexes show convenient relaxation properties to be used as 19F MRI contrast agents.

Cross-bridged cyclam derivatives bearing two phosphonate (H4L1), bis(phosphinate) (H4L2), or phosphinate (H2L3) pendant arms were synthesized and studied with respect to their application as copper radioisotope carriers in nuclear medicine. The ligands show high macrocycle basicity (pK1> 14) and high Cu(II) complex stability (log K= 20–24). The complexation and dissociation kinetics of the Cu(II) complexes were studied by ultraviolet–visible spectroscopy. Phosphonate Cu(II)-H4L1and bis(phosphinate) Cu(II)-H4L2complexes form very quickly, reaching quantitative formation within 1 s at pH ∼6 and millimolar concentrations. Conversely, the formation of the phosphinate complex Cu(II)-H2L3is much slower (9 min at pH ∼6) due to the low stability of the out-of-cagereaction intermediate. All studied complexes are highly kinetically inert, showing half-lives of 120, 11, and 111 h for Cu(II)-H4L1, Cu(II)-H4L2, and Cu(II)-H2L3complexes, respectively, in 1 M HClO4at 90 °C. The high thermodynamic stability, fast formation, and extreme kinetic inertness of Cu(II) complexes indicate that phosphonate and bis(phosphinate) derivatives are promising ligands for nuclear medicine.

1,8-Bis(2,2,2-trifluoroethyl)cyclam (te2f) derivatives with two coordinating pendant arms involving methylenecarboxylic acid (H2te2f2a), methylenephosphonic acid (H4te2f2p), (2-pyridyl)methyl (te2f2py), and 2-aminoethyl arms (te2f2ae) in 4,11-positions were prepared, and their nickel(II) complexes were investigated as possible 19F MR tracers. The solid-state structures of several synthetic intermediates, ligands, and all complexes were confirmed by X-ray diffraction analysis. The average Ni···F distances were determined to be about 5.2 Å. All complexes exhibit a trans-III cyclam conformation with pendant arms bound in the apical positions. Kinetic inertness of the complexes is increased in the ligand order te2f2ae≪ te2f< te2f2py≈ H4te2f2p≪ H2te2f2a.The [Ni(te2f2a)] complex is the most kinetically inert Ni(II) complex reported so far. Paramagnetic divalent nickel caused a shortening of 19F NMR relaxation time down to the millisecond range. Solubility, stability, and cell toxicity were only satisfactory for the [Ni(te2f2p)]2–complex. This complex was visualized by 19F MRI utilizing an ultrashort echo time (UTE) imaging pulse sequence, which led to an increase in sensitivity gain. Mesenchymal stem cells were successfully loaded with the complex (up to 0.925/5.55 pg Ni/F per cell).19F MRI using a UTE pulse sequence provided images with a good signal-to-noise ratio within the measurement time, as short as tens of minutes. The data thus proved a major sensitivity gain in 19F MRI achieved by utilization of the paramagnetic (transition) metal complex as 19F MR tracers coupled with the optimal fast imaging protocol.

Protonation of a distant, noncoordinated group of metal-based magnetic resonance imaging contrast agents potentially changes their relaxivity. The effect of a positive charge of the drug on the human serum albumin (HSA)–drug interaction remains poorly understood as well. Accordingly, a (dibenzylamino)methylphosphinate derivative of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was efficiently synthesized using pyridine as the solvent for a Mannich-type reaction of tBu3DO3A, formaldehyde, and Bn2NCH2PO2H2ethyl ester. The ligand protonation and metal ion (Gd3+, Cu2+, and Zn2+) stability constants were similar to those of the parent DOTA, whereas the basicity of the side-chain amino group of the complexes (logKA= 5.8) was 1 order of magnitude lower than that of the free ligand (log KA= 6.8). The presence of one bound water molecule in both deprotonated and protonated forms of the gadolinium(III) complex was deduced from the solid-state X-ray diffraction data [gadolinium(III) and dysprosium(III)], from the square antiprism/twisted square antiprism (SA/TSA) isomer ratio along the lanthanide series, from the fluorescence data of the europium(III) complex, and from the 17O NMR measurements of the dysprosium(III) and gadolinium(III) complexes. In the gadolinium(III) complex with the deprotonated amino group, water exchange is extremely fast (τM= 6 ns at 25 °C), most likely thanks to the high abundance of the TSA isomer and to the presence of a proximate protonable group, which assists the water-exchange process. The interaction between lanthanide(III) complexes and HSA is pH-dependent, and the deprotonated form is bound much more efficaciously (∼13% and ∼70% bound complex at pH = 4 and 7, respectively). The relaxivities of the complex and its HSA adduct are also pH-dependent, and the latter is approximately 2–3 times increased at pH = 4–7. The relaxivity for the supramolecular HSA–complex adduct (r1b) is as high as 52 mM–1s–1at neutral pH (at 20 MHz and 25 °C). The findings of this study stand as a proof-of-concept, showing the ability to manipulate an albumin–drug interaction, and thus the blood pool residence time of the drug, by introducing a positive charge in a side-chain amino group.

Bifunctional derivatives of bis(phosphinate)-bearing cyclam (BPC) chelators bearing a carboxylate, amine, isothiocyanate, azide, or cyclooctyne in the BP side chain were synthesized. Conjugations required no protection of phosphinate or ring secondary amine groups. The ring amines were not reactive (proton protected) at pH < ∼8. For isothiocyanate coupling, oligopeptide N-terminal α-amines were more suitable than alkyl amines, e.g., Lys ω-amine (pKa∼7.5–8.5 and ∼10–11, respectively) due to lower basicity. The Cu-64 labeling was efficient at room temperature (specific activity ∼100 GBq/μmol; 25 °C, pH 6.2, ∼100 ligand equiv, 10 min). A representative Cu-64-BPC was tested in vivo showing fast clearance and no nonspecific radioactivity deposition. The monoclonal anti-PSCA antibody 7F5conjugates with thiocyanate BPC derivative or NODAGA were radiolabeled and studied in PC3-PSCA tumor bearing mice by PET. The radiolabeled BPC conjugate was accumulated in the prostate tumor with a low off-target uptake, unlike Cu-64-labeled NODAGA–antibody conjugate. The BPC chelators have a great potential for theranostic applications of the Cu-64/Cu-67 matched pair.

H3nota derivatives are among the most studied macrocyclic ligands and are widely used for metal ion binding in biology and medicine. Despite more than 40 years of chemical research on H3nota, the comprehensive study of its solution chemistry has been overlooked. Thus, the coordination behavior of H3nota with several divalent metal ions was studied in detail with respect to its application as a chelator for copper radioisotopes in medical imaging and therapy. In the solid-state structure of the free ligand in zwitterionic form, one proton is bound in the macrocyclic cavity through a strong intramolecular hydrogen-bond system supporting the high basicity of the ring amine groups (log Ka= 13.17). The high stability of the [Cu(nota)]−complex (log KML= 23.33) results in quantitative complex formation, even at pH <1.5. The ligand is moderately selective for Cu(II) over other metal ions (e.g., log KML(Zn) = 22.32 and log KML(Ni) = 19.24). This ligand forms a more stable complex with Mg(II) than with Ca(II) and forms surprisingly stable complexes with alkali-metal ions (stability order Li(I) > Na(I) > K(I)). Thus, H3nota shows high selectivity for small metal ions. The [Cu(nota)]−complex is hexacoordinated at neutral pH, and the equatorial N2O2interaction is strengthened by complex protonation. Detailed kinetic studies showed that the Cu(II) complex is formed quickly (millisecond time scale at cCu≈ 0.1 mM) through an out-of-cageintermediate. Conversely, conductivity measurements revealed that the Zn(II) complex is formed much more slowly than the Cu(II) complex. The Cu(II) complex has medium kinetic inertness (τ1/246 s; pH 0, 25 °C) and is less resistant to acid-assisted decomplexation than Cu(II) complexes with H4dota and H4teta. Surprisingly, [Cu(nota)]−decomplexation is decelerated in the presence of Zn(II) ions due to the formation of a stable dinuclear complex. In conclusion, H3nota is a good carrier of copper radionuclides because the [Cu(nota)]−complex is predominantly formed over complexes with common impurities in radiochemical formulations, Zn(II) and Ni(II), for thermodynamic and, primarily, for kinetic reasons. Furthermore, the in vivo stability of the [Cu(nota)]−complex may be increased due to the formation of dinuclear complexes when it interacts with biometals.

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

We report here the improved synthesis of the tripodal picolinate chelator Tpaa, with an overall yield of 41% over five steps, in comparison to the previously reported 6% yield. Tpaawas investigated for its coordination chemistry with Ga(III) and radiolabeling properties with gallium-68 (68Ga). The obtained crystal structure for [Ga(Tpaa)] shows that the three picolinate arms coordinate to the Ga(III) ion, fully occupying the octahedral coordination geometry. This is supported by 1H NMR which shows that the three arms are symmetrical when coordinated to Ga(III). Assessment of the thermodynamic stability through potentiometry gives log KGa-Tpaa= 21.32, with a single species being produced across the range of pH 3.5–7.5. Tpaaachieved >99% radiochemical conversion with 68Ga under mild conditions ([Tpaa] = 6.6 μM, pH 7.4, 37 °C) with a molar activity of 3.1 GBq μmol–1. The resulting complex, [68Ga][Ga(Tpaa)], showed improved stability over the previously reported [68Ga][Ga(Dpaa)(H2O)] in a serum challenge, with 32% of [68Ga][Ga(Tpaa)] remaining intact after 30 min of incubation with fetal bovine serum.

The bifunctional chelator NOPO (1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]) shows remarkably high GaIIIcomplexation efficiency and comprises one carboxylic acid moiety which is not involved into metal ion coordination. An improved synthetic protocol affords NOPO with 45% overall yield. Stepwise protonation constants (log Ka), determined by potentiometry, are 11.96, 5.22, 3.77, and 1.54; the stability constant of the Ga(III) complex is log KGaL= 25.0. Within 5 min, 68Ga(III) incorporation by NOPO is virtually quantitative at room temperature between pH 3 and 4, and at 95 °C at pH ranging from 0.5 to 7, at NOPO concentrations of 30 μM and 10 μM, respectively. During amide bond formation at the distant carboxylate using the HATU coupling reagent, an intramolecular phosphinic acid ester (phosphilactone) is formed, which is cleaved during 68Ga complexation or in acidic media, such as trifluoroacetic acid (TFA). Phosphilactone formation can also be suppressed by complexation of Zn2+prior to conjugation, the resulting zinc-containing conjugates nevertheless being suitable for direct 68Ga-labeling. In AR42J (rat pancreatic carcinoma) xenografted CD-1 nude mice, 68Ga-labeled NOPO–NaI3–octreotide conjugate (68Ga–NOPO–NOC) showed high and fully blockable tumor uptake (13.9 ± 5% ID/g, 120 min p.i., compared to 0.9 ± 0.4% ID/g with 5 mg/kg of nonlabeled peptide). Uptake in other tissues was generally below 3% ID/g, except appearance of excretion-related activity accumulation in kidneys. NOPO-functionalized compounds tend to be more hydrophilic than the corresponding DOTA- and NODAGA-conjugates, thus promoting fast and extensive renal excretion of 68Ga-NOPO-radiopharmaceuticals. NOPO-functionalized peptides provide suitable pharmacokinetics in vivo and meet all requirements for efficient 68Ga-labeling even at room temperature in a kit-like manner.

Three compounds that are based on cyclen and contain three methylphosphonate pendant arms ― (1,4,7,10‐tetraazacyclododecane‐1,4,7‐triyl)tris(methylene)triphosphonic acid (H6do3p), 3‐{4,7,10‐tris[(dihydroxyphosphoryl)methyl]‐1,4,7,10‐tetraazacyclododecan‐1‐yl}propanoic acid (H7do3p1pr) and [10‐(3‐hydroxypropyl)‐1,4,7,10‐tetraazacyclododecane‐1,4,7‐triyl]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(methylene)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 acid–base 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.

The lanthanide (Ln3+) complexes of three cyclen‐based ligands containing three methylphosphonate pendant arms were studied, the ligands being 1,4,7,10‐tetraazacyclododecane‐1,4,7‐triyltris(methylphosphonic acid) (H6do3p), 3‐[4,7,10‐tris(phosphonomethyl)‐1,4,7,10‐tetraazacyclododec‐1‐yl]propanoic acid (H7do3p1pr), and 10‐(3‐hydroxypropyl)‐1,4,7,10‐tetraazacyclododecane‐1,4,7‐triyltris(methylphosphonic acid) (H6do3p1ol). The three macrocyclic ligands form complexes of very high thermodynamic stability with all studied Ln3+ions. Kinetic studies showed that the acid‐assisted dissociation of Ce3+complexes of these ligands is much faster than for the complex of the related ligand H8dotp [1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetrayltetrakis(methylphosphonic acid)]. The number of water molecules coordinated to the Eu3+and Gd3+complexes was estimated to be < 1 for the do3p1ol ligand but ca. 1 for the other two ligands, as obtained by time‐resolved luminescence spectroscopy and by 1H and 17O relaxometric measurements. The NMR spectroscopic data indicate the existence of a considerable contribution from second‐sphere water molecules to the relaxivity of all the Gd3+complexes studied. The 1H and 31P NMR spectra of the Eu3+, Yb3+and Lu3+complexes showed that the propionate arm in the [Ln(do3p1pr)]4–complexes and the propanol arm in the [Ln(do3p1ol)]3–complexes are not bound to the Ln3+ion. The [Ln(do3p)]3–and [Ln(do3p1pr)]4–complexes have a clear preference for the TSAP (twisted square antiprismatic) isomer, while both SAP (square antiprismatic) and TSAP isomers are present in solutions of the [Ln(do3p1ol)]3–complexes.

A veritable gallium TRAP: Triazacyclononane‐phosphinic acid chelators (TRAP) form highly stable complexes with Ga3+(see figure) extremely efficiently over a wide pH range. Homo‐ and heteromultimeric bioconjugates can be synthesized in a straightforward manner, all of which renders TRAP a chelator with ideal properties for 68Ga positron emission tomography (PET) imaging agent elaboration.

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 TiO2colloidal 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 TiO2surface 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 TiO2particle surface.

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–3in [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 Iconformation.

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 GdIIIcomplex 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‐F0.1‐β‐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 ∼22 s−1mM−1per GdIIIor ∼150 s−1mM−1per molecule of the final conjugate (20 MHz, 25 °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.

Complexes of 4,10‐bis(phosphonomethyl)‐1,4,7,10‐tetraazacyclododecane‐1,7‐diacetic acid (trans‐H6do2a2p, H6L) with transition metal and lanthanide(III) ions were investigated. The stability constant values of the divalent and trivalent metal‐ion complexes are between the corresponding values of H4dota and H8dotp complexes, as a consequence of the ligand basicity. The solid‐state structures of the ligand and of nine lanthanide(III) complexes were determined by X‐ray diffraction. All the complexes are present as twisted‐square‐antiprismatic isomers and their structures can be divided into two series. The first one involves nona‐coordinated complexes of the large lanthanide(III) ions (Ce, Nd, Sm) with a coordinated water molecule. In the series of Sm, Eu, Tb, Dy, Er, Yb, the complexes are octa‐coordinated only by the ligand donor atoms and their coordination cages are more irregular. The formation kinetics and the acid‐assisted dissociation of several LnIII–H6Lcomplexes were investigated at different temperatures and compared with analogous data for complexes of other dota‐like ligands. The [Ce(L)(H2O)]3−complex is the most kinetically inert among complexes of the investigated lanthanide(III) ions (Ce, Eu, Gd, Yb). Among mixed phosphonate–acetate dota analogues, kinetic inertness of the cerium(III) complexes is increased with a higher number of phosphonate arms in the ligand, whereas the opposite is true for europium(III) complexes. According to the 1H NMR spectroscopic pseudo‐contact shifts for the Ce–Eu and Tb–Yb series, the solution structures of the complexes reflect the structures of the [Ce(HL)(H2O)]2−and [Yb(HL)]2−anions, respectively, found in the solid state. However, these solution NMR spectroscopic studies showed that there is no unambiguous relation between 31P/1H lanthanide‐induced shift (LIS) values and coordination of water in the complexes; the values rather express a relative position of the central ions between the N4and O4planes.

For application in positron emission tomography (PET), PrP9, a N,N′,N′′‐trisubstituted triazacyclononane with methyl(2‐carboxyethyl)phosphinic acid pendant arms, was developed as 68Ga3+complexing agent. The synthesis is short and inexpensive. GaIIIand FeIIIcomplexes of PrP9were characterized by single‐crystal X‐ray diffraction. Stepwise protonation constants and thermodynamic stabilities of metal complexes were determined by potentiometry. The GaIIIcomplex possesses a high thermodynamic stability (log K[GaL]=26.24) and a high degree of kinetic inertness. 68Ga labeling of PrP9is 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 68Ge/68Ga generator (typically consisting of 0.1 MHCl) can be directly used for labeling purposes. The rate of 68Ga activity incorporation at pH 3.3 and 20 °C is higher than for the established chelators DOTA and NOTA. Tris‐amides of PrP9with amino acid esters were synthesized to act as models for multimeric peptide conjugates. These conjugates exhibit radiolabeling properties similar to those of unsubstituted PrP9.

This work intends to investigate samarium and holmium complexes with a set of H4dotaanalogues bearing methylphosphonatemethylphosphinic acid pendant arms H5do3ap, H5do3apPrAand 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 vitroand in vivostability, 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 SmIII and HoIII 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 lanthanideIII 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.

The macrocyclic ligand with two methylphosphonic acid pendant arms, 4,11dimethyl1,4,8,11tetraazacyclotetradecane1,8bismethylphosphonic acid 1,8H4Me2te2p, H4L3, was synthesized by a new simple approach. The product of the reaction of quarternized formaldehyde cyclam aminal with the sodium salt of diethyl phosphite was hydrolyzed to give a very high yield of the title ligand. The H6L32+cation in the solid state is protonated on all ring nitrogen atoms and on each phosphonate group. In the solidstate structure of [CuH3L3][CuH2L3]PF6·3H2O, neutral as well as positively charged complex species are present. Molecular structures of both species are very similar having the copperII ion in a coordination environment between squarepyramidal and trigonalbipyramidal arrangements τ= 0.43 and 0.48 with one pendant arm noncoordinated. The ligand forms stable complexes with transitionmetal ions showing a high selectivity for divalent copper atoms. The formation of complexes of the ligand with CuII, ZnIIand CdIIis fast, confirming the acceleration of complexation due to the presence of the strongly coordinating pendant arms. Acidassisted decomplexation is fast for all three metal ions. Therefore, the copperII complex is not suitable for medicinal applications employing copper radioisotopes, but the title ligand motive can be employed in copperII separation. © WileyVCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009

The chelator Bn2DT3Awas used to produce a novel 68Ga complex for positron emission tomography (PET). Unusually, this system is stabilized by a coordinated hydroxide in aqueous solutions above pH 5, which confers sufficient stability for it to be used for PET. Bn2DT3Acomplexes Ga3+in a hexadentate manner, forming a mer-mercomplex with log K([Ga(Bn2DT3A)]) = 18.25. Above pH 5, the hydroxide ion coordinates the Ga3+ion following dissociation of a coordinated amine. Bn2DT3Aradiolabeling displayed a pH-dependent speciation, with [68Ga][Ga(Bn2DT3A)(OH)]−being formed above pH 5 and efficiently radiolabeled at pH 7.4. Surprisingly, [68Ga][Ga(Bn2DT3A)(OH)]−was found to show an increased stability in vitro(for over 2 h in fetal bovine serum) compared to [68Ga][Ga(Bn2DT3A)]. The biodistribution of [68Ga][Ga(Bn2DT3A)(OH)]−in healthy rats showed rapid clearance and excretion viathe kidneys, with no uptake seen in the lungs or bones.

Five DOTAlike ligands lacking a water molecule in the first coordination sphere of their GdIIIcomplexes, namely the phosphinates H4DOTPH, H4DOTPhmand H4DOTPEt, and the phosphonate monoesters H4DOTPOEtand H4DOTPOBu, were synthesized with the aim of exploring the influence of the second hydration sphere on the relaxivity of GdIIIcomplexes. The H4DOTPH, H4DOTPhmand H4DOTPOEtligands and their LnIIIcomplexes were characterized by potentiometry and timeresolved luminescence; the GdIIIcomplexes are thermodynamically much less stable than that of H4DOTA, and no water is coordinated in the inner sphere. The crystal structures of the free ligand H4DOTPOEtand of the GdIIIcomplexes of H4DOTPHand H4DOTPOEtwere determined by Xray diffraction. The complexes have the expected octadentate coordination mode with an N4O4arrangement; no water molecule is bound to the GdIIIion. Information on the structures of the LnIIIcomplexes of all five ligands in aqueous solution were obtained from 1H and 31P NMR spectra. The NMR spectra of the [LnDOTPhm]–and [LnDOTPEt]–complexes show that these compounds have a clear preference for a specific arrangement of phosphorus atoms which gives rise to the symmetrical RRRRor SSSS isomer. However, many diastereoisomers were observed for all other complexes. LnIIIinduced 17O NMR shift data reveal that the spatial location of the secondsphere water molecules for the two groups of complexes differs. The parameters governing the effect of the second hydration sphere on the relaxivity of the GdIIIcomplexes of all ligands were evaluated by EPR, variabletemperature 17O NMR spectroscopy and 1H NMRD relaxometry. The presence of secondsphere 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 andor on the isomerism present in solution, the secondsphere water molecules should be located close to the phosphorus–oxygen atoms.© WileyVCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009

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)

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 Å) between the metal centres. These units form a coordination polymeric chain. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

A series of dendrimeric conjugates based on a PAMAM (polyamidoamine) backbone with macrocyclic Gd−DO3A-PABncomplexes (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-PBnNCS)8, G2−(Gd−DO3A-PBnNCS)16, and G4−(Gd−DO3A-PBnNCS)59showed relaxivities of 10.1, 14.1, and 18.6 s-1mM-1at 20 MHz and 37 °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-PBnNCS)16conjugate. As confirmed by 1H 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 17O NMR and 1H 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, 298M, for the conjugates studied was ca. 45−70 ns, which is longer than the value found for the monomeric model compound Gd−DO3A-PABn(16 ns) but short enough so as not to limit the relaxivity. The global rotational correlation time, 298Rg, 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 S2(∼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-PBnNCS)8conjugate) 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 1H relaxometric data obtained for the G2−(Gd−DO3A-PBnNCS)16−poly(Lys)59adduct. Importantly, it was proved that the adduct formation did not hamper the water exchange process.

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 presence of excess of concurrent metal ions [copper(II) or europium(III)] are about 2–3 orders of magnitude shorter compared to H5dtpa and its amide derivatives. The behaviour can probably be attributed to steric strain in the new complexes, to the high affinity of phosphonate ligand for proton, and/or to easy formation of binuclear complexes, which act as intermediates in the complex dissociation. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Divalent metal complexes of macrocyclic ligand 1,4,8,11-tetraazacyclotetradecane-1,8-bis(methylphosphonic acid)) (1,8-H4te2p, H4L) were investigated in solution and in the solid state. The majority of transition-metal ions form thermodynamically very stable complexes as a consequence of high affinity for the nitrogen atoms of the ring. On the other hand, complexes with Mn2+, Pb2+and alkaline earth ions interacting mainly with phosphonate oxygen atoms are much weaker than those of transition-metal ions and are formed only at higher pH. The same tendency is seen in the solid state. Zinc(ii) ion in the octahedral trans-O,O-[Zn(H2L)] complex is fully encapsulated within the macrocycle (N4O2coordination mode with protonated phosphonate oxygen atoms). The polymeric {[Pb(H2L)(H2O)2]·6H2O}ncomplex has double-protonated secondary amino groups and the central atom is bound only to the phosphonate oxygen atoms. The phosphonate moieties bridge lead atoms creating a 3D-polymeric network. The [{(H2O)5Mn}2(µ-H2L)](H2L)·21H2O complex contains two pentaaquamanganese(ii) moieties bridged by a ligand molecule protonated on two nitrogen atoms. In the complex cation, oxygen atoms of the phosphonate groups on the opposite sites of the ring occupy one coordination site of each metal ion. The second ligand molecule is diprotonated and balances the positive charge of the complex cation. Complexation of zinc(ii) and cadmium(ii) by the ligand shows large differences in reactivity of differently protonated ligand species similarly to other cyclam-like complexes. Acid-assisted dissociations of metal(ii) complexes occur predominantly through triprotonated species [M(H3L)]+and take place at pH < 5 (Zn2+) and pH < 6 (Cd2+).

A novel “ditopic” ligand containing two monophosphinate triacetate DOTA-like units linked by a thiourea bridge has been synthesized and its complexes with Ln3ions (Ln = Y, Eu, Gd, Dy) investigated by NMR spectroscopy and relaxometry. The presence of one water molecule in the first coordination sphere has been determined by the measurement of the dysprosium(iii)-induced 17O NMR shifts. The 1H and 31P NMR spectra of the EuIIIderivative indicate a higher abundance of the fast-exchanging twisted square antiprismatic (m) isomer than the isomeric square antiprismatic (M; m/M= 3 : 2) complex. The analysis of the 89Y and 13C T1NMR relaxation times in the GdIII/YIIImixed complex have provided useful structural information. Values of ca.6.3 and 8.2 Å for the GdY and GdC distances, respectively, have been estimated which indicate a rather compact solution structure. This result finds support in the value of the relaxivity whose increase (at 20 MHz and 298 K) on passing from the monomeric (5.7 s−1mM−1) to the ditopic complex (8.2 s−1mM−1) can be attributed to the doubling of the inner-sphere term following the doubling of the molecular size. The structural and dynamic relaxivity-controlling parameters were assessed by a simultaneous fitting of the variable temperature 17O NMR and 1H NMRD relaxometric data. The mean water residence lifetime (298τM) has been found to be 53 ns, one of the shortest values reported for ditopic complexes. The reorientational correlation time is two times longer (298τR= 183 ps) than the corresponding value of the parent monomeric GdIIIcomplex, thus supporting the view of a limited degree of internal rotation. The possible influence of magnetic Gd–Gd coupling has been excluded by a comparison of the 1H NMRD profiles of the homodinuclear GdIII/GdIIIand the heterodinuclear GdIII/YIIIcomplexes.

Abstract The luminescence lifetimes of europium(III) complexes with new monophosphorus acid derivatives of H4dota were measured by means of time-resolved laser-induced luminescence spectroscopy in H2O and D2O. 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 H3do3a and H4dota 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 H2O can be satisfactorily used for estimation of the hydration numbers.

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 LnIIIions 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 (τM) in the GdIIIcomplex is much smaller than for [Gd(dota)(H2O)]−. The exchange rate appears to be dependent on the pH of the solution. The values of τMare 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 τM. The relaxivity of the GdIIIcomplex is almost independent of the pH and is equal to 4.7 s−1mM−1(20 MHz, pH 7 and 37 °C). The solid‐state structure was determined for the NdIIIcomplex. 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 Å.

The new ligand, 1,4,8,11-tetraazacyclotetradecan-1-ylmethylphosphonic acid H2te1P, H2L, was synthesized and its complexing properties towards selected metal ions were studied potentiometrically. The ligand forms a very stable complex with copperii logβCuL 27.34, with a high selectivity over binding of other metal ions i.e.logβZnL 21.03. The crystal structures of the free ligand in its protonated form with bromide as counter-ion and two copperii complexes obtained by crystallization at various pH were determined. The free ligand adopts the common conformation for such macrocycles with the protonated nitrogen atoms in the corners of a virtual rectangle. In the trans-Br,O-CuBrHte1P·H2O species, the central metal ion is surrounded by four in planenitrogen atoms, one oxygen atom of the pendant moiety in the apical position and a bromide anion positioned transto the oxygen atom, forming a distorted octahedral coordination sphere. In the compound CuH2te1PCuHte1PBr3·6H2O, obtained from a highly acidic solution, the bromide anions are placed further away from the copperii ion and the coordination environment N4O is thus square-pyramidal. In both structures, the protons are associated with non-coordinated phosphonate oxygen atoms.

Three novel phosphorus-containing analogues of H5DTPA (DTPA = diethylenetriaminepentaacetate) were synthesised (H6L¹, H5L², H5L³). These compounds have a -CH2-P(O)(OH)-R function (R = OH, Ph, CH2NBn2) attached to the central nitrogen 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 P&bond;O oxygen atom and four carboxylate oxygen atoms. The complexed ligand occurs in several enantiomeric forms due to the chirality of the central nitrogen atom and the phosphorus atom upon coordination. All lanthanide complexes studied have one coordinated water molecule. The residence times (τ${{298\hfill \atop {\rm M}\hfill}}$) of the coordinated water molecules in the gadolinium(III) complexes of H6L¹ and H5L² are 88 and 92 ns, respectively, which are close to the optimum. This is particularly important upon covalent and noncovalent attachment of these Gd³⁺ chelates to polymers. The relaxivity of the complexes studied is further enhanced by the presence of at least two water molecules in the second coordination sphere of the Gd³⁺ ion, which are probably bound to the phosphonate/phosphinate moiety by hydrogen bonds. The complex [Gd(L³)(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, 37 °C) even though it has a less favourable τM value (685 ns). Transmetallation experiments with Zn²⁺ indicate that the complexes have a kinetic stability that is comparable to—or better than—those of [Gd(dtpa)(H2O)]²⁻ and [Gd(dtpa-bma)(H2O)].

Three novel phosphorus‐containing analogues of H5DTPA (DTPA = diethylenetriaminepentaacetate) were synthesised (H6L1, H5L2, H5L3). These compounds have a ‐CH2‐P(O)(OH)‐R function (R = OH, Ph, CH2NBn2) attached to the central nitrogen 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 PO oxygen atom and four carboxylate oxygen atoms. The complexed ligand occurs in several enantiomeric forms due to the chirality of the central nitrogen atom and the phosphorus atom upon coordination. All lanthanide complexes studied have one coordinated water molecule. The residence times (τ${{298\hfill \atop {\rm M}\hfill}}$) of the coordinated water molecules in the gadolinium(III) complexes of H6L1and H5L2are 88 and 92 ns, respectively, which are close to the optimum. This is particularly important upon covalent and noncovalent attachment of these Gd3+chelates to polymers. The relaxivity of the complexes studied is further enhanced by the presence of at least two water molecules in the second coordination sphere of the Gd3+ion, which are probably bound to the phosphonate/phosphinate moiety by hydrogen bonds. The complex [Gd(L3)(H2O)]2−shows strong binding ability to HSA, and the adduct has a relaxivity comparable to MS‐325 (40 s−1mM−1at 40 MHz, 37 °C) even though it has a less favourable τMvalue (685 ns). Transmetallation experiments with Zn2+indicate that the complexes have a kinetic stability that is comparable to—or better than—those of [Gd(dtpa)(H2O)]2−and [Gd(dtpa‐bma)(H2O)].

In an aqueous solution at room temperature, 1,4,8,11-tetraazacyclotetradecane-1,8-bis(methylphosphonic acid) (H4L¹) and Cu^II form a pentacoordinated (pc) complex, pc-[Cu(L¹)]²⁻, exhibiting conformation I of the cyclam ring. At high temperature, the complex isomerises to a hexacoordinated isomer, trans-O,O-[Cu(L¹)]²⁻, with a trans-III conformation of the cyclam ring. In pc-[Cu(L¹)]²⁻, four ring nitrogen atoms and one phosphonate oxygen atom are arranged around Cu^II 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(L¹)]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) (H4L²), forms an analogous pentacoordinated complex, pc-[Cu(L²)]²⁻, at room temperature. However, the complex does not isomerise to the octahedral complex analogous to trans-O,O-[Cu(L¹)]²⁻. Because of the high thermodynamic stability of pc-[Cu(L¹)]²⁻, (log β=25.40(4), 25 °C, I=0.1 mol dm⁻³ KNO3) and the formation of protonated species, Cu^II is fully complexed in acidic solution (−log [H⁺]≈3). Acid-assisted decomplexation of both of the isomers of [Cu(H2L¹)] 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 τ1/2=19.7 min for pc-[Cu(H2L¹)] and τ1/2 about seven months for trans-O,O-[Cu(H2L¹)] for decomplexation in 5 M HClO4 at 25 °C. The mechanism of formation of pc-[Cu(L¹)]²⁻ is similar to those observed for other macrocyclic complexes.For classification of the cyclam ring conformation in complexes, see B. Bosnich, K. Poon, M. Tobe, Inorg. Chem. 1965, 4, 1102.

In an aqueous solution at room temperature, 1,4,8,11‐tetraazacyclotetradecane‐1,8‐bis(methylphosphonic acid) (H4L1) and CuIIform a pentacoordinated (pc) complex, pc‐[Cu(L1)]2−, exhibiting conformation Iof the cyclam ring. At high temperature, the complex isomerises to a hexacoordinated isomer, trans‐O,O‐[Cu(L1)]2−, with a trans‐IIIconformation of the cyclam ring. In pc‐[Cu(L1)]2−, four ring nitrogen atoms and one phosphonate oxygen atom are arranged around CuIIin 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(L1)]2−isomer, the nitrogen atoms form a plane and the phosphonic acid groups are in a mutually transconfiguration. A structurally very similar ligand, 4‐methyl‐1,4,8,11‐tetraazacyclotetradecane‐1,8‐bis(methylphosphonic acid) (H4L2), forms an analogous pentacoordinated complex, pc‐[Cu(L2)]2−, at room temperature. However, the complex does not isomerise to the octahedral complex analogous to trans‐O,O‐[Cu(L1)]2−. Because of the high thermodynamic stability of pc‐[Cu(L1)]2−, (log β=25.40(4), 25 °C, I=0.1 mol dm−3KNO3) and the formation of protonated species, CuIIis fully complexed in acidic solution (−log [H+]≈3). Acid‐assisted decomplexation of both of the isomers of [Cu(H2L1)] 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 τ1/2=19.7 min for pc‐[Cu(H2L1)] and τ1/2about seven months for trans‐O,O‐[Cu(H2L1)] for decomplexation in 5 MHClO4at 25 °C. The mechanism of formation of pc‐[Cu(L1)]2−is similar to those observed for other macrocyclic complexes.For classification of the cyclam ring conformation in complexes, see B. Bosnich, K. Poon, M. Tobe, Inorg. Chem.1965, 4, 1102.

Bisaminomethylphosphinic acid, NH2CH22PO2H HL, was synthesized using a new procedure. Its coordination ability towards Coiiiii, Niii, Cuii and Znii 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 aminoalkylphosphinic acids. Consequently, the values of the determined stability constants are comparable with those found for aminoalkylphosphonic acids. NMR titrations of Znii 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-MCl2H2L-O2H2O2Cl2, where Mii are Mnii, Coii, Niii, Cuii, Znii, Caii, and Cdii, crystallized from acid solutions. The central ion is octahedrally coordinated with two phosphinate oxygen atoms, two molecules of water and two chlorides in all-transarrangement. 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′-CoL-N,N,O2. On the other hand, in the zincii complex, two phosphinate oxygen atoms and two amine nitrogen atoms transto 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 zincii ion and the other amino group is bound to the neighbouring ion creating an infinite chain. Nickelii forms a trans-O,O′-NiH2O2L-N,N2 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.

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 pK_A, it is able to bind metal ions at lower pH than other coordinating groups do.

The complexing properties of the phosphinic acid analogues of glycylglycine ([(glycylamino)methyl]phosphinic acids) NH₂CH₂C(O)–NHCH₂P(O)(R)(OH) [GlyGly(PR)] (R = Ph, Me and tert-Bu) towards Co2+, Ni2+, Cu2+ and Zn2+ ions in aqueous solutions are investigated using potentiometry, and absorption and EPR spectroscopies. The potentiometric results indicate different properties of the Cu2+–GlyGly(PR) systems in comparison with glycylglycine and its phosphonic acid analogue NH₂CH₂C(O)–NHCH₂P(O)(OH)₂ [GlyGly(P)]. The phosphinic dipeptides GlyGly(PR) readily form complexes with Cu2+/ligand molar ratio 1 ∶ 2 exhibiting the (N_amine, N_amide)₂ coordination mode above pH 9 even in solutions with only a slight excess of the ligand. In the system with GlyGly, the Cu2+ complex is observed at pH 12–13 and a metal ∶ ligand ratio of 1 ∶ 500. The metal-induced deprotonation of the amide nitrogen and the extent of formation of the 1 ∶ 2 complexes depend on the acidity of the phosphinic acid group which is influenced by the substituent at the phosphorus atom. The models based on potentiometry are confirmed by spectroscopic measurements. Stability constants of the phosphinic dipeptides GlyGly(PR) with the other metal ions are the same as for glycylglycine and, therefore, the same binding pattern through the amine group and peptide oxygen is proposed. The presence of protonated complexes is assumed in all the systems studied. In the protonated complexes, the peptide is bound through the phosphinic acid group whereas the amino group remains protonated. The presence of the species in the system containing the phosphonic acid analogue of glycylglycine [GlyGly(P)] with Cu2+, which was investigated by potentiometry previously, is confirmed by EPR spectroscopy.

Two phenylphosphinic acid derivatives of tetraaza macrocycles, (1,4,7,10-tetraazacyclododecanetetrayl)tetrakis(methylene)tetrakis(phenylphosphinic acid)] (H4L¹) and (1,4,8,11-tetraazacyclotetradecanetetrayl)tetrakis(methylene)tetrakis(phenylphosphinic acid)] (H4L²), were synthesised and the crystal structures of H4L² and its bis(1-adamantylammonium) salt were determined. In both the structures, the ring conformation is virtually the same and is stabilised by hydrogen bonds. Protonation constants of the acids and stability constants of their Zn²⁺ and Cd²⁺ complexes were determined pH-metrically at 25 °C and at an ionic strength of 0.1 mol dm^–3 (KNO3). The pKA values found for both the compounds are lower than those for their carboxylic analogues and correspond to the expected electron-withdrawing ability of the –P(Ph)O2H moiety. The value pK1 of the last dissociation constant of H4L¹ is surprisingly high. The complexes of Zn²⁺ and Cd²⁺ with (L¹)^4– and (L²)^4– are less stable than those with other similar ligands, which is in accordance with lower overall basicity of H4L¹ and H4L². A pronounced drop in the stability of the complexes of H4L² can be explained by partial coordination of the ligand to the metal ions. The solution properties of the ligands were also investigated by ³¹P-NMR spectroscopy. The spectra observed suggest stable (on the NMR time scale) conformations of the protonated ligands in solution. A comparison of NMR spectra in solution and CP/MAS-NMR spectra indicates that the structures of the conformers roughly correspond to the structures observed in the solid state. The conformations are stabilised by intramolecular hydrogen bonds and by hydrophobic interactions of phenylphosphinic moieties. The conformers are stable even at 90 °C, but not in the presence of complexing metal ions.

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 Ln–O_w distance is strongly dependent on Ln(III), it varies from 2.815(6) Å in the La complex to 4.448(10) Å 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.

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

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.

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.

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.

The complexing properties of aminomethylphosphonic acid, Gly-(P), and glycylaminomethylphosphonic acid, Gly-Gly-(P), with PtII and PdII were investigated pH-metrically at 25 °C and at an ionic strength of 0.1 mol dm-3 (KNO3) using ‘out of cell’ titrations. The stability constants calculated indicate formation of complexes with a metal∶ligand molar ratio of 1∶1 and 1∶2. The species and their distribution determined pH-metrically were confirmed by 31P and 1H NMR titrations. Comparison of our results for Gly-(P) and Gly-Gly-(P) with those for glycine and glycylglycine and other common dipeptides shows that the complexing properties of PdII and PtII towards both types are very similar.

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 KNO3). The protonation and stability constants for complex formation with Co2+, Ni2+ and Zn2+ indicate co-ordination only via the amine, carbonyl peptide and phosphonic groups and, for Cu2+, 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 31P-{1H} and 1H NMR titrations of the systems involving PdII and PtII.

A marked increase of relaxivity has been observed upon rigidifying the internal frame of Gd-containing PAMAM dendrimers: the effect has been attained by either protonation of the dendrimer or by forming supramolecular adducts with cationic polyaminoacids.

The presence of a six-membered chelate ring involving a pyridine N-oxide moiety induces exclusive Misomer formation throughout the whole lanthanide series endowed with a fast water exchange in the case of the Gdiii complex.

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