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An easy and cheap method for measurement of GaIII complexation kinetics was developed. The method is based on UV-Vis quantification of non-complexed chelators after the addition of CuII ions at individual time points. The method was evaluated using established ligands, H3nota and H6notPPr, and was utilized to study the kinetics of GaIII complexation with four new symmetric derivatives of 1,4,7-triazacyclononane bearing methylphosphonate/phosphinate pendant arms - TRAP ligands. Chelators bearing ethoxy groups (H3L¹) or 2,2,2-trifluoroethyl groups (H3L²) on the phosphorus atoms showed fast formation (t99% = 21 and 10 min, respectively, at pH 2.0) and efficient radiolabelling which were comparable to the previously reported chelators bearing the 2-carboxyethyl group (H6notPPr). Chelators bearing (N,N-dibenzyl-amino)methyl (H3L³) and aminomethyl (H3L4) substituents showed a significantly slower complexation (t99% = 4.4 and 3.6 h, respectively, at pH 2.0) and inefficient radiolabelling, mainly at room temperature or low pH. This was caused by protonation of the amino groups of the pendant arms leading to coulombic repulsion between the GaIII ion and the positively charged protonated amines. The trends in complexation rates determined by the UV-Vis method correlated well with the results of the 68Ga radiolabelling study. [ABSTRACT FROM AUTHOR]

Biological phosphates can coordinate metal ions and their complexes are common in living systems. Dynamics of mutual oxygen atom exchange in the tetrahedral group in complexes has not been investigated. Here, we present a direct experimental proof of exchange ("phosphonate rotation") in model Ln(III) complexes of monophosphonate H4dota analogue which alters phosphorus atom chirality of coordinated phosphonate monoester. Combination of macrocycle‐based isomerism with P‐based chirality leads to several diastereoisomers. (Non)‐coordinated oxygen atoms were distinguished through 17O‐labelled phosphonate group and their mutual exchange was followed by various NMR techniques and DFT calculations. The process is sterically demanding and occurs through bulky bidentate (κ2‐PO2)− coordination and was observed only in twisted‐square antiprism (TSA) diastereoisomer of large Ln(III) ions. Its energy demands increase for smaller Ln(III) ions (298ΔG≠(exp./DFT)=51.8/52.1 and 61.0/71.5 kJ mol−1 for La(III) and Eu(III), respectively). These results are helpful in design of such complexes as MRI CA and for protein paramagnetic NMR probes. It demonstrates usefulness of 17O NMR to study solution dynamics in complexes involving phosphorus acid derivatives and it may inspire use of this method to study dynamics of phosphoric acid derivatives (as e. g. phosphorus acid‐based inhibitors of metalloenzymes) in different areas of chemistry. [ABSTRACT FROM AUTHOR]

A new hexadentate 1,4,7-triazacyclononane-based ligand bearing three coordinating methylene-(2,2,2-trifluoroethyl)phosphinate pendant arms was synthesized and its coordination behaviour towards selected divalent (Mg2+, Ca2+, Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+) and trivalent (Cr3+, Fe3+, Co3+) transition metal ions was studied. The ligand forms stable complexes with late divalent transition metal ions (from Co2+ to Zn2+) and the complexes of these metal ions are formed above pH ∼3. A number of complexes with divalent metal ions were structurally characterized by means of single-crystal X-ray diffraction. The complex of the larger Mn2+ ion adopts a twisted trigonally antiprismatic geometry with a larger coordination cavity and smaller torsion of the pendant arms, whereas the smaller ions Ni2+, Cu2+ and Zn2+ form octahedral species with a smaller cavity and larger pendant arm torsion. In the case of the Co2+ complexes, both coordination arrangements were observed. The complexes with paramagnetic metal ions were studied from the point of view of potential utilization in 19F magnetic resonance imaging. A significant shortening of the 19F NMR longitudinal relaxation times was observed: a sub-millisecond range for complexes of Cr3+, Mn2+ and Fe3+ with symmetric electronic states (t2g3 and HS-d5), the millisecond range for the Ni2+ and Cu2+ complexes and tens of milliseconds for the Co2+ complex. Such short relaxation times are consistent with a short distance between the paramagnetic metal ion and the fluorine atoms (∼5.5–6.5 Å). Among the redox-active complexes (Mn3+/Mn2+, Fe3+/Fe2+, Co3+/Co2+, Cu2+/Cu+), the cobalt complexes show sufficient stability and a paramagnetic–diamagnetic changeover with the redox potential lying in a physiologically relevant range. Thus, the Co3+/Co2+ complex pair can be potentially used as a smart redox-responsive contrast agent for 19F MRI. [ABSTRACT FROM AUTHOR]

A new cyclam-based ligand bearing two methylene(2,2,2-trifluoroethyl)phosphinate pendant arms was synthesized and its coordination behaviour towards selected divalent transition metal ions [Co(II), Ni(II), Cu(II), Zn(II)] was studied. The ligand was found to be very selective for the Cu(II) ion according to the common Williams–Irving trend. Complexes with all the studied metal ions were structurally characterized. The Cu(II) ion forms two isomeric complexes; the pentacoordinated isomer pc-[Cu(L)] is the kinetic product and the octahedral trans-O,O′-[Cu(L)] isomer is the final (thermodynamic) product of the complexation reaction. Other studied metal ions form octahedral cis-O,O′-[M(L)] complexes. The complexes with paramagnetic metal ions showed a significant shortening of 19F NMR longitudinal relaxation times (T1) to the millisecond range [Ni(II) and Cu(II) complexes] or tens of milliseconds [Co(II) complex] at the temperature and magnetic field relevant for 19F magnetic resonance imaging (MRI). Such a short T1 results from a short distance between the paramagnetic metal ion and the fluorine atoms (∼6.1–6.4 Å). The complexes show high kinetic inertness towards acid-assisted dissociation; in particular, the trans-O,O′-[Cu(L)] complex was found to be extremely inert with a dissociation half-time of 2.8 h in 1 M HCl at 90 °C. Together with the short relaxation time, it potentially enables in vitro/in vivo utilization of the complexes as efficient contrast agents for 19F MRI. [ABSTRACT FROM AUTHOR]

A series of Cu(II) complexes with cyclam-based ligands containing two N-(2,2,2-trifluoroethyl)-aminoalkyl pendant arms in 1,8-positions (L1: 1,2-ethylene spacer, L2: 1,3-propylene spacer; L3: 1,4-butylene spacer) was studied in respect to potential use as contrast agents for 19F magnetic resonance imaging (MRI). A number of structures of the complexes as well as of several organic precursors were determined by single-crystal X-ray diffraction analysis. Geometric parameters (especially distances between fluorine atoms and the central metal ion) were determined for each complex and the identity of isomeric complex species present in solution was established. The NMR longitudinal relaxation times (T1) of 19F nuclei in the ligands at clinically relevant fields and temperatures (1–2 s) were significantly shortened upon Cu(II) binding to 7–10 ms for [Cu(L1)]2+, 20–30 ms for [Cu(L2)]2+ and 20–50 ms for [Cu(L3)]2+. The trend of the relaxation time shortening is in accordance with the distance and number of chemical bonds between fluorine atoms and the Cu(II) ion. The signals show promising T2*/T1 ratios in the range 0.25–0.55, assuring their good applicability to 19F NMR/MRI. The results show that even the Cu(II) ion, with a small magnetic moment, causes significant relaxation enhancement with a long-range effect and can be considered as a highly suitable metal ion for efficient 19F MRI contrast agents. [ABSTRACT FROM AUTHOR]

NOTA monoamides are commonly and widely used chelators for the complexation of copper radioisotopes applied in molecular imaging and targeted nuclear therapy. However, information about their coordination behavior remains scarce. In this study, two NOTA‐monoamides, N‐ethyl (H2L1) and N,N‐diethyl (H2L2), were synthesized as model ligands and tested to probe differences in their coordination behavior between the secondary and tertiary amide pendant arms for potential applications as copper radioisotope carriers. Our results demonstrated that the solid [Cu(L1)] and [Cu(L2)] complex have a distorted octahedral arrangement, similar to structure of the [Cu(Hnota)] complex. As shown by equilibrium data, the ligands have a slightly lower basicity, and thus complexes with divalent metal ions and LiI have slightly lower stability constants than those of the parent ligand, H3nota. The dissociation constants of the CuII, ZnII and NiII complexes with H2L1 also indicate deprotonation and N‐coordination of the secondary amide group at pH>9. Complexation of CuII ions with the title ligands is slower than that with H3nota but still very fast (quantitative binding in <1 s, pH 2, millimolar concentrations), and CuII complexes of both monoamide ligands are more resistant to acid‐assisted decomplexation than the CuII‐H3nota complex. Therefore, our coordination data highlight that NOTA‐monoamides are suitable chelators for molecular imaging and nuclear medicine. [ABSTRACT FROM AUTHOR]

Ligands combining a bis(phosphonate) group with a macrocycle function as metal isotope carriers for radionuclide-based imaging and for treating bone metastases associated with several cancers. However, bis(phosphonate) pendant arms often slow down complex formation and decrease radiochemical yields. Nevertheless, their negative effect on complexation rates may be mitigated by using a suitable spacer between bis(phosphonate) and the macrocycle. To demonstrate the potential of bis(phosphonate) bearing macrocyclic ligands as a copper radioisotope carrier, we report the synthesis of a new cyclam derivative bearing a phosphinate-bis(phosphonate) pendant (H5te1PBP). The ligand showed a high selectivity to CuII over ZnII and NiII ions, and the bis(phosphonate) group was not coordinated in the CuII complex, strongly interacting with other metal ions in solution. The CuII complex formed quickly, in 1 s, at pH 5 and at a millimolar scale. The complexation rates significantly differed under a ligand or metal ion excess due to the formation of reaction intermediates differing in their metal-to-ligand ratio and protonation state, respectively. The CuII-te1PBP complex also showed a high resistance to acid-assisted hydrolysis (t1/2 2.7 h; 1 M HClO4, 25 °C) and was effectively adsorbed on the hydroxyapatite surface. H5te1PBP radiolabeling with [64Cu]CuCl2 was fast and efficient, with specific activities of approximately 30 GBq 64Cu per 1 μmol of ligand (pH 5.5, room temperature, 30 min). In a pilot experiment, we further demonstrated the excellent suitability of [64Cu]CuII-te1PBP for imaging active bone compartments by dedicated small animal PET/CT in healthy mice and subsequently in a rat femoral defect model, in direct comparison with [18F]fluoride. Moreover, [64Cu]CuII-te1PBP showed a higher uptake in critical bone defect regions. Therefore, our study highlights the potential of [64Cu]CuII-te1PBP as a PET radiotracer for evaluating bone healing in preclinical and clinical settings with a diagnostic value similar to that of [18F]fluoride, albeit with a longer half-life (12.7 h) than 18F (1.8 h), thereby enabling extended observation times. [ABSTRACT FROM AUTHOR]

The pyrophosphate AdNHP(S)(OEt)OP(S)(OEt)(OH) is yielded upon thermolysis in inert solvents of O-ethyl N-adamantylphosphoramidothioate. The fractionation is effected by abolishing the amine fraction accompanied by freeing of ethyl metathiophosphate (EtOP S O). The starting material phosphoramidothioate undergoes phosphorylation by the released EtOP S O. A similar but more intricate reaction affords O-ethyl N,N-diethylphosphoramidothioate. Both products are functional thiophosphorylating agents for OH groups such as alcohols, a silanol and the silanol groups of silica gel.

A bicyclic ligand, 1,4,7‐triazacyclononane 1,4‐bridged with methylene‐bis(phosphinate) and bearing benzyl substituent on the remaining amino group, was synthesized from N‐benzyl‐tacn and CH2(PO2H2)2 by two sequential Mannich‐type reactions in a high yield. Basicity of the macrocycle is high (pK1=12.25). Complexes with CuII and NiII ions show dimeric structures in the solid state. The structures exhibit distorted octahedral environment with two ring amino groups from one molecule and two oxygen atoms of chelating bis(phosphinate) anion from the other molecule in the equatorial plane, and with the apical positions occupied by the remaining macrocycle amino group and by one of the phosphinate oxygen atoms. The metal ions in the dimers are additionally bridged by one phosphinate group. Stability of the CuII complex is more than ten orders of magnitude lower than that of the [Cu(nota)]− complex due to a different number and different nature of the pendant arms, and inappropriate arrangement of donor atoms in the ligand bicyclic structure. Rigidity of the short P−C−P chain of the geminal methylene‐bis(phosphinate) does not allow simultaneous coordination of both phosphinate groups and the ring amines to the same metal ion. The low solubility of NiII and ZnII complexes disabled determination of their stability constants. [ABSTRACT FROM AUTHOR]

Al(III) complexes are extensively studied as [18F]fluoride carriers in positron emission tomography. However, our limited knowledge on their thermodynamic and kinetic properties has hindered efforts to easily prepare radiochemically pure compounds while simultaneously reducing the overall labeling time. Thus, to improve our understanding of fluoride binding to coordinatively unsaturated Al(III) complexes, we investigated the ternary system Al(III)–H3NTA–F− (H3NTA = nitrilo-triacetic acid) by NMR, potentiometry and X-ray diffraction. Our results show that the [Al(NTA)] complex binds two water molecules, which are replaced by fluorides. Individual species and isomers show separate 19F NMR signals and different stability constants. The two available positions on the [Al(NTA)] complex feature significantly different properties in terms of basicity of the coordinated water molecules and preferential binding of fluoride anions. Fluorides are effectively bound in weakly acidic or neutral solutions, whereas hydroxido species are preferentially formed in alkaline solutions. Our experimental observations were rationalized by theoretical calculations: predictions of the energy ordering of complexes and isomers, interpretation of 19F NMR chemical shifts, and natural bonding orbital analysis. Radiolabeling of [Al(NTA)] with [18F]fluoride gave low yields that confirmed a high affinity of the complex for hydroxide anions. [ABSTRACT FROM AUTHOR]

A series of lanthanide(III) complexes of a monophosphinate analogue of H4dota, 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic-10-methyl[(N,N-dibenzylamino)methyl]phosphinic acid (H4do3apDBAm = H4L1), were prepared and their solid-state structures were studied using single-crystal X-ray diffraction. In all structures, the ligand anion was octadentately coordinated to the Ln(III) or Sc(III) ions similarly to other DOTA-like ligands, i.e. forming parallel N4- and O4-planes. The lighter lanthanide(III) complexes (till dysprosium) were nonacoordinated in the twisted square-antiprismatic (TSA) configuration with the apical coordination of water molecules or oxygen atoms from the neighbouring complex unit. The heavier lanthanide(III) complexes (from terbium) were found as the "anhydrous" octacoordinated twisted square-antiprismatic (TSA′) isomer. For the terbium(III) ion, both forms were structurally characterized. The structural data of the Ln(III)–H4L1 complexes and complexes of several related DOTA-like ligands were analysed. It clearly showed that the structural parameters for the square-antiprismatic (SA) isomers were clustered in a small range while those for the TSA/TSA′ isomers were significantly more spread. The analysis also gave useful information about the influence of various pendant arms on the structure of the complexes of the DOTA-like ligands. The twist angle (torsion) of the chelate ring containing a larger phosphorus atom was similar to those of the remaining three acetate pendants. It led to a larger separation of the N4⋯O4 planes and to smaller trans-O–Ln–O angles than the parameters found in the complexes of H4dota and its tetraamide derivatives dotam(R). It resulted in a relatively long bond between the metal ion and the coordinated water molecule. It led, together with the negative charge of the oxygen atoms forming the O4-plane, to an extremely fast water exchange rate reported for the Gd(III)–H4L1 complex and, generally, to a fast water exchange of Gd(III) complexes with the monophosphorus acid analogues of H4dota, H5do3ap/H4do3apR. [ABSTRACT FROM AUTHOR]

Investigations of Ln(III) complexes wtih amide derviatives of H4dota in solution were done. The structural parameters determined for TSA, TSA', and SA species of the [Y(Hdo3aP(super ABn)] complex and parameters found for the series of Ln(III) complexes indicate that structures of both TSA and TSA' spheres are flexible.

A novel macrocyclic DOTA like ligand is evaluated to study the therapy, which contains a monoamide bis(phosphonic acid) that targets the bone group. The result shows that the amide bis(phosphonate) moiety is the sole element responsible to bind the complex to hydroxyapatite.

A series of lanthanide(III) complexes formulated as M[Ln(Hdo3ap)].xH2O (M = Li or H and Ln = Tb, Dy, Er, Lu, and Y) with the monophosphonate analogue of H4dota, 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic-10-methylphosphonic acid (H5do3ap), is prepared in the solid state. The comparison of structures of Ln(III) complexes with DOTA-like ligands shows that the twisted-square-antiprismatic (TSA) arrangement is flexible, and the derived structural parameters are almost identical for different ligands and lanthanide(III) ions.

1H spin-lattice relaxation studies of water solutions of Bismuth-ethylenediamine-tetraacetic acid (Bi-EDTA), Bismuth-ethylenediamine-tetrakis(methylenephosphonic) acid (Bi-EDTP), Bismuth-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Bi-DOTA), Bismuth-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylenephosphonic acid) (Bi-DOTP) and Bismuth-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (Bi-DO3A) have been performed in order to compare Quadrupole Relaxation Enhancement (QRE) effects with Paramagnetic Relaxation Enhancement (PRE) from the perspective of exploiting the first one as a novel contrast mechanism for Magnetic Resonance Imaging (MRI). The selected compounds can be considered as 209Bi counterparts of Gd3+ complexes. The relaxation experiments have been performed in a broad frequency range of 5 kHz-30 MHz. The relaxation contribution associated with QRE has been extracted from the data and compared with PRE. Similarities and differences between the two effects have been discussed. [ABSTRACT FROM AUTHOR]

Objective: 19F MRI requires biocompatible and non-toxic soluble contrast agents with high fluorine content and with suitable 19F relaxation times. Probes based on a DOTP chelate with 12 magnetically equivalent fluorine atoms (DOTP-tfe) and a lanthanide(III) ion shortening the relaxation times were prepared and tested.Methods: Complexes of DOTP-tfe with trivalent paramagnetic Ce, Dy, Ho, Tm, and Yb ions were synthetized and characterized. 19F relaxation times were determined and compared to those of the La complex and of the empty ligand. In vitro and in vivo 19F MRI was performed at 4.7 T.Results: 19F relaxation times strongly depended on the chelated lanthanide(III) ion. T1 ranged from 6.5 to 287 ms, T2 from 3.9 to 124.4 ms, and T2* from 1.1 to 3.1 ms. All complexes in combination with optimized sequences provided sufficient signal in vitro under conditions mimicking experiments in vivo (concentrations 1.25 mM, 15-min scanning time). As a proof of concept, two contrast agents were injected into the rat muscle; 19F MRI in vivo confirmed the in vivo applicability of the probe.Conclusion: DOTP-based 19F probes showed suitable properties for in vitro and in vivo visualization and biological applications. The lanthanide(III) ions enabled us to shorten the relaxation times and to trim the probes according to the actual needs. Similar to the clinically approved Gd3+ chelates, this customized probe design ensures consistent biochemical properties and similar safety profiles. [ABSTRACT FROM AUTHOR]