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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]

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.