NOTA Complexes with Copper(II) and Divalent Metal Ions: Kinetic and Thermodynamic Studies

Abstract

Hnota 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 Hnota, the comprehensive study of its solution chemistry has been overlooked. Thus, the coordination behavior of Hnota 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 K = 13.17). The high stability of the [Cu(nota)] complex (log K = 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 K(Zn) = 22.32 and log K(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, Hnota shows high selectivity for small metal ions. The [Cu(nota)] complex is hexacoordinated at neutral pH, and the equatorial NO interaction is strengthened by complex protonation. Detailed kinetic studies showed that the Cu(II) complex is formed quickly (millisecond time scale at c ≈ 0.1 mM) through an out-of-cage intermediate. 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 (τ 46 s; pH 0, 25 °C) and is less resistant to acid-assisted decomplexation than Cu(II) complexes with Hdota and Hteta. Surprisingly, [Cu(nota)] decomplexation is decelerated in the presence of Zn(II) ions due to the formation of a stable dinuclear complex. In conclusion, Hnota 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.

Translation of ceragenin affinity for bacteria to an imaging reagent for infection

“…NOTA has been well characterized as a thermodynamically and kinetically stable copper binding ligand suitable for conjugating to a variety of targeting groups. 18 An oligo-ethylene glycol linker was used to separate the ceragenin and NOTA to ensure that the bound copper ion did not interfere with interactions with bacterial membranes. In efforts to determine the structural features of conjugates 1 and 2 that impact bacterial labelling and imaging, structural variants 3 and 4 were prepared.…”

Radiochemical and radiopharmacological characterization of a 64Cu‐labeled α‐MSH analog conjugated with different chelators

“…If the pH was too low, 64 Cu flouts out from the Cu chelator complex decreasing the labeling yield. If the pH is too high, Cu(OH) 2 will be formed, and 64 Cu cannot efficiently coordinate with the chelators . A range of molar activity from 12 to 45 GBq/μmoL obtained for [ 64 Cu]Cu‐ 1 , [ 64 Cu]Cu‐ 2 , and [ 64 Cu]Cu‐ 3 was comparable with that for other 64 Cu‐labeled chelators or 64 Cu‐labeled bioconjugates .…”

A Luminescent NOTA-Based Terbium(III) “Turn-Off” Sensor for Copper

“…For thermodynamic and kinetic reasons, H3NOTA and other NOTA derivatives are widely used carriers of copper radionuclides as they predominantly form the Cu 2+ complex over complexes with common impurities in radiochemical formulations, such as Zn 2+ and Ni 2+ . [52][53][54] As such, NOTA is an ideal receptor to trap Cu 2+ ions in a fast and practically irreversible way at low concentrations and potentially even in the presence of biologically more abundant Zn 2+ . Luminescent lanthanide complexes with carbostyril sensitizers are well known to possess high luminescence quantum yields, millisecond lifetimes and excellent stability in aqueous solutions.…”

“…concomitant strong luminescence quenching effect, whereas no or only minor effects were observed with other cations(Figures 3 and 4). It was previously shown that the [Cu(NOTA)] − complex shows high thermodynamic stability (log K = 23.33) and fast quantitative formation, even at pH < 1.5 52. The NOTA ligand is very selective for Cu 2+ ions over alkali and earth alkali metal ions (log K = 2-5 and log K = 7-11, respectively) and moderately selective over other transition metal ions (e.g., log K (Mn 2+ ) = 16.30 and log K (Zn 2+ ) = 22.32) 52.…”

“…It was previously shown that the [Cu(NOTA)] − complex shows high thermodynamic stability (log K = 23.33) and fast quantitative formation, even at pH < 1.5 52. The NOTA ligand is very selective for Cu 2+ ions over alkali and earth alkali metal ions (log K = 2-5 and log K = 7-11, respectively) and moderately selective over other transition metal ions (e.g., log K (Mn 2+ ) = 16.30 and log K (Zn 2+ ) = 22.32) 52. Besides thermodynamic considerations, former studies demonstrated that the complexation of NOTA with Cu 2+ ions is kinetically preferred over several competing ions, including Zn 2+ 52.…”