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.

Dedicated to Professor Jean-Claude Bünzli on the occasion of his 65th birthday in friendshipThe protonation constants of 2-[4,7,10-tris(phosphonomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-acetic acid (H 7 DOA3P) and of the complexes [Ln(DOA3P)] 4À (Ln ¼ Ce, Pr, Sm, Eu, and Yb) have been determined by multinuclear NMR spectroscopy in the range pD 2 -13.8, without control of ionic strength. Seven out of eleven protonation steps were detected (pK H i ¼ 13. 66, 12.11, 7.19, 6.15, 5.77, 2.99, and 1.99), and the values found compare well with the ones recently determined by potentiometry for H 7 DOA3P, and for other related ligands. The overall basicity of H 7 DOA3P is higher than that of H 4 DOTA and trans-H 6 DO2A2P but lower than that of H 8 DOTP. Based on multinuclear-NMR spectroscopy, the protonation sequence for H 7 DOA3P was also tentatively assigned. Three protonation constants (pK MHL , pK MH2L , and pK MH3L ) were determined for the lanthanide complexes, and the values found are relatively high, although lower than the protonation constants of the related ligand (pK Introduction. -Acyclic and macrocyclic polyamino chelators bearing coordinating pendant arms have been largely investigated as ligands for lanthanide(III) (Ln III ) complexation, looking for compounds suitable for medical applications [1] [2]. For such applications, an ideal ligand is the one which forms lanthanide (Ln) complexes with high termodynamic stability and, even more imperative, with extremely high kinetic inertness. Indeed, a high thermodynamic stability does not necessarily prevent complex dissociation in vivo, even if a good selectivity for the lanthanide ion over other endogeneous metal ions (e.g. Ca

No abstract

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.

No abstract