Ligands macrocycliques renforcés, leurs complexes ainsi que leurs utilisations.

The invention relates to new macrocyclic ligands of formula (I) and complexes thereof, particularly radioactive complexes, and to the uses thereof and a method for preparing same. The ligands have a reinforced pyclene core.La présente invention concerne de nouveaux ligands macrocycliques de formule (I) et leurs complexes, notamment radioactifs, leurs utilisations ainsi que leur procédé de préparation. Lesdits ligands présentant un noyau pyclène renforcé

Pyclen-Based Ligands Bearing Pendant Picolinate Arms for Gadolinium Complexation

We report the synthesis of two pyclen-based regioisomer ligands (pyclen = 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca1(15),11,13-triene) functionalized with picolinic acid pendant arms either at positions 3,9-pc2pa (L5) or 3,6-pc2pa (L6) of the macrocyclic fragment. The ligands were prepared by regiospecific protection of one of the amine nitrogen atom of the macrocycle using Boc and Alloc protecting groups, respectively. The X-ray structure of the Gd(III) complex of L5 contains trinuclear [(GdL5)3(H2O)3] 3+ entities in which the monomeric units are joined by 2- 1 : 1 carboxylate groups. However, the 1H and 89Y NMR spectra of its Y(III) analogue support the formation of monomeric complexes in solution. The Tb(III) complexes are highly luminescent, with emission quantum yields of up to 50% for [TbL5] + . The luminescence lifetimes recorded in H2O and D2O solutions indicate the presence of a water molecule coordinated to the metal ion, as also evidenced by the 1H relaxivities measured for the Gd(III) analogues. The Gd(III) complexes present very different exchange rates of the coordinated water molecule (kex 298 = 87.1 and 1.06 106 s -1 for [GdL5] + and [GdL6] + , respectively). The very high water exchange rate of [GdL5] + is associated to the steric hindrance originated by the coordination of the ligand around the water binding site, which favors a dissociatively activated water exchange process. The Gd(III) complexes present rather high thermodynamic stabilities (logKGdL = 20.47 and 19.77 for [GdL5] + and [GdL6] + , respectively). Furthermore, these complexes are remarkably inert with respect to their acid-assisted dissociation, in particular the complex of L5

Pyclen-Based Ligands Bearing Pendant Picolinate Arms for Gadolinium Complexation

We report the synthesis of two pyclen-based regioisomer ligands (pyclen = 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca1(15),11,13-triene) functionalized with picolinic acid pendant arms either at positions 3,9-pc2pa (L5) or 3,6-pc2pa (L6) of the macrocyclic fragment. The ligands were prepared by regiospecific protection of one of the amine nitrogen atom of the macrocycle using Boc and Alloc protecting groups, respectively. The X-ray structure of the Gd(III) complex of L5 contains trinuclear [(GdL5)3(H2O)3] 3+ entities in which the monomeric units are joined by 2- 1 : 1 carboxylate groups. However, the 1H and 89Y NMR spectra of its Y(III) analogue support the formation of monomeric complexes in solution. The Tb(III) complexes are highly luminescent, with emission quantum yields of up to 50% for [TbL5] + . The luminescence lifetimes recorded in H2O and D2O solutions indicate the presence of a water molecule coordinated to the metal ion, as also evidenced by the 1H relaxivities measured for the Gd(III) analogues. The Gd(III) complexes present very different exchange rates of the coordinated water molecule (kex 298 = 87.1 and 1.06 106 s -1 for [GdL5] + and [GdL6] + , respectively). The very high water exchange rate of [GdL5] + is associated to the steric hindrance originated by the coordination of the ligand around the water binding site, which favors a dissociatively activated water exchange process. The Gd(III) complexes present rather high thermodynamic stabilities (logKGdL = 20.47 and 19.77 for [GdL5] + and [GdL6] + , respectively). Furthermore, these complexes are remarkably inert with respect to their acid-assisted dissociation, in particular the complex of L5

Expanding the Scope of Pyclen-Picolinate Lanthanide Chelates to Po-Tential Theranostic Applications

A family of three picolinate pyclen based ligands, previously investigated for the complexation of Y3+ and some lanthanide ions (Gd3+, Eu3+), was studied with 161Tb and 177Lu in view of potential radiotherapeutic applications. The set of six Tb3+ and Lu3+ complexes was synthesized and fully characterized. The coordination properties in the solid state and in solution were thoroughly studied. Potentiometric titrations, corroborated by DFT calculations, showed the very high stability constants of the Tb3+ and Lu3+ complexes, which are associated to remarkable kinetic inertness. A complete radiolabeling study performed with both 161Tb and 177Lu radionuclides, including experiments with regard to the stability with and without scavengers and kinetic inertness using challenging agents, proved that the ligands could reasonably compete with the DOTA analogue. To conclude, the potential of using the same ligand for both radiotherapy and optical imaging was highlighted for the first time

Expanding the Scope of Pyclen-Picolinate Lanthanide Chelates to Po-Tential Theranostic Applications

A family of three picolinate pyclen based ligands, previously investigated for the complexation of Y3+ and some lanthanide ions (Gd3+, Eu3+), was studied with 161Tb and 177Lu in view of potential radiotherapeutic applications. The set of six Tb3+ and Lu3+ complexes was synthesized and fully characterized. The coordination properties in the solid state and in solution were thoroughly studied. Potentiometric titrations, corroborated by DFT calculations, showed the very high stability constants of the Tb3+ and Lu3+ complexes, which are associated to remarkable kinetic inertness. A complete radiolabeling study performed with both 161Tb and 177Lu radionuclides, including experiments with regard to the stability with and without scavengers and kinetic inertness using challenging agents, proved that the ligands could reasonably compete with the DOTA analogue. To conclude, the potential of using the same ligand for both radiotherapy and optical imaging was highlighted for the first time