Octadentate Bispidine Chelators for Tb(III) Complexation: Pyridine Carboxylate versus Pyridine Phosphonate Donors

With their rigid and preorganized skeleton, bispidine (3,7-diazabicyclo[3.3.1]nonane) chelators are very appealing for the preparation of metal complexes with high kinetic inertness. With the aim to develop new Tb(III)-based medical imaging probes, this study describes the synthesis and physicochemical properties of two novel terbium(III) complexes with octadentate bispidine-based ligands substituted with either pyridine-phosphonate (H₆<b>L</b>^<b>1</b>) or picolinate (H₄<b>L</b>^<b>2</b>) subunits. Thermodynamic stability constants of the corresponding Tb(III) complexes have been determined by potentiometric, UV-visible absorption spectrophotometric and spectrofluorimetric methods. Despite their apparent similarity, these two octadentate ligands differ in their most stable conformation: <i>chair</i>-<i>chair</i> conformation for H₄<b>L</b>^<b>2</b> and <i>boat</i>-<i>chair</i> conformation for H₆<b>L</b>^<b>1</b>, as confirmed by ¹H NMR studies and suggested by physicochemical investigations. This conformational change induces different protonation schemes for the two ligands. The kinetic inertness of the Tb complexes has been studied in various media and assessed by transmetalation and transchelation experiments. In particular, Tb(<b>L</b>^<b>2</b>) displayed a remarkable kinetic inertness with no measurable dissociation over two months in mouse serum at 10^-5 M concentration. The complex was also very inert in the presence of a 50-fold excess of Zn(II) in H₂O at pH = 7.4 (7% of dissociation over two months). The complexes with ligand <b>L</b>^<b>1</b> are significantly less inert, emphasizing the influence of the ligand conformation on the kinetic inertness of the Ln(III) complexes. Finally, the luminescence properties of the isolated complexes have also been investigated. A bright green luminescence was observed, especially for Tb(<b>L</b>^<b>2</b>), which displays a high quantum yield value of 50% in H₂O (60% in D₂O; λ_exc = 263 nm). In addition, luminescence lifetimes of 1.9(2) and 1.7(2) ms have been measured for Tb(<b>L</b>^<b>1</b>) and Tb(<b>L</b>^<b>2</b>), respectively, hence confirming the formation of nona-coordinated complexes with one inner-sphere water molecule. These data on a bispidine scaffold pave the way for developing bright, inert luminescent probes for bioimaging and for radiolabeling applications with Tb(III) radioisotopes.