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

Abstract

A family of three picolinate pyclen based ligands, previously investigated for the complexation of Y 3+ and some lanthanide ions (Gd 3+ , Eu 3+), was studied with 161 Tb and 177 Lu in view of potential radiotherapeutic applications. The set of six Tb 3+ and Lu 3+ complexes was synthesized and fully characterized. The coordination properties in the solid state and in solution were thoroughly studied. Potentiometric titrations, corroborated by Density Functional Theory (DFT) calculations, showed the very high stability constants of the Tb 3+ and Lu 3+ complexes, which are associated to remarkable kinetic inertness for up to 30 days in 1 M HCl. A complete radiolabeling study performed with both 161 Tb and 177 Lu 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. short mission in Villigen in 2019. C.M. and N.vdM. acknowledge Fan Sozzi-Guo for assistance of the experiments involving 161 Tb.

Chelation of Theranostic Copper Radioisotopes with S-Rich Macrocycles: From Radiolabelling of Copper-64 to In Vivo Investigation

“…Radiolabelling were performed by adding [ 64 Cu]CuCl 2 diluted in 0.05 M HCl (~2.5 MBq, 2 µL) to an aliquot of ligand solution (20 µL) mixed with 0.05 M HCl + 0.5 M sodium acetate 5:1 v/v ratio (98 µL and 20 µL, respectively) [47]. The final pH was equal to 4.5.…”

“…A flow rate of 0.35 mL/min was employed. The [ 64 Cu]Cu 2+ complexes were retained at characteristic retention time (t R ) equal to: ~6.9 min for [ 64 TLC silica gel 60 F254 plates, developed using a mixture of 10% ammonium acetate and methanol (1:1 v/v ratio, pH 5.5), were used as stationary phase with DO2A2S, DOTA and NODAGA-RDG [47]. Under these conditions, the free [ 64 Cu]Cu 2+ remains at the baseline (retention factor, R f = 0) while the [ 64 Cu]Cu 2+ complexes migrate with the liquid phase (R f ~0.6 for [ 64 Cu]Cu-NODAGA-RDG and R f ~0.4 for [ 64 Cu][Cu(DO2A2S)]).…”

“…Both low and high molar activities (0.1 MBq/nmol and 25 MBq/nmol, respectively) were employed to evaluate the effect of radiolysis. Radioprotectants (ethanol 10% v/v or ascorbic acid 10% v/v) were added to PBS to quench the radiolysis phenomena [47]. The [ 64 Cu]Cu 2+ complex stabilities were investigated at different time points after preparation using the TLC or UHPLC protocols reported previously.…”

Pyclen-Based Ligands Bearing Pendant Picolinate Arms for Gadolinium Complexation

“…18−20 More recently, we investigated the series of pyclen-based ligands, named L1−L4 here for simplicity (Chart 1), which form very stable Ln(III) complexes; in particular the dipicolinate deriatives L3 and L4 21,22 (pc1a2pa-sym and -disym, respectively) offer nine donor atoms for coordination to the Ln(III) center. 23 These ligands form more stable Gd(III) complexes in comparison to the heptadentate pcta ligand. 22 The picolinate units can be further functionalized to yield highly luminescent Ln(III) probes for one-and two-photon bioimaging applications in vitro and in vivo.…”

Pyclen-Based Ligands Bearing Pendant Picolinate Arms for Gadolinium Complexation

“…17 More recently, we investigated the series of pyclen-based ligands, named here L1-L4 for simplicity (Chart 1), which form very stable Ln(III) complexes, in particular those with the dipicolinate pyclen chelators L3 and L4 18,19 (pc1a2pa -sym anddisym respectively) that offer 9 donor atoms for coordination to the Ln(III) center. 20 These ligands form more stable Gd(III) complexes than the heptadentate pcta ligand. 19 The picolinate units can be further functionalized to yield highly luminescent Ln(III) probes for one-and two-photon bioimaging applications in vitro and in vivo.…”