Synthesis, characterization and biological evaluation of In(iii) complexes anchored by DOTA-like chelators bearing a quinazoline moiety

Abstract

Following previous studies with a DOTA-like bifunctional chelator (H₃L1) containing an ethylenic linker between the macrocycle backbone and a quinazoline pharmacophore, we synthesized and fully characterized a congener macrocyclic ligand (H₃L2) having a longer, five-carbon spacer for the linkage of the quinazoline moiety. Both H₃L1 and H₃L2 were used to prepare indium(III) complexes aiming at their evaluation as radioactive probes for in vivo targeting of EGFR-TK. The protonation constants (log K_Hi) of H₃L2 were determined by potentiometry and UV-Vis spectrophotometry and the values found are 12.18, 9.74, 4.99, 3.91 and 2.53. The stability and protonation constants of InL (L = L1, L2) were also obtained from a combined potentiometry and UV-VIS spectrophotometry study. The reaction of InCl₃ with H₃L1 and H₃L2 led to the formation of the well-defined complexes InL1 and InL2, containing In(III) ions coordinated by a seven (N₄,O₃) donor atom set. These new complexes were fully characterized by spectroscopic methods (IR, NMR, ESI-MS), HPLC and by X-ray diffraction analysis in the case of InL1. The radioactive congener ¹¹¹InL2 was prepared from the reaction of ¹¹¹In–chloride with H₃L2, in high yield and high radiochemical purity. ¹¹¹InL2 is a neutral complex that presents a hydrophilic character and exhibits a high in vitro and in vivo stability. H₃L2 and InL2 do not inhibit the cell growth of A431 cervical carcinoma cells. In this EGFR-expressing cell line, ¹¹¹InL2 has shown very low cell internalization. These findings indicate that these DOTA-like chelators are not the best suited bifunctional ligands to obtain In(III) complexes with adequate biological properties for targeting the EGFR-TK.