Synthesis, characterization and biological evaluation of In(III) complexes anchored by DOTA-like chelators bearing a quinazoline moiety.
Following previous studies with a DOTA-like bifunctional chelator (H(3)L1) containing an ethylenic linker between the macrocycle backbone and a quinazoline pharmacophore, we synthesized and fully characterized a congener macrocyclic ligand (H(3)L2) having a longer, five-carbon spacer for the linkage of the quinazoline moiety. Both H(3)L1 and H(3)L2 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 H(3)L2 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 InCl(3) with H(3)L1 and H(3)L2 led to the formation of the well-defined complexes InL1 and InL2, containing In(iii) ions coordinated by a seven (N(4),O(3)) 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 (111)InL2 was prepared from the reaction of (111)In-chloride with H(3)L2, in high yield and high radiochemical purity. (111)InL2 is a neutral complex that presents a hydrophilic character and exhibits a high in vitro and in vivo stability. H(3)L2 and InL2 do not inhibit the cell growth of A431 cervical carcinoma cells. In this EGFR-expressing cell line, (111)InL2 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.
Unidade de Ciências Químicas e Radiofarmacêuticas, Instituto Tecnológico e Nuclear, Estrada Nacional 10, Sacavém, Portugal.
Raquel
R
Garcia
Vojtěch
V
Kubíček
Bohuslav
B
Drahoš
Lurdes
L
Gano
Isabel C
IC
Santos
Paula
P
Campello
António
A
Paulo
Eva
E
Tóth
Isabel
I
Santos
D000818:Animals; D002460:Cell Line; D002614:Chelating Agents / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006801:Humans; D007204:Indium / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D011199:Potentiometry; D011799:Quinazolines / Q000737:chemistry*; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D014018:Tissue Distribution
D002614:Chelating Agents; D006573:Heterocyclic Compounds, 1-Ring; D011799:Quinazolines; D007204:Indium; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid