Synthesis And Properties Study Of EDTA、DTPA Derivatives Of Nitroimidazole

Magnetic resonance imaging (MRI) is one of the widely used clinical diagnostic technology. However, most small molecule para-magnetic contrast agents that used in the clinical is non-targeting, it will be metabolized quickly by blood circulation after injection. The most commonly used way to improve the imaging is to increasing the does, but it will aggravate the toxicity at the same time. Therefore, designing and synthesizing a safety and targeted contrast agent have become focus research topic in MRI field.Nitroimidazole can target to tumor due to the special structure and physiological environment of tumor. In this paper, two new contrast ligands(named L1 and L2) were got by using nitroimidazol to modify the structure of EDTA and DTPA, subsequently their Gd-complexes were synthesized by reacting with Gd2O3. The octanol-water partition coefficients, stability constant and relaxation rate of Gd-complexes were made afterward.(1) Two new compounds L1 and L2 have been synthesized by acylation reaction of EDTAA and DTPAA with 1-(2-Aminoethyl)-2-nitromidazole. The optimum condition of experiment is:the ratio of 1.2:1 for 1-(2-Aminoethyl)-2-nitromidazole and EDTAA/DTPAA, use DMF/Py as the solvent and react 24h in room temperature. The FTIR spectrum of the two Gd-complexes showed a blue shift of carbonyl group which confirmed the coordination of carboxylate and Gd3+. While the nitroimidazole infrared absorption band remained the same as the ligands, which indicated that nitroimidazole have not coordinated with Gd3+(2) The pH potentiometric titration was carried out to determined the protonation constant of ligands and stability constant of metal complexes. The result indicated that the number of protonation constant was dependent on the free hydrogen. Following was the stability constant of the complexes:log KG-L1=7.05, log Kcu-L1=9.87, log Kca-L1= 6.63; log KGd-L2= 10.87, log KCu-L2= 12.85, log KCa-L2=9.66.(3) The fluorescence spectra of two ligands and their interaction with different metal ion was measured on the condition of pH=7.4 buffer solution, room temperature. The complexes showed quenching with Cu2+ and Gd3+. The ratio of the metal and complexes were made by Job’ plot.(4) The lgP of Gd-L1 and Gd-L2 were tested by UV spectrophotometry to evaluate the water solubility. The in vitro relaxation of Gd-L1 and Gd-L2 were measured by Inversion Recovery. The result shows that the relaxation rate of two complexes are higher than Gd-DTPA, which may owe to the structure of nitromidazole.