Properties Of Gd（Ⅲ）,^99mTc（Ⅴ） Chelates Containing Nitroimidazole Derivation As MRI, SPECT Contrast Agents

With the increasing number of cancer, multi-mode medical imaging technology which could provide abundant clinical information showed more practical advantage in clinical diagnosis. Magnetic Resonance Imaging (MRI) and Single Photon Emission Computed Tomography (SPECT) are two kinds of medical imaging technology that play important roles in the clinical diagnosis of cancers. Lesions were easily distinguished after MRI contrast agent (MRI CAs) injection, which could improve the proton relaxation rate. However, clinical used contrast agents were of poor capability for tumor recognition. SPECT was used for detecting the hypoxic tissue by the means of the selective retention of isotope-labeled nitroimidazole compound, with tumor-targeting, high sensitively and non-invasive characteristics. The combination of MRI and SPECT helps the doctor obtained both the location and anatomic information of the tumor. Therefore, the studies of SPECT/MRI dual-mode contrast agent become a hot spot in modern medical imaging science.In this thesis, by the use of pH potentiometric titration and UV spectrophotometry, we evaluated the stability and hydrophilic properties of three prepared Gd(III) complexes, Gd-L1, Gd-L2 and Gd-L3. Particularly, we chose Gd-L1 as a potential contrast agent, and determined its properties, such as acute toxicity and in vitro/vivo relaxation. Radiolabeled with 99mTc, a novel complexes 99mTc-L1 was synthesized. We investigated the biodistribution and scintigraphic image of 99mTc-L1 in nude mice bearing A549 tumor cell, as follow,(1) The protonation constants of H5DTPA, H3L1, H2L2, H3L3 were determined by potentiometric titration in 0.1 mol·L-1 NaCl at 25 ℃. Stability constants were measured to evaluate the possibility of using Gd-L1, Gd-L2 and Gd-L3 for MRI Contrast agents. We found that log KGd-L of all the three Gd-L(log KGd-L1 12.61, log KGd-L2=9.32, logKGd-L3= 11.37) was smaller than that of Gd-DTPA(log KGd-DTPA=22.40), which means that the stability of Gd-L1, Gd-L2, Gd-L3 were reduced compared with Gd-DTPA.(2) The butanol/water coefficients of Gd-L1, Gd-L2 and Gd-L3 were tested by UV spectrophotometry to evaluate the hydrophilic properties. The result indicated that Gd-L1, Gd-L2, Gd-L3(log DGd.L1=-2.05±0.01, log DGd-L2=-1.99 ±0.02, log DGd-L3=-1.79±0.01.) were of good water solubility like clinical used CAs Gd-DTPA-BMA(log DGd-L3=-2.13). In addition, we investigated the in vitro/vivo relaxation and acute toxicity of Gd-L1 by determined the semi-lethal dose LD50 and relaxation rate R1. The experiment results suggested that Gd-L1 was of more toxicity(LD50=4.88 g/kg) than Gd-DTPA(LD50=9.411 g/kg), while less toxicity than another clinical used MRI contrast agents Mn-DPDP(LD50= 1.439 g/kg). On the other hand, Gd-L1 has better relaxation rate(R1=6.422 mM-1s-1) than Gd-DTPA(R1;=4.305 mM-1s-1). In vivo relaxation imaging of Gd-L1 was tested by weighted spin echo imaging. Result showed that the MRI signals in mice kidney were obviously strengthened.(3) We found that proper reaction condition(n(SnCl2):n(H3L1)=1:1.2, pH=6, two-step feeding) can help to improve the radiochemical purity of 99mTc-L1 to 87.32% and to keep stability at room temperature within 6h more than 86.52%. The in vivo bio-distribution and scintigraphic image experiments of 9mTc-L1 in nude mice bearing A549 tumor cell showed that the uptake of hypoxic tumor was clear observed after being injected. The 99mTc-L1 has the highest T/M(7.31) at 4h and T/B(6.39) at 6h, which suggested that 99mTc-L1 has good tumor-targeting.