Synthesis and Biological Evaluation of Technetium-99m Labeled Glucose and Thymidine Analogues as SPECT Tumor Proliferation Probes

• Main Authors: Dian-Rong Tsai, 蔡典蓉
• Other Authors: Chuan-Lin Chen
• Format: Others
• Language: zh-TW
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/71427052156412072801

碩士 === 國立陽明大學 === 生物醫學影像暨放射科學系 === 100 === Two glucose derivatives, MAMA-MDG 11 and MAMA-DDG 15, were synthesized to serve as precursors, whereas Re-MAMA-MDG 16 and Re-MAMA-DDG 17 were synthesized as two cold standards. The structures of these compounds were verified with 1H-NMR, 13C-NMR, and high resolution mass spectrometry. Via a two-step, one-pot reaction, the newly synthesized 99mTc-labeled glucose derivatives were purified with high-performance liquid chromatography (HPLC). In this study, I successfully synthesized and radio labeled Technetium-99m on the two glucose analogs, 99mTc-MAMA-MDG 27 and 99mTc-MAMA-DDG 28. These glucose derivaticves were efficiently labeled with high chemical yield (>70%) and were purified with high radio chemical purity (≧95%) which were stable for at least 8 hours in serum. The log P of complex 27 and 28 were -1.85 and -2.00, respectively. In cell cultures, both complexes can accumulate in A549, where complex 28 accumulated more than complex 27(0.68±0.08 and 0.47±0.01 % dose/106 cell, respectively). MicroSPECT imaging and biodistribution study in mice showed that both complex 27 and 28 can significantly accumulate in tumor cells. The tumor-to-muscle ratio after injecting complex 28 was higher than that of complex 27(0.59±0.07, 0.46±0.06, 0.47±0.01(28) and 0.38±0.07, 0.38±0.01, 0.40±0.05(27), respectively), demonstrating that complex 28 exhibits a higher affinity to tumor than complex 27. Both 28 and 27 complexes can serve as potential SPECT imaging agents in detecting proliferating tumor cells. This study thereby demonstrated that this general idea of probe design can be applied to develop more imaging agent for cancer diagnosis in the future.   Two thymidine derivatives, MAMA-(PEG)3-T 25 and MAMA-(PEG)5-T 26, were synthesized to serve as precursors, whereas Re-MAMA-(PEG)5-T 27 and Re-MAMA-(PEG)5-T 28 were synthesized as two cold standards. Their structures were identified with 1H-NMR, 13C-NMR and high resolution mass spectrometry. Via a two-step, one-pot reaction, the newly synthesized 99mTc-labeled thymidine derivatives were purified with high-performance liquid chromatography (HPLC). These thymidine conjugates were efficiently labeled with high yield (>80%) and radio chemical purity (≧95%). The log P of complex 25 and 26 were 0.66 and 0.36, respectively. The cellular accumulation was not significant might related with lipophilicity (0.02~0.15 % dose/106 cell). In dynamic gamma imaging showed that after i.v. inject compound 25 and 26 around 1 hour, maximum tumor to muscle ratio was observed, 2.1 and 1.6, respectively. In our study, N3-functionalized thymidine was showed higher cellular uptake ratio than C3′-functionalized thymidine. Although the result of planar image revealed these thymidine analogues delineate the tumor lesion not very well, modified with long carbon chain at N3 position may demonstrate more potential than C3′ position for further thymidine analogues modification as tumor proliferation probes.