Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering, Kansai University, 3-3-35, Yamatecho, Suita-shi, Osaka 564-8680, Japan.
Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada.
J Inorg Biochem. 2018 Aug;185:63-70. doi: 10.1016/j.jinorgbio.2018.04.009. Epub 2018 Apr 13.
With the aim to prepare hypoxia tumor imaging agents, technetium(I) and rhenium(I) tricarbonyl complexes with dipyridylamine (L1 = N-{[1-(2,2-dioxido-1,2-benzoxathiin-6-yl)-1H-1,2,3-triazol-4-yl]methyl}-N-(2-pyridinylmethyl)-2-pyridinemethanamine; L3 = N-{[1-[N-(4-aminosulfonylphenyl)]-1H-1,2,3-triazol-4-yl]methyl}-N-(2-pyridinyl-methyl)-2-pyridinemethanamine), and iminodiacetate (HL2 = N-{[1-(2,2-dioxido-1,2-benzoxathiin-6-yl)-1H-1,2,3-triazole-4-yl]methyl}-N-(carboxy-methyl)-glycine; HL4 = N-{[1-[N-(4-aminosulfonylphenyl)]-1H-1,2,3-triazole-4-yl]methyl}-N-(carboxymethyl)-glycine) ligands appended to sulfonamide or sulfocoumarin carbonic anhydrase inhibitors were synthesized. The Re(I) complexes were characterized using H/C NMR, MS, EA, and in one case the X-ray structure of [EtNH][Re(CO)(L2)] was obtained. As expected, the Re coordination geometry is distorted octahedral, with a tridentate iminodiacetate ligand in a fac arrangement dictated by the three strong-field CO ligands. Inhibition studies of human carbonic anhydrases (hCAs) showed that the Re sulfocoumarin derivatives were inactive against hCA-I, -II and -IV, but had moderate affinity for hCA-IX. The Re sulfonamides showed improved affinity against all tested hCAs, with [Re(CO)(L4)] being the most active and selective for the hCA-IX isoform. The corresponding Tc complexes were synthesized from fac-[Tc(CO)(HO)], purified by HPLC, and obtained with average 41-76% decay-corrected radiochemical yields and with >99% radiochemical purity. Uptake in HT-29 tumors at 1 h post-injection was highest for [Tc(CO)(L4)] (0.14 ± 0.10%ID/g) in comparison to [Tc(CO)(L1)] (0.06 ± 0.01%ID/g), [Tc(CO)(L2)] (0.03 ± 0.00%ID/g), and [Tc(CO)(L3)] (0.07 ± 0.03%ID/g). The uptake in tumors was further reduced at 4 h post-injection. For potential imaging application with single photon emission computed tomography, further optimization is needed to improve the affinity to hCA-IX and uptake in hCA-IX expressing tumors.
为了制备缺氧肿瘤成像剂，合成了带有二吡啶基胺（L1= N-（[1-（2,2-二氧代-1,2-苯并恶噻嗪-6-基）-1H-1,2,3-三唑-4-基]甲基）-N-（2-吡啶基甲基）-2-吡啶甲胺；L3= N-（[1-[N-（4-氨基磺酰基苯基）]-1H-1,2,3-三唑-4-基]甲基）-N-（2-吡啶基甲基）-2-吡啶甲胺）、亚氨基二乙酸（HL2= N-（[1-（2,2-二氧代-1,2-苯并恶噻嗪-6-基）-1H-1,2,3-三唑-4-基]甲基）-N-（羧甲基）-甘氨酸；HL4= N-（[1-[N-（4-氨基磺酰基苯基）]-1H-1,2,3-三唑-4-基]甲基）-N-（羧甲基）-甘氨酸）配体连接到磺酰胺或磺酰基香豆素碳酸酐酶抑制剂上。使用 H/C NMR、MS、EA 对 Re(I) 配合物进行了表征，在一种情况下，获得了 [EtNH][Re(CO)(L2)] 的 X 射线结构。正如预期的那样，Re 配位几何形状是扭曲的八面体，具有由三个强场 CO 配体决定的面式排列的三齿亚氨基二乙酸配体。对人碳酸酐酶（hCA）的抑制研究表明，Re 磺酰基香豆素衍生物对 hCA-I、-II 和 -IV 没有活性，但对 hCA-IX 具有中等亲和力。Re 磺酰胺对所有测试的 hCA 表现出改善的亲和力，其中 [Re(CO)(L4)] 对 hCA-IX 同工型最具活性和选择性。通过 fac-[Tc(CO)(HO)] 合成了相应的 Tc 配合物，通过 HPLC 进行了纯化，并以 41-76%的平均衰减校正放射性化学产率获得，并具有 >99%的放射性化学纯度。与 [Tc(CO)(L1)]（0.06±0.01%ID/g）、[Tc(CO)(L2)]（0.03±0.00%ID/g）和 [Tc(CO)(L3)]（0.07±0.03%ID/g）相比，[Tc(CO)(L4)]（0.14±0.10%ID/g）在注射后 1 小时在 HT-29 肿瘤中的摄取最高。在注射后 4 小时，肿瘤中的摄取进一步减少。为了在单光子发射计算机断层扫描中进行潜在的成像应用，需要进一步优化以提高对 hCA-IX 的亲和力和在 hCA-IX 表达肿瘤中的摄取。
