Laboratory of Radiopharmacy, KU Leuven, Leuven, Belgium.
Department of Radiation Oncology (Maastro Lab), GROW - School for Oncology and Development Oncology, Maastricht University Medical Centre, Maastricht, The Netherlands.
Eur J Med Chem. 2014 Jan;71:374-84. doi: 10.1016/j.ejmech.2013.10.027. Epub 2013 Oct 30.
In vivo visualization of tumor hypoxia related markers, such as the endogenous transmembrane protein CA IX may lead to novel therapeutic and diagnostic applications in the management of solid tumors. In this study 4-(2-aminoethyl)benzene sulfonamide (AEBS, K(i) = 33 nM for CA IX) has been conjugated with bis(aminoethanethiol) (BAT) and mercaptoacetyldiglycine (MAG2) tetradendate ligands and the conjugates radiolabelled with (99m)Tc, to obtain anionic and neutral (99m)Tc-labeled sulfonamide derivatives, respectively. The corresponding rhenium analogues were also prepared and showed good inhibitory activities against hCA IX (K(i) = 59-66 nM). In addition, a second generation bis AEBS was conjugated with MAG2 and labeled with (99m)Tc, and the obtained diastereomers were also evaluated in targeting CA IX. Biodistribution studies in mice bearing HT-29 colorectal xenografts revealed a maximum tumor uptake of <0.5% ID/g at 0.5 h p.i for all the tracers. In vivo radiometabolite analysis indicated that at 1 h p.i. MAG₂ tetradendate ligands were more stable in plasma (>50% intact) compared to the neutral complex (28% intact). This preliminary data suggest that negatively charged (99m)Tc-labeled sulfonamide derivatives with modest lipophilicity and longer circulation time could be promising markers to target CA IX.
在体可视化肿瘤乏氧相关标志物，如内源性跨膜蛋白 CAIX，可能导致新的治疗和诊断应用于实体瘤的治疗。在这项研究中，4-（2-氨乙基）苯磺酰胺（AEBS，对 CAIX 的 K(i) = 33 nM）已与双（氨乙基硫醇）（BAT）和巯基乙酰二甘氨酸（MAG2）四齿配体缀合，并分别用（99m）Tc 放射性标记缀合物，得到阴离子和中性（99m）Tc 标记的磺酰胺衍生物。相应的铼类似物也被制备出来，并显示出对 hCA IX 的良好抑制活性（K(i) = 59-66 nM）。此外，第二个第二代双 AEBS 与 MAG2 缀合并用（99m）Tc 标记，所得到的非对映异构体也用于靶向 CA IX。在携带 HT-29 结肠直肠癌异种移植的小鼠中进行的生物分布研究表明，所有示踪剂在 0.5 h p.i.时的最大肿瘤摄取率<0.5% ID/g。体内放射性代谢物分析表明，在 1 h p.i.时，MAG₂四齿配体在血浆中的稳定性更高（>50%完整），而中性复合物（28%完整）。这些初步数据表明，带负电荷的（99m）Tc 标记的磺酰胺衍生物具有适度的亲脂性和更长的循环时间，可能是靶向 CA IX 的有前途的标志物。
