Schmidt Alexander, Wirtz Martina, Färber Stefanie Felicitas, Osl Theresa, Beck Roswitha, Schottelius Margret, Schwaiger Markus, Wester Hans-Jürgen
Pharmaceutical Radiochemistry, Department of Chemistry, Technical University Munich, Walther-Meißner-Street 3, 85748 Garching, Germany.
Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University Munich, Ismaninger Street 22, 81675 Munich, Germany.
ACS Omega. 2018 Jul 31;3(7):8278-8287. doi: 10.1021/acsomega.8b00790. Epub 2018 Jul 25.
To investigate the effect of carbohydrate moieties on the pharmacokinetic profile of prostate-specific membrane antigen (PSMA) inhibitors, carbohydrated derivatives of the established PSMA-targeted radiopharmaceutical PSMA I&T were developed and evaluated. As observed for the reference PSMA I&T, the Ga/Lu complexes of the respective galactose-, mannose-, and cellobiose-conjugated analogs showed high PSMA affinity. Carbohydration had almost no effect on the lipophilicity, whereas PSMA-mediated internalization was reduced. The specific binding toward human serum albumin (HSA) decreased from 78.6% for [Lu]PSMA I&T to 19.9% for the Lu-labeled cellobiose derivative. Compared to [Ga]PSMA I&T, [Ga]PSMA galactose displayed lower nonspecific tissue and kidney accumulation but also slightly lower tumor uptake in small-animal positron emission tomography (μPET) imaging. Biodistribution studies confirmed reduced unspecific uptake in nontarget tissue and decreased renal accumulation of the metabolically stable [Ga]PSMA galactose derivative, resulting in overall improved tumor-to-tissue ratios. However, carbohydration has no significant beneficial in vivo effect on the targeting performance of PSMA I&T. Nevertheless, carbohydration expands the repertoire of feasible modifications within the linker area and might be a valuable tool for the future development of PSMA inhibitors with decreased kidney uptake.
为研究碳水化合物部分对前列腺特异性膜抗原（PSMA）抑制剂药代动力学特征的影响，我们开发并评估了已确立的靶向PSMA的放射性药物PSMA I&T的碳水化合物衍生物。正如参考药物PSMA I&T所观察到的那样，各自的半乳糖、甘露糖和纤维二糖共轭类似物的镓/镥配合物显示出对PSMA的高亲和力。碳水化合物化对亲脂性几乎没有影响，而PSMA介导的内化作用则有所降低。对人血清白蛋白（HSA）的特异性结合从[镥]PSMA I&T的78.6%降至镥标记的纤维二糖衍生物的19.9%。与[镓]PSMA I&T相比，[镓]PSMA半乳糖在小动物正电子发射断层扫描（μPET）成像中显示出较低的非特异性组织和肾脏蓄积，但肿瘤摄取也略低。生物分布研究证实，代谢稳定的[镓]PSMA半乳糖衍生物在非靶组织中的非特异性摄取减少，肾脏蓄积降低，从而总体上改善了肿瘤与组织的比率。然而，碳水化合物化对PSMA I&T的靶向性能在体内没有显著的有益影响。尽管如此，碳水化合物化扩展了连接区可行修饰的范围，可能是未来开发肾脏摄取降低的PSMA抑制剂的有价值工具。
