p-SCN-Bn-HOPO: A Superior Bifunctional Chelator for (89)Zr ImmunoPET.
p-SCN-Bn-HOPO: A Superior Bifunctional Chelator for (89)Zr ImmunoPET.
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DOI：
10.1021/acs.bioconjchem.5b00572
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发表时间：
2015-12-16
影响因子：
4.7
通讯作者：
Francesconi LC
中科院分区：
文献类型：
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作者：
Deri MA;Ponnala S;Kozlowski P;Burton-Pye BP;Cicek HT;Hu C;Lewis JS;Francesconi LC
Zirconia-89 具有理想的半衰期，适用于基于抗体的 PET 成像；然而，当与螯合剂 DFO 一起使用时，骨骼中会积聚放射性，这表明 89Zr4+ 阳离子正在体内释放。因此，更强大的 89Zr 螯合剂可以减少体内释放和对非靶组织的剂量。配体3,4,3-(LI-1,2-HOPO)的评估表明89Zr4+的有效结合和高稳定性；因此，我们开发了一种双功能衍生物 p-SCN-Bn-HOPO，用于与抗体缀合。获得的 Zr-HOPO 晶体结构表明 Zr 与八齿 HOPO 配体完全配位，正如预期的那样，形成稳定的络合物。 p-SCN-Bn-HOPO 是通过一种新途径合成的。 p-SCN-Bn-HOPO 和 p-SCN-Bn-DFO 均与曲妥珠单抗缀合，并用 89Zr 放射性标记。两种复合物均被有效标记并达到约 2 mCi/mg 的比活性。 BT474 肿瘤裸鼠 (n = 4) 的 PET 成像研究显示，两种化合物的肿瘤摄取均良好，但 89Zr-HOPO-曲妥珠单抗图像的骨摄取显着下降。生物分布数据证实了较低的骨活性，测量 89Zr-DFO-曲妥珠单抗在 336 小时的骨中为 17.0%ID/g，而 89Zr-HOPO-曲妥珠单抗只有 2.4%ID/g。我们成功合成了p-SCN-Bn-HOPO，一种3,4,3-(LI-1,2-HOPO)的双功能衍生物，作为89Zr的潜在螯合剂。体内研究表明，成功使用 89Zr-HOPO-曲妥珠单抗对 BT474 乳腺癌进行成像，具有低背景、良好的肿瘤与器官对比度，而且重要的是，骨吸收非常低。 89Zr-HOPO-曲妥珠单抗观察到的骨吸收减少表明 89Zr-HOPO 复合物具有优异的稳定性。
Zirconium-89 has an ideal half-life for use in antibody-based PET imaging; however, when used with the chelator DFO, there is an accumulation of radioactivity in the bone, suggesting that the 89Zr4+ cation is being released in vivo. Therefore, a more robust chelator for 89Zr could reduce the in vivo release and the dose to nontarget tissues. Evaluation of the ligand 3,4,3-(LI-1,2-HOPO) demonstrated efficient binding of 89Zr4+ and high stability; therefore, we developed a bifunctional derivative, p-SCN-Bn-HOPO, for conjugation to an antibody. A Zr-HOPO crystal structure was obtained showing that the Zr is fully coordinated by the octadentate HOPO ligand, as expected, forming a stable complex. p-SCN-Bn-HOPO was synthesized through a novel pathway. Both p-SCN-Bn-HOPO and p-SCN-Bn-DFO were conjugated to trastuzumab and radiolabeled with 89Zr. Both complexes labeled efficiently and achieved specific activities of approximately 2 mCi/mg. PET imaging studies in nude mice with BT474 tumors (n = 4) showed good tumor uptake for both compounds, but with a marked decrease in bone uptake for the 89Zr-HOPO-trastuzumab images. Biodistribution data confirmed the lower bone activity, measuring 17.0%ID/g in the bone at 336 h for 89Zr-DFO-trastuzumab while 89Zr-HOPO-trastuzumab only had 2.4%ID/g. We successfully synthesized p-SCN-Bn-HOPO, a bifunctional derivative of 3,4,3-(LI-1,2-HOPO) as a potential chelator for 89Zr. In vivo studies demonstrate the successful use of 89Zr-HOPO-trastuzumab to image BT474 breast cancer with low background, good tumor to organ contrast, and, importantly, very low bone uptake. The reduced bone uptake seen with 89Zr-HOPO-trastuzumab suggests superior stability of the 89Zr-HOPO complex.