p-SCN-Bn-HOPO: A Superior Bifunctional Chelator for 89Zr ImmunoPET

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• 作者：Melissa A. Deri ; Shashikanth Ponnala ; Paul Kozlowski ; Benjamin P. Burton-Pye ; Huseyin T. Cicek ; Chunhua Hu ; Jason S. Lewis ; Lynn C. Francesconi
• 刊名：Bioconjugate Chemistry
• 出版年：2015
• 出版时间：December 16, 2015
• 年：2015
• 卷：26
• 期：12
• 页码：2579-2591
• 全文大小：597K
• ISSN：1520-4812

文摘

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.