p-SCN-Bn-HOPO: A superior bifunctional chelator for 89Zr immunoPET Journal Article
| Authors: | Deri, M. A.; Ponnala, S.; Kozlowski, P.; Burton-Pye, B. P.; Cicek, H. T.; Hu, C.; Lewis, J. S.; Francesconi, L. C. |
| Article Title: | p-SCN-Bn-HOPO: A superior bifunctional chelator for 89Zr immunoPET |
| Abstract: | 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. © 2015 American Chemical Society. |
| Keywords: | controlled study; unclassified drug; nonhuman; positron emission tomography; mass spectrometry; animal cell; mouse; animal tissue; breast cancer; in vivo study; in vitro study; tumor xenograft; drug synthesis; immunoreactivity; isotope labeling; crystal structure; high performance liquid chromatography; trastuzumab; nuclear magnetic resonance; drug conjugation; infrared spectroscopy; hydroxamic acid; zirconium 89; drug stability; deferoxamine; chelating agent; pyridone derivative; female; article; p scn bn hopo |
| Journal Title: | Bioconjugate Chemistry |
| Volume: | 26 |
| Issue: | 12 |
| ISSN: | 1043-1802 |
| Publisher: | American Chemical Society |
| Date Published: | 2015-12-16 |
| Start Page: | 2579 |
| End Page: | 2591 |
| Language: | English |
| DOI: | 10.1021/acs.bioconjchem.5b00572 |
| PROVIDER: | scopus |
| PUBMED: | 26550847 |
| PMCID: | PMC4962612 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 7 January 2016 -- 2579 -- Source: Scopus |
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