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

• Published in: Bioconjugate chemistry Vol. 26; no. 12; pp. 2579 - 2591
• Main Authors: Deri, Melissa A, Ponnala, Shashikanth, Kozlowski, Paul, Burton-Pye, Benjamin P, Cicek, Huseyin T, Hu, Chunhua, Lewis, Jason S, Francesconi, Lynn C
• Format: Journal Article
• Language: English
• Published: United States 16.12.2015
• Subjects: Animals; Breast - diagnostic imaging; Breast Neoplasms - diagnostic imaging; Cell Line, Tumor; Chelating Agents - chemistry; Chelating Agents - pharmacokinetics; Deferoxamine - chemistry; Deferoxamine - pharmacokinetics; Female; Humans; Immunoconjugates - chemistry; Immunoconjugates - pharmacokinetics; Mice, Nude; Models, Molecular; Positron-Emission Tomography - methods; Pyridones - chemistry; Pyridones - pharmacokinetics; Tissue Distribution; Trastuzumab - chemistry; Zirconium - chemistry; Zirconium - pharmacokinetics
• ISSN: 1520-4812
• DOI: 10.1021/acs.bioconjchem.5b00572

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 (89)Zr(4+) cation is being released in vivo. Therefore, a more robust chelator for (89)Zr 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 (89)Zr(4+) 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 (89)Zr. 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 (89)Zr-HOPO-trastuzumab images. Biodistribution data confirmed the lower bone activity, measuring 17.0%ID/g in the bone at 336 h for (89)Zr-DFO-trastuzumab while (89)Zr-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 (89)Zr. In vivo studies demonstrate the successful use of (89)Zr-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 (89)Zr-HOPO-trastuzumab suggests superior stability of the (89)Zr-HOPO complex.