title: p-SCN-Bn-HOPO: A Superior Bifunctional Chelator for (89)Zr 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 (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.
authors.affiliation: Department of Radiology and the Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.|Department of Chemistry, Hunter College of the City University of New York , 695 Park Avenue, New York, New York 10065, United States.|Ph.D. Program in Chemistry, The Graduate Center of the City University of New York , 365 Fifth Ave, New York, New York 10016, United States.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Deri
authors.affiliation: Department of Radiology and the Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.|Department of Chemistry, Hunter College of the City University of New York , 695 Park Avenue, New York, New York 10065, United States.
authors.forename: Shashikanth
authors.initials: S
authors.lastname: Ponnala
authors.affiliation: Department of Radiology and the Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.|Department of Chemistry, Hunter College of the City University of New York , 695 Park Avenue, New York, New York 10065, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Kozlowski
authors.affiliation: Department of Chemistry, Hunter College of the City University of New York , 695 Park Avenue, New York, New York 10065, United States.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Burton-Pye
authors.affiliation: Department of Chemistry, Hunter College of the City University of New York , 695 Park Avenue, New York, New York 10065, United States.
authors.forename: Huseyin T
authors.initials: HT
authors.lastname: Cicek
authors.affiliation: Department of Chemistry, New York University , 100 Washington Square East, New York, New York 10003, United States.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Radiology and the Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.affiliation: Department of Chemistry, Hunter College of the City University of New York , 695 Park Avenue, New York, New York 10065, United States.|Ph.D. Program in Chemistry, The Graduate Center of the City University of New York , 365 Fifth Ave, New York, New York 10016, United States.
authors.forename: Lynn C
authors.initials: LC
authors.lastname: Francesconi
mesh_terms: D000818:Animals; D001940:Breast / Q000000981:diagnostic imaging*; D001943:Breast Neoplasms / Q000000981:diagnostic imaging*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D003676:Deferoxamine / Q000737:chemistry* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000493:pharmacokinetics; D008819:Mice, Nude; D008958:Models, Molecular; D049268:Positron-Emission Tomography / Q000379:methods*; D011728:Pyridones / Q000737:chemistry* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D000068878:Trastuzumab / Q000737:chemistry; D015040:Zirconium / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D002614:Chelating Agents; D018796:Immunoconjugates; D011728:Pyridones; D015040:Zirconium; D003676:Deferoxamine; D000068878:Trastuzumab; C546958:1-hydroxy-2(1H)-pyridinone