title: A comparative evaluation of the chelators H4octapa and CHX-A″-DTPA with the therapeutic radiometal (90)Y.
abstract: To compare the radiolabeling performance, stability, and practical efficacy of the chelators CHX-A″-DTPA and H4octapa with the therapeutic radiometal (90)Y.
  
  
  
  The bifunctional chelators p-SCN-Bn-H4octapa and p-SCN-Bn-CHX-A″-DTPA were conjugated to the HER2-targeting antibody trastuzumab. The resulting immunoconjugates were radiolabeled with (90)Y to compare radiolabeling efficiency, in vitro and in vivo stability, and in vivo performance in a murine model of ovarian cancer.
  
  
  
  High radiochemical yields (>95%) were obtained with (90)Y-CHX-A″-DTPA-trastuzumab and (90)Y-octapa-trastuzumab after 15min at room temperature. Both (90)Y-CHX-A″-DTPA-trastuzumab and (90)Y-octapa-trastuzumab exhibited excellent in vitro and in vivo stability. Furthermore, the radioimmunoconjugates displayed high tumoral uptake values (42.3±4.0%ID/g for (90)Y-CHX-A″-DTPA-trastuzumab and 30.1±7.4%ID/g for (90)Y-octapa-trastuzumab at 72h post-injection) in mice bearing HER2-expressing SKOV3 ovarian cancer xenografts. Finally, (90)Y radioimmunotherapy studies performed in tumor-bearing mice demonstrated that (90)Y-CHX-A″-DTPA-trastuzumab and (90)Y-octapa-trastuzumab are equally effective therapeutic agents, as treatment with both radioimmunoconjugates yielded substantially decreased tumor growth compared to controls.
  
  
  
  Ultimately, this work demonstrates that the acyclic chelators CHX-A″-DTPA and H4octapa have comparable radiolabeling, stability, and in vivo performance, making them both suitable choices for applications requiring (90)Y.
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Price
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Edwards
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carnazza
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
authors.forename: Sean D
authors.initials: SD
authors.lastname: Carlin
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States; Department of Chemistry, Hunter College and the Ph.D. Program in Chemistry, the Graduate Center of the City University of New York, 413 East 69th Street, New York, NY 10021, United States.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Zeglis
authors.affiliation: TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2A3.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Adam
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, Canada V6T 1Z1.
authors.forename: Chris
authors.initials: C
authors.lastname: Orvig
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States; Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States; Weill Cornell Medical College, 1300 York Ave, New York, NY 10065, United States. Electronic address: lewisj2@mskcc.org.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002614:Chelating Agents / Q000737:chemistry*; D005021:Ethylamines / Q000737:chemistry*; D005260:Female; D017879:Isothiocyanates / Q000737:chemistry*; D007553:Isotope Labeling; D051379:Mice; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000737:chemistry*; D016499:Radioimmunotherapy; D014018:Tissue Distribution; D000068878:Trastuzumab / Q000737:chemistry / Q000493:pharmacokinetics; D015021:Yttrium Radioisotopes / Q000737:chemistry* / Q000627:therapeutic use*
chemical_list: D002614:Chelating Agents; D005021:Ethylamines; D017879:Isothiocyanates; C000596870:N,N'-((6-carboxylato)pyridin-2-yl)methyl)-N,N'-diacetic acid-1,2-diaminoethane; D011725:Pyridines; D015021:Yttrium Radioisotopes; C085678:N-(2-amino-3-(4-isothiocyanatophenyl)propyl)cyclohexane-1,2-diamine-N,N',N',N'',N''-pentaacetic acid; D004369:Pentetic Acid; D000068878:Trastuzumab
keywords: CHX-A″-DTPA; H(4)octapa; Radioimmunotherapy; Radiometal; Trastuzumab; Yttrium-90