title: 89Zr-DFO-J591 for immunoPET of prostate-specific membrane antigen expression in vivo.
abstract: (89)Zr (half-life, 78.41 h) is a positron-emitting radionuclide that displays excellent potential for use in the design and synthesis of radioimmunoconjugates for immunoPET. In the current study, we report the preparation of (89)Zr-desferrioxamine B (DFO)-J591, a novel (89)Zr-labeled monoclonal antibody (mAb) construct for targeted immunoPET and quantification of prostate-specific membrane antigen (PSMA) expression in vivo.
  
  
  METHODS
  The in vivo behavior of (89)Zr-chloride, (89)Zr-oxalate, and (89)Zr-DFO was studied using PET. High-level computational studies using density functional theory calculations have been used to investigate the electronic structure of (89)Zr-DFO and probe the nature of the complex in aqueous conditions. (89)Zr-DFO-J591 was characterized both in vitro and in vivo. ImmunoPET in male athymic nu/nu mice bearing subcutaneous LNCaP (PSMA-positive) or PC-3 (PSMA-negative) tumors was conducted. The change in (89)Zr-DFO-J591 tissue uptake in response to high- and low-specific-activity formulations in the 2 tumor models was measured using acute biodistribution studies and immunoPET.
  
  
  RESULTS
  The basic characterization of 3 important reagents-(89)Zr-chloride, (89)Zr-oxalate, and the complex (89)Zr-DFO-demonstrated that the nature of the (89)Zr species dramatically affects the biodistribution and pharmacokinetics. Density functional theory calculations provide a rationale for the observed high in vivo stability of (89)Zr-DFO-labeled mAbs and suggest that in aqueous conditions, (89)Zr-DFO forms a thermodynamically stable, 8-coordinate complex by coordination of 2 water molecules. (89)Zr-DFO-J591 was produced in high radiochemical yield (>77%) and purity (>99%), with a specific activity of 181.7 +/- 1.1 MBq/mg (4.91 +/- 0.03 mCi/mg). In vitro assays demonstrated that (89)Zr-DFO-J591 had an initial immunoreactive fraction of 0.95 +/- 0.03 and remained active for up to 7 d. In vivo biodistribution experiments revealed high, target-specific uptake of (89)Zr-DFO-J591 in LNCaP tumors after 24, 48, 96, and 144 h (34.4 +/- 3.2 percentage injected dose per gram [%ID/g], 38.0 +/- 6.2 %ID/g, 40.4 +/- 4.8 %ID/g, and 45.8 +/- 3.2 %ID/g, respectively). ImmunoPET studies also showed that (89)Zr-DFO-J591 provides excellent image contrast, with tumor-to-muscle ratios greater than 20, for the delineation of LNCaP xenografts between 48 and 144 h after administration.
  
  
  CONCLUSIONS
  These studies demonstrate that (89)Zr-DFO-labeled mAbs show exceptional promise as radiotracers for immunoPET of human cancers. (89)Zr-DFO-J591 displays high tumor-to-background tissue contrast in immunoPET and can be used to delineate and quantify PSMA-positive prostate tumors in vivo.
authors.affiliation: Radiochemistry Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Holland
authors.forename: Vadim
authors.initials: V
authors.lastname: Divilov
authors.forename: Neil H
authors.initials: NH
authors.lastname: Bander
authors.forename: Peter M
authors.initials: PM
authors.lastname: Smith-Jones
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics; D003627:Data Interpretation, Statistical; D004355:Drug Stability; D018796:Immunoconjugates; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography; D017430:Prostate-Specific Antigen / Q000096:biosynthesis*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D007074:Immunoglobulin G; C478680:J591 monoclonal antibody; D019275:Radiopharmaceuticals; D017430:Prostate-Specific Antigen