title: A (99m)Tc-labeled dual-domain cytokine ligand for imaging of inflammation.
abstract: BACKGROUND
  Interleukin (IL)-1 and IL-18 are potent proinflammatory cytokines in inflammation-related diseases. Their actions are regulated by IL-1 receptor antagonist (IL-1ra) and IL-18 binding protein (IL-18bp). This study was designed to (99m)Tc-radiolabel an IL-1ra and IL-18bp dual-domain cytokine ligand, IL-18bp-Fc-IL-1ra, for specific inflammation targeting.
  
  
  METHODS
  The (99m)Tc-IL-18bp-Fc-IL-1ra was obtained by direct labeling via 2-iminothiolane reduction. Competitive binding of (99m)Tc-labeled and unlabeled IL-18bp-Fc-IL-1ra to rat polymorphonuclear leukocytes was assessed in vitro. A mouse ear edema model was used to evaluate specific targeting properties of (99m)Tc-IL-18bp-Fc-IL1ra in vivo. The correlation between (99m)Tc-IL-18bp-Fc-IL-1ra uptake and (111)In-labeled polymorphonuclear neutrophil infiltration was studied using ischemic-reperfused rat hearts.
  
  
  RESULTS
  Direct (99m)Tc-labeling yielded a stable dual-domain cytokine radioligand with radiochemical purity greater than 95% after gel filtration. Competitive binding studies showed specific targeting of (99m)Tc-IL-18bp-Fc-IL-1ra to inflammatory cells. The (99m)Tc-IL-18bp-Fc-IL-1ra uptake was 1.80±0.17 % injected dose per gram (%ID/g) in the inflamed ear without blocking, whereas uptake in the presence of IL-18bp-Fc-IL-1ra was 1.09±0.08 %ID/g (P<.05). The amounts of IL-1β and IL-18 were significantly increased in the inflamed ears compared to the vehicle controls. A significant correlation of (99m)Tc-IL-18bp-Fc-IL-1ra with (111)In-labeled neutrophil distribution was observed in the ischemic-reperfused hearts (P<.001).
  
  
  CONCLUSIONS
  Targeting proinflammatory cytokines with (99m)Tc-IL-18bp-Fc-IL-1ra may provide a suitable approach for specific detection of inflammatory sites.
authors.affiliation: Department of Radiology, University of Arizona, Tucson, P.O. Box 245067 Tucson, AZ 85724-5067, USA. zliu@radiology.arizona.edu
authors.forename: Zhonglin
authors.initials: Z
authors.lastname: Liu
authors.forename: Leonie
authors.initials: L
authors.lastname: wyffels
authors.forename: Christy
authors.initials: C
authors.lastname: Barber
authors.forename: Mizhou M
authors.initials: MM
authors.lastname: Hui
authors.forename: James M
authors.initials: JM
authors.lastname: Woolfenden
mesh_terms: D000818:Animals; D006801:Humans; D007249:Inflammation / Q000000981:diagnostic imaging / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007962:Leukocytes / Q000000981:diagnostic imaging / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D015609:Organotechnetium Compounds / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D012871:Skin Diseases / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000009:adverse effects / Q000031:analogs & derivatives; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D020382:Interleukin-18; D053583:Interleukin-1beta; D008024:Ligands; D015609:Organotechnetium Compounds; C118370:interleukin-18 binding protein; C032975:12-O-tetradeca-2,4,6,8-tetranoylphorbol-13-acetate; D013755:Tetradecanoylphorbol Acetate