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A Novel Neutrophil-Specific PET Imaging Agent: cFLFLFK-PEG-⁶⁴Cu

¹ Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia; ² Department of Chemistry, University of Virginia, Charlottesville, Virginia; ³ Department of Radiology, University of Virginia, Charlottesville, Virginia; ⁴ Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia; and ⁵ Department of Pediatrics, University of Virginia, Charlottesville, Virginia

View larger version (14K): [in this window] [in a new window]   FIGURE 1.  Representative saturation curve of cFLFLF-PEG-64Cu specifically bound to human neutrophils. Binding affinity was computed to be 17.7 nM. Binding data have also been plotted as Scatchard plot. Nonspecific binding was computed in presence of excess cold compound and is estimated to contribute to 20%–30% of total binding.

View larger version (10K): [in this window] [in a new window]   FIGURE 2.  Stimulation of neutrophil oxidative burst by cFLFLFK-PEG-Cu and fMLF as detected by luminol-enhanced chemiluminescence. Results are reported as peak chemiluminescence as percentage of TNF-primed and fMLF-stimulated (10–6M) control. cFLFLFK-PEG-Cu demonstrated no agonist activity toward neutrophils (EC50 value not computable), whereas fMLF stimulated neutrophil superoxide release with EC50 of 3.7 x 10–7 M. Data are reported as mean ± SEM for at least 2 independent measurements.

View larger version (9K): [in this window] [in a new window]   FIGURE 3.  Tissue and organ accumulation of cFLFLFK-PEG-64Cu at 18 h after injection in control and Klebsiella-infected mice, expressed as %ID/g of tissue. Mean lung radioactivity is 3.8 times greater in infected lungs than in control lungs (*P < 0.05).

View larger version (81K): [in this window] [in a new window]   FIGURE 4.  Examples of micro-CT and small-animal PET images of control and Klebsiella-infected mice. PET images were obtained 18 h after tail vein injection of cFLFLFK-PEG-64Cu. Both transverse (top row) and coronal (bottom row) images are shown. In mice administered Klebsiella, there is extensive attenuation in lungs on CT scans, compared with controls. PET scans revealed that Klebsiella-infected mice had visually more tracer uptake in lung tissue than did controls, as was quantified by ROI analysis. Color bar along side indicates increasing tissue radioactivity on PET images. H = heart; L = liver.

View larger version (18K): [in this window] [in a new window]   FIGURE 5.  Lung SUVs for control and Klebsiella-infected mice. Lung SUVs were 5.8 times greater in Klebsiella-infected mice than in controls (*P < 0.005).

View larger version (25K): [in this window] [in a new window]   FIGURE 6.  Myeloperoxidase activity in lung homogenates, expressed as change in optical density (15) per minute per milligram of tissue. Myeloperoxidase activity measured in Klebsiella-infected lungs was approximately 6-fold higher than that measured in control lungs (*P < 0.05). OD = change in optical density.

View larger version (121K): [in this window] [in a new window]   FIGURE 7.  Immunohistochemical staining of neutrophils (stained with rat antimouse IgG [MCA771G; Serotec]) and macrophages (stained with anti MAC-2 IgG [ACL8942P; Accurate]) in lung tissue excised from control and Klebsiella-infected mouse (42 h after administration). Immunostained cells appear dark brown. Control lungs revealed no neutrophils (A) or macrophages (B), only normal alveolar wall structure. Infected lungs had significant neutrophil accumulation (C), with little macrophage infiltration (D, indicated by arrows). (Magnification, x400.)