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¹⁸F-CPFPX PET Identifies Changes in Cerebral A₁ Adenosine Receptor Density Caused by Glioma Invasion

¹ Institute of Medicine, Research Center Jülich, Jülich, Germany
² C. & O. Vogt Institute for Brain Research, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
³ Institute of Nuclear Chemistry, Research Center Jülich, Jülich, Germany
⁴ Central Institute for Electronics, Research Center Jülich, Jülich, Germany
⁵ Department of Internal Medicine, University of South Florida, Tampa, Florida

View larger version (41K): [in a new window]   FIGURE 1. Autoradiographic studies. (A) Quantification of data from F98 glioma ex vivo animal experiments reveals that receptor densities in tumor margin, tumor (total), and control region (contralateral temporal cortex [Temp. ctx.]) differ significantly (P < 0.01) (asterisks). WW = wet weight. Error bars indicate SDs. (B) Two representative ex vivo autoradiographs display intense accumulation of 3H-CPFPX at periphery of tumor. Left panel displays solid tumor; right panel displays tumor with central necrosis. Ex vivo experiments were performed 10 d after implantation of F98 tumor cells in right caudate putamen. (C) Same sections as in B. Ex vivo autoradiographs obtained with 18F-FET delineate solid tumor mass. For direct reading of absolute receptor density and amino acid (AA) uptake, see black–white scales between sections. (D) Histograms of 3H-CPFPX (red line), 18F-FET (green line), and Nissl stain (blue line) taken from levels indicated by respective colored lines in B, C, and E. A1AR density peaks at margin of solid tumor mass. OD = optical density. (E) Nissl stains of 2 sections depicted in B and C.

View larger version (83K): [in a new window]   FIGURE 2. Immunohistochemical analyses and fluorescence microscopy of sections from rat brain gliomas 10 d after implantation of tumor cells in right caudate putamen. (A) GFAP immunoreactivity of reactive astrocytes is increased in immediate vicinity of tumor (Tu), as indicated by arrowheads. Scale bar = 1 mm. (B) OX-42 immunoreactivity as a marker of activated microglia spreads far beyond peritumoral zone into cortical and limbic regions, as indicated by arrowheads. Scale bar = 1 mm. (C) Confocal fluorescence images of GFAP (green) and A1AR (red) in tumor periphery indicate that a subpopulation of GFAP-immunopositive cells expresses A1ARs (yellow). Tumor cells in solid tumor mass as well as in invasion zone (arrowheads) are also immunoreactive for A1ARs (red). Scale bar =200 µm. (D) High magnification of C. Subpopulation of astrocytes closely associated with a vessel (V) in tumor margin is immunoreactive for both GFAP (green) and A1ARs (red). Cellular colocalization is indicated by yellow. A1AR immunoreactivity (red) is also found next to cells staining for GFAP. Scale bar = 25 µm. (E) Confocal microscopy of neuronal marker SMI311 (green) and A1AR (red) indicating cellular colocalization of both immunostains (yellow). Scale bar = 50 µm.

View larger version (43K): [in a new window]   FIGURE 3. Representative examples of tumor-bearing rat 10 d after implantation of F98 cells in left caudate putamen, as measured by 18F-CPFPX and high-resolution small-animal PET. (A) MRI depicting tumor (red arrows) as hypointense zone in coronal (left) and horizontal (right) sections. (B) Summed PET images of coronal (left) and horizontal (right) sections (frames 3–10, 48-min scan time). White tracing outlines outer brain contour based on individually coregistered MRI datasets depicted in A, which were subsequently superimposed onto PET datasets. Note significant tracer accumulation at tumor border (red arrows), coinciding with outer border of hypointense zone determined by MRI (red arrows in A). Other signals represent normal cerebral tracer accumulation and the tracer and its metabolites in blood vessels. (C) Ex vivo autoradiograph (left) taken from PET experiment shown in B confirms circumferential accumulation of 18F-CPFPX in tumor region at highest spatial resolution. Histogram (right) constructed from data measured along superimposed yellow line shows that accumulation of radiotracer at periphery of tumor (red arrows) clearly exceeds that in normal brain tissue. WW = wet weight. Scale bar in all panels = 10 mm.

View larger version (80K): [in a new window]   FIGURE 4. Human PET study. (A) Coregistered planes of contrast agent–enhanced MR image (left) and 18F-CPFPX PET image (right) of recurrent glioblastoma multiforme in right temporal region. Circular zone (white arrowheads) in MR image indicates top of solid tumor and surrounding tissue. (B) Circular accumulation (boxed area) of 18F-CPFPX (right) corresponding to contrast agent–enhanced region in MR image (left). (C) High magnification of B. Adjacent to circular peritumoral ligand accumulation, a zone of gray matter, most likely temporal cortex, has been compressed and displaced by tumor (arrowheads).