BackgroundThe integrin αvβ3 plays an important role in angiogenesis and tumor cell metastasis, and is currently being evaluated as a target for new therapeutic approaches. Several techniques are being studied to enable noninvasive determination of αvβ3 expression. We developed [18F]Galacto-RGD, a 18F-labeled glycosylated αvβ3 antagonist, allowing monitoring of αvβ3 expression with positron emission tomography (PET).Methods and FindingsHere we show by quantitative analysis of images resulting from a small-animal PET scanner that uptake of [18F]Galacto-RGD in the tumor correlates with αvβ3 expression subsequently determined by Western blot analyses. Moreover, using the A431 human squamous cell carcinoma model we demonstrate that this approach is sensitive enough to visualize αvβ3 expression resulting exclusively from the tumor vasculature. Most important, this study shows, that [18F]Galacto-RGD with PET enables noninvasive quantitative assessment of the αvβ3 expression pattern on tumor and endothelial cells in patients with malignant tumors.ConclusionsMolecular imaging with [18F]Galacto-RGD and PET can provide important information for planning and monitoring anti-angiogenic therapies targeting the αvβ3 integrins and can reveal the involvement and role of this integrin in metastatic and angiogenic processes in various diseases.

Purpose: The integrin a v h 3 plays a key role in angiogenesis and tumor cell metastasis and is therefore an important target for new therapeutic and diagnostic strategies. We have developed [18 F]Galacto-RGD, a highly a v h 3 -selective tracer for positron emission tomography (PET). Here, we show, in man, that the intensity of [ 18 F]Galacto-RGD uptake correlates with a v h 3 expression. Experimental Design: Nineteen patients with solid tumors (musculoskeletal system, n = 10; melanoma, n = 4; head and neck cancer, n = 2; gliobastoma, n = 2; and breast cancer, n = 1) were examined with PET using [

Purpose: [ 18 F]Galacto-RGD has been developed for positron emission tomography (PET)î maging of avh3 expression, a receptor involved in angiogenesis and metastasis. Our aim was to study the feasibility of PET imaging with [ ]Galacto-RGD, static emission scans 60 min post injection from the head to the abdomen (n = 11) and dynamic scans >60 min covering the tumor region (n = 6) for kinetic modeling were acquired. Standardized uptake values (SUV) were measured in tumors, muscle and oral mucosa. Immunohistochemistry was done using an avh3-specific antibody (n = 7). Image fusion with magnetic resonance imaging and/or computed tomography (CT) scans (n = 8) and calculation of tumor subvolumes based on SUVs was done using the iPlan software (BrainLAB).

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RESULTS.Light microscopic study showed that BSCC was composed of relatively versity, Düsseldorf, Germany.small tumor cells, arranged in solid lobules with abundant comedo-type necrosis.

The integrin a v b 3 is a key player in angiogenesis and metastasis. Our aim was to study the uptake patterns of the a v b 3 -selective PET tracer 18 F-galacto-RGD in invasive ductal breast cancer. Methods: Sixteen patients with primary (n 5 12) or metastasized breast cancer (n 5 4) were examined with 18 F-galacto-RGD PET.Standardized uptake values (SUVs) were derived by region-ofinterest analysis, and immunohistochemistry of a v b 3 expression was performed (n 5 5). Results: 18 F-Galacto-RGD PET identified all invasive carcinomas, with SUVs from 1.4 to 8.7 (mean 6 SD, 3.6 6 1.8; tumor-to-blood and tumor-to-muscle ratios, 2.7 6 1.6 and 6.2 6 2.2, respectively). Lymph-node metastases were detected in 3 of 8 patients (mean SUV, 3.3 6 0.8). SUVs in distant metastases were heterogeneous (2.9 6 1.4). Immunohistochemistry confirmed a v b 3 expression predominantly on microvessels (5/5) and, to a lesser extent, on tumor cells (3/5). Conclusion: Our results suggest generally elevated and highly variable a v b 3 expression in human breast cancer lesions. Consequently, further imaging studies with 18 F-galacto-RGD PET in breast cancer patients for assessment of angiogenesis or planning of a v b 3 -targeted therapies are promising.

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This study aimed to address the relative contributions of the proinflammatory cytokine interleukin‐6 (IL‐6) and the cytokine‐like hormone leptin to the genomic activation of brain cells during lipopolysaccharide (LPS)‐induced systemic inflammation. Wildtype and IL‐6KO mice were injected with LPS (50 μg/kg, intraperitoneally) and the brains analyzed by immunohistochemistry and reverse‐transcriptase polymerase chain reaction (RT‐PCR). LPS induced a pronounced nuclear translocation of the signal transducer and activator of transcription (STAT3) throughout the brains of wildtype mice, an effect that was significantly diminished, but not abolished, in the IL‐6KOs. The remnant STAT3‐activation, although still observed within some of the same areas activated by IL‐6, was most intense in ependymal and meningial cells and along distinct blood vessels throughout the brain. This expression was almost totally abolished in the presence of an anti‐leptin antiserum. Interestingly, the induction of cyclooxygenase 2 and microsomal prostaglandin E synthase (mPGES), the rate‐limiting enzymes for synthesis of PGE2 by LPS, was diminished to a degree that correlated with the absence of IL‐6 but not entirely with leptin. These results demonstrate that the induction of the inflammatory pathway in the brain is mediated by both IL‐6 and leptin, which appear to work in tandem. Unlike IL‐6, however, the contribution of leptin to this response was limited to distinct cell types/brain areas and STAT3‐responsive target genes implicated in the brain‐controlled sickness‐type response. The physiological significance of leptin's action on meningeal and endothelial cells remains to be clarified but might reflect a role in LPS‐induced immune cell infiltration into the brain. J. Comp. Neurol. 511:373–395, 2008. © 2008 Wiley‐Liss, Inc.