Abstract
BackgroundRecent studies reported on high uptake of the PSMA ligands [68Ga]HBED-CC (68Ga-PSMA) and 18F-DCFPyL in cerebral gliomas. This study explores the regional uptake and cellular targets of 68Ga-PSMA and 18F-DCFPyL in three different rat glioma models.MethodsF98, 9 L, or U87 rat gliomas were implanted into the brains of 38 rats. After 13 days of tumor growth, 68Ga-PSMA (n = 21) or 18F-DCFPyL (n = 17) was injected intravenously, and animals were sacrificed 40 min later. Five animals for each tracer and tumor model were additionally investigated by micro-PET at 20–40 min post injection. Cryosections of the tumor bearing brains were analyzed by ex vivo autoradiography and immunofluorescence staining for blood vessels, microglia, astrocytes, and presence of PSMA. Blood-brain barrier (BBB) permeability was tested by coinjection of Evans blue dye (EBD). 68Ga-PSMA uptake after restoration of BBB integrity by treatment with dexamethasone (Dex) was evaluated in four animals with U87 gliomas. Competition experiments using the PSMA-receptor inhibitor 2-(phosphonomethyl)pentane-1,5-dioic acid (PMPA) were performed for both tracers in two animals each.ResultsAutoradiography demonstrated a strong 68Ga-PSMA and 18F-DCFPyL binding in the peritumoral area and moderate binding in the center of the tumors. PMPA administration led to complete inhibition of 68Ga-PSMA and 18F-DCFPyL binding in the peritumoral region. Restoration of BBB by Dex treatment reduced EBD extravasation but 68Ga-PSMA binding remained unchanged. Expression of activated microglia (CD11b) was low in the intra- and peritumoral area but GFAP staining revealed strong activation of astrocytes in congruency to the tracer binding in the peritumoral area. All tumors were visualized in micro PET, showing a lower tumor/brain contrast with 68Ga-PSMA than with 18F-DCFPyL.ConclusionsHigh uptake of 68Ga-PSMA and 18F-DCFPyL in the peritumoral area of all glioma models is presumably caused by activated astrocytes. This may represent a limitation for the clinical application of PSMA ligands in gliomas.
Highlights
PET ligands for the prostate specific membrane antigen (PSMA) are very successful in the diagnostic assessment of prostate cancer [1, 2]
PSMA is expressed by a variety of nonprostate cancers, often on the endothelium of tumorassociated neovasculature [5], and initial studies have explored the application of PSMA ligands in breast, lung, bladder, pancreatic and colorectal cancer, renal cell carcinoma, and glioblastoma [6]
We explored the regional binding of the well-established PSMA ligands 68Ga-PSMA and 18FDCFPyL in three different rat glioma models including the human U87 glioma cell line
Summary
PET ligands for the prostate specific membrane antigen (PSMA) are very successful in the diagnostic assessment of prostate cancer [1, 2]. PSMA is expressed by a variety of nonprostate cancers, often on the endothelium of tumorassociated neovasculature [5], and initial studies have explored the application of PSMA ligands in breast, lung, bladder, pancreatic and colorectal cancer, renal cell carcinoma, and glioblastoma [6]. Most of the reported findings with PSMA-targeted radiotracers in non-prostate malignancies, are limited to small series of patients, and further investigations are needed to explore the potential of PSMA ligands outside prostate cancer. Recent studies reported on high uptake of the PSMA ligands [68Ga]HBED-CC (68Ga-PSMA) and 18FDCFPyL in cerebral gliomas. This study explores the regional uptake and cellular targets of 68Ga-PSMA and 18FDCFPyL in three different rat glioma models
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