High uptake of (68)Ga-PSMA and (18)F-DCFPyL in the peritumoral area of rat gliomas due to activated astrocytes

BACKGROUND: Recent studies reported on high uptake of the PSMA ligands [(68)Ga]HBED-CC ((68)Ga-PSMA) and (18)F-DCFPyL in cerebral gliomas. This study explores the regional uptake and cellular targets of (68)Ga-PSMA and (18)F-DCFPyL in three different rat glioma models. METHODS: F98, 9 L, or U87 rat gliomas were implanted into the brains of 38 rats. After 13 days of tumor growth, (68)Ga-PSMA (n = 21) or (18)F-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). (68)Ga-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. RESULTS: Autoradiography demonstrated a strong (68)Ga-PSMA and (18)F-DCFPyL binding in the peritumoral area and moderate binding in the center of the tumors. PMPA administration led to complete inhibition of (68)Ga-PSMA and (18)F-DCFPyL binding in the peritumoral region. Restoration of BBB by Dex treatment reduced EBD extravasation but (68)Ga-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 (68)Ga-PSMA than with (18)F-DCFPyL. CONCLUSIONS: High uptake of (68)Ga-PSMA and (18)F-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.