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

Abstract

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, 9L 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) were 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 postinjection. 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.

Prostate-Specific Membrane Antigen as Target for Neuroimaging of Central Nervous System Tumors

“…They used an anti-PSMA mAB clone SP29 (Biogenex) for immunohistochemistry and quantified the extent and intensity of PSMA staining in vascular endothelial cells. They found PSMA 68 Ga-PSMA and 18 F-DCFPyL binding were studied on ex vivo autoradiography in 38 rats, implanted with either F98, 9L, or U87 glioma cells [23]. They found that both PSMA-targeting tracers exhibited strong binding in the peritumoral area but moderate binding in the tumor core.…”

Molecular and Cellular Complexity of Glioma. Focus on Tumour Microenvironment and the Use of Molecular and Imaging Biomarkers to Overcome Treatment Resistance

“…Very few astrocytes were noted in the centre of the tumours. These data suggest that PSMA radioligand could also visualize astrocytes activation [ 266 ].…”