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

Dennis Oliveira, Carina Stegmayr, Alexander Heinzel, Johannes Ermert, Bernd Neumaier, N. Jon Shah, Felix M. Mottaghy, Karl-Josef Langen*, Antje Willuweit

*Corresponding author for this work

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Abstract

Background Recent studies reported on high uptake of the PSMA ligands [Ga-68]HBED-CC (Ga-68-PSMA) and F-18-DCFPyL in cerebral gliomas. This study explores the regional uptake and cellular targets of Ga-68-PSMA and F-18-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, Ga-68-PSMA (n = 21) or F-18-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). Ga-68-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 Ga-68-PSMA and F-18-DCFPyL binding in the peritumoral area and moderate binding in the center of the tumors. PMPA administration led to complete inhibition of Ga-68-PSMA and F-18-DCFPyL binding in the peritumoral region. Restoration of BBB by Dex treatment reduced EBD extravasation but Ga-68-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 Ga-68-PSMA than with F-18-DCFPyL. Conclusions High uptake of Ga-68-PSMA and F-18-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.

Original languageEnglish
Article number55
Number of pages11
JournalEJNMMI Research
Volume10
Issue number1
DOIs
Publication statusPublished - 25 May 2020

Keywords

  • GLUTAMATE CARBOXYPEPTIDASE II
  • MEMBRANE ANTIGEN
  • O-(2-F-18-FLUOROETHYL)-L-TYROSINE UPTAKE
  • EXPRESSION
  • PET
  • PSMA

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