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

doi:10.1186/s13550-020-00642-0

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

Research output: Contribution to journal › Article › Academic › peer-review

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 language	English
Article number	55
Number of pages	11
Journal	EJNMMI Research
Volume	10
Issue number	1
DOIs	https://doi.org/10.1186/s13550-020-00642-0
Publication status	Published - 25 May 2020

Keywords

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

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@article{ef3962afe2a2485b8c030a60ce13e409,

title = "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 [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.",

keywords = "GLUTAMATE CARBOXYPEPTIDASE II, MEMBRANE ANTIGEN, O-(2-F-18-FLUOROETHYL)-L-TYROSINE UPTAKE, EXPRESSION, PET, PSMA",

author = "Dennis Oliveira and Carina Stegmayr and Alexander Heinzel and Johannes Ermert and Bernd Neumaier and Shah, {N. Jon} and Mottaghy, {Felix M.} and Karl-Josef Langen and Antje Willuweit",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = may,

day = "25",

doi = "10.1186/s13550-020-00642-0",

language = "English",

volume = "10",

journal = "EJNMMI Research",

issn = "2191-219X",

publisher = "SpringerOpen",

number = "1",

}

TY - JOUR

T1 - High uptake of 68Ga-PSMA and 18F-DCFPyL in the peritumoral area of rat gliomas due to activated astrocytes

AU - Oliveira, Dennis

AU - Stegmayr, Carina

AU - Heinzel, Alexander

AU - Ermert, Johannes

AU - Neumaier, Bernd

AU - Shah, N. Jon

AU - Mottaghy, Felix M.

AU - Langen, Karl-Josef

AU - Willuweit, Antje

PY - 2020/5/25

Y1 - 2020/5/25

N2 - 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.

AB - 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.

KW - GLUTAMATE CARBOXYPEPTIDASE II

KW - MEMBRANE ANTIGEN

KW - O-(2-F-18-FLUOROETHYL)-L-TYROSINE UPTAKE

KW - EXPRESSION

KW - PET

KW - PSMA

U2 - 10.1186/s13550-020-00642-0

DO - 10.1186/s13550-020-00642-0

M3 - Article

C2 - 32451793

SN - 2191-219X

VL - 10

JO - EJNMMI Research

JF - EJNMMI Research

IS - 1

M1 - 55

ER -