Quantitative, Preclinical PET of Translocator Protein Expression in Glioma Using 18F-N-Fluoroacetyl-N-(2,5-Dimethoxybenzyl)-2-Phenoxyaniline

On the one hand, the translocator protein (TSPO) radioligand N, N-diethyl-2-(2-(4-(2-18 F-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo [1,5-a]pyrimidin-3-yl)acetamide ( 18 F-DPA-714) has been suggested to serve as an alternative radiotracer to image human glioma, and on the other hand the alkylphosphocholine erufosine (ErPC3) has been reported to induce apoptosis in otherwise highly apoptosisresistant glioma cell lines. The induction of apoptosis by ErPC3 requires TSPO, a mitochondrial membrane protein highly expressed in malignant gliomas. In this preclinical study, we monitored the effect of ErPC3 treatment in vivo using 18 F-DPA-714 PET. Methods: In vitro studies investigated the antitumor effect of ErPC3 in 9L rat gliosarcoma cells. In vivo, glioma-bearing rats were imaged with 18 F-DPA-714 for the time of treatment. Results: A significant decrease in 9L cell proliferation and viability and a significant increase in apoptosis and caspase-3 activation were demonstrated on ErPC3 treatment in cell culture. In the rat model, ErPC3 administration resulted in significant changes in 18 F-DPA-714 tumor uptake over the course of the treatment. Immunohistochemistry revealed reduced tumor volume and increased cell death in ErPC3-treated animals accompanied by infiltration of the tumor core by CD11b-positive microglia/macrophages and glial fibrillary acidic proteinpositive astrocytes. Conclusion: Our findings demonstrate a potent antitumor effect of ErPC3 in vitro, in vivo, and ex vivo. PET imaging of TSPO expression using 18 F-DPA-714 allows effective monitoring and quantification of disease progression and response to ErPC3 therapy in intracranial 9L gliomas.

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confidence: 99%

The Translocator Protein Radioligand ¹⁸F-DPA-714 Monitors Antitumor Effect of Erufosine in a Rat 9L Intracranial Glioma Model

Awde¹,

Boisgard²,

Thézé³

et al. 2013

“…The evidence that the single nucleotide polymorphism in exon 4 of the TSPO gene affects the binding of second-generation ligands (11) led us to opt for 11 C-(R)PK11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide). In addition, most second-generation TSPO ligands have been used only in experimental animals and are not fully characterized in humans (12)(13)(14).…”

mentioning

confidence: 99%

The 18-kDa Mitochondrial Translocator Protein in Human Gliomas: An ¹¹C-(R)PK11195 PET Imaging and Neuropathology Study

Su¹,

Roncaroli²,

Durrenberger³

et al. 2015

The 18-kDa mitochondrial translocator protein (TSPO) is upregulated in high-grade astrocytomas and can be imaged by PET using the selective radiotracer 11 C-(R)PK11195. We investigated 11 C-(R)PK11195 binding in human gliomas and its relationship with TSPO expression in tumor tissue and glioma-associated microglia/macrophages (GAMs) within the tumors. Methods: Twenty-two glioma patients underwent dynamic 11 C-(R)PK11195 PET scans and perfusion MR imaging acquisition. Parametric maps of 11 C-(R)PK11195 binding potential (BP ND ) were generated. Coregistered MR/PET images were used to guide tumor biopsy. The tumor tissue was quantitatively assessed for TSPO expression and infiltration of GAMs using immunohistochemistry and double immunofluorescence. The imaging and histopathologic parameters were compared among different histotypes and grades and correlated with each other. Results: BP ND of 11 C-(R)PK11195 in high-grade gliomas was significantly higher than in low-grade astrocytomas and low-grade oligodendrogliomas. TSPO in gliomas was expressed predominantly by neoplastic cells, and its expression correlated positively with BP ND in the tumors. GAMs only partially contributed to the overall TSPO expression within the tumors, and TSPO expression in GAMs did not correlate with tumor BP ND . Conclusion: PET with 11 C-(R)PK11195 in human gliomas predominantly reflects TSPO expression in tumor cells. It therefore has the potential to effectively stratify patients who are suitable for TSPO-targeted treatment.

“…Additionally, TSPO is significantly overexpressed in breast, prostate, colon, and brain cancer (7), with protein expression linked to cancer progression and poor survival rates (7), suggesting that the protein may be a useful marker in predicting cancer using PET. TSPO ligands have proved promising in preliminary studies for the quantitative assessment of human glioma (8) and in animal studies for imaging breast cancer (9). However, use of TSPO PET ligands for such applications is currently in preclinical stages and has not yet been fully utilized in human patients.…”

mentioning

confidence: 99%

The Translocator Protein

Scarf¹,

Kassiou²

2011

142

The translocator protein (TSPO) is expressed at low levels in the healthy human brain and is markedly upregulated in response to brain injury and inflammation. This increase in TSPO expression is correlated to the extent of microglial activation, making the measurement of TSPO density a useful indicator of active brain disease. Several classes of TSPO radioligands have therefore been developed and evaluated for use in PET, to track the progression and severity of neuroinflammatory disease. TSPO is also overexpressed in cancer and peripheral inflammation, making TSPO PET ligands possible candidates for the imaging of a multitude of pathologies. However, we currently possess a limited understanding about the molecular structure of TSPO and about the interaction of ligands with the protein. Furthermore, the incomplete characterization of multiple TSPO binding sites and the role of TSPO polymerization suggest that current interpretation of PET data may require further refinement.