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

Abstract

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.

Preclinical Imaging Evaluation of Novel TSPO-PET Ligand 2-(5,7-Diethyl-2-(4-(2-[18F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ([18F]VUIIS1008) in Glioma

“…TSPO plays numerous roles in key biological processes in healthy tissue and disease, which include the metabolism of cholesterol, biosynthesis of steroids biosynthesis, proliferation, and apoptosis [5–6]. Accordingly, TSPO expression is elevated in several clinically important disease states, including Alzheimer’s disease[7–8], Huntington’s disease[9], Parkinson’s disease[10], and cancer.…”

“…In cancer, TSPO expression is reportedly associated with advanced disease and diminished survival [11–13]. We have explored TSPO as a molecular imaging target in colon cancer [14], breast cancer [15], and glioma [16–18], as TSPO PET could potentially serve as a useful cancer imaging biomarker [6]. …”

PET and MR imaging of neuroinflammation in hepatic encephalopathy

“…It has a longer half-life than [ 11 C]PK11195 (110 min compared to 20 min). [ 18 F]DPA-714 PET has a potential to serve as a novel modality for dynamically monitoring the brain inflammatory response and disease progression (Awde et al 2013;Tang et al 2012;Wang et al 2014). [ 18 F]DPA-714 has recently been used in seven healthy volunteers and showed excellent in vivo stability and biodistribution.…”

The use of amino acid PET and conventional MRI for monitoring of brain tumor therapy

“…However, 11 C-(R)PK11195, like MET, is limited to PET centers with a cyclotron due to its short half-life. More recently, the TSPO ligand 18 F-DPA-714 labeled with 18 F (half-life, 110 min) has been synthesized (Winkeler et al, 2012) and evaluated in glioma animal models (Awde et al, 2013). Results in human glioma patients are pending.…”