TSPO Imaging in Glioblastoma Multiforme: A Direct Comparison Between <sup>123</sup>I-CLINDE SPECT, <sup>18</sup>F-FET PET, and Gadolinium-Enhanced MR Imaging

Jensen, Peter Kjær Mackie; Feng, Li; Law, Ian; Svarer, Claus; Knudsen, Gitte M.; Mikkelsen, Jens D.; Nijs, Robin de; Larsen, Vibeke Andrée; Dyssegaard, Agnete; Thomsen, Gerda; Fischer, Walter; Guilloteau, Denis; Pinborg, Lars H.

doi:10.2967/jnumed.115.158998

Cited by 40 publications

(29 citation statements)

References 19 publications

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“…The other important finding within this study is the advanced/early detection of the invasively growing glioma 40 and results from a preclinical TSPO-PET study using human glioma xenotransplants 26 the authors suggested that the unique tissue areas at the tumor margins are of high interest, as they might be related to sites of glioma infiltration, an aspect supported by the outcome of the present study.…”

Section: Discussionsupporting

confidence: 61%

TSPO-PET and diffusion-weighted MRI for imaging a mouse model of infiltrative human glioma

et al. 2019

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Section: Discussionsupporting

confidence: 61%

TSPO-PET and diffusion-weighted MRI for imaging a mouse model of infiltrative human glioma

et al. 2019

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“…Additionally, in almost all types of CNS pathologies, TSPO levels are increased, and in some psychiatric disorders, such as schizophrenia, the TSPO signal in PET is decreased [34]. Although TSPO ligands are widely used in molecular imaging in all sorts of CNS pathologies, little is known about the role of TSPO expression and neuroinflammation in glioblastoma patients and PET imaging with TSPO radioligands is not yet standard for the imaging of brain tumor patients [18,19,[35][36][37]. In this study, we could show that the expression of TSPO is higher in brain tumor samples compared to those from epilepsy patients.…”

Section: Discussionmentioning

confidence: 99%

Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells

Cai

Kirchleitner

Zhao

et al. 2020

IJMS

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Molecular imaging is essential for diagnosis and treatment planning for glioblastoma patients. Positron emission tomography (PET) with tracers for the detection of the solute carrier family 7 member 5 (SLC7A5; also known as the amino acid transporter light chain L system, LAT1) and for the mitochondrial translocator protein (TSPO) is successfully used to provide additional information on tumor volume and prognosis. The current approaches for TSPO-PET and the visualization of tracer ([18F] Fluoroethyltyrosine, FET) uptake by LAT1 (FET-PET) do not yet exploit the full diagnostic potential of these molecular imaging techniques. Therefore, we investigated the expression of TSPO and LAT1 in patient glioblastoma (GBM) samples, as well as in various GBM mouse models representing patient GBMs of different genetic subtypes. By immunohistochemistry, we found that TSPO and LAT1 are upregulated in human GBM samples compared to normal brain tissue. Next, we orthotopically implanted patient-derived GBM cells, as well as genetically engineered murine GBM cells, representing different genetic subtypes of the disease. To determine TSPO and LAT1 expression, we performed immunofluorescence staining. We found that both TSPO and LAT1 expression was increased in tumor regions of the implanted human or murine GBM cells when compared to the neighboring mouse brain tissue. While LAT1 was largely restricted to tumor cells, we found that TSPO was also expressed by microglia, tumor-associated macrophages, endothelial cells, and pericytes. The Cancer Genome Atlas (TCGA)-data analysis corroborates the upregulation of TSPO in a bigger cohort of GBM patient samples compared to tumor-free brain tissue. In addition, AIF1 (the gene encoding for the myeloid cell marker Iba1) was also upregulated in GBM compared to the control. Interestingly, TSPO, as well as AIF1, showed significantly different expression levels depending on the GBM genetic subtype, with the highest expression being exhibited in the mesenchymal subtype. High TSPO and AIF1 expression also correlated with a significant decrease in patient survival compared to low expression. In line with this finding, the expression levels for TSPO and AIF1 were also significantly higher in (isocitrate-dehydrogenase wild-type) IDHWT compared to IDH mutant (IDHMUT) GBM. LAT1 expression, on the other hand, was not different among the individual GBM subtypes. Therefore, we could conclude that FET- and TSPO-PET confer different information on pathological features based on different genetic GBM subtypes and may thus help in planning individualized strategies for brain tumor therapy in the future. A combination of TSPO-PET and FET-PET could be a promising way to visualize tumor-associated myeloid cells and select patients for treatment strategies targeting the myeloid compartment.

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“…This series also contains, as PET-imaging probes, [ 11 C]CLINME [23,24] and [ 18 F]PBR111 [25][26][27][28][29], and as Single Photon Emission Tomography (SPET) probe, the iodine-123-labelled derivative [ 123 I]CLINDE [30][31][32][33]. [ 123 I]CLINDE and [ 18 F]PBR111 are today both engaged in humans studies [34,35], respectively with indications for multiform glioblastoma [36] and microglial activation imaging in patients with multiple sclerosis [37].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and in vitro characterization of novel fluorinated derivatives of the translocator protein 18 kDa ligand CfO-DPA-714

Cacheux¹,

Médran-Navarrete²,

Dollé³

et al. 2017

European Journal of Medicinal Chemistry

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The translocator protein 18 kDa (TSPO) is today a validated target for a number of therapeutic applications, but also a well-recognized diagnostic/imaging biomarker for the evaluation of inflammatory related-disease state and progression, prompting the development of specific and dedicated TSPO ligands worldwide. For this purpose, pyrazolo[1,5-a]pyrimidine acetamides constitute a unique class of high affinity and selectivity TSPO ligands; it includes DPA-714, a fluorine-containing derivative that has also been labelled with the positron-emitter fluorine-18, and is nowadays widely used as a Positron Emission Tomography imaging probe. Recently, to prevent defluorination issues encountered in vivo with this tracer, a first series of analogues was reported where the oxygen atom bridging the phenyl ring of the core structure and the fluorinated moiety was replaced with a more robust linkage. Among this new series, CfO-DPA-714 was discovered as a highly promising TSPO ligand. Herein, a novel series of fluorinated analogues of the latter molecule were synthesized and in vitro characterized, where the pharmacomodulation at the amide position of the molecule was explored. Thirteen compounds were thus prepared from a common key-ester intermediate (synthesized in 7 steps from 4-iodobenzoate - 11% overall yield) and a set of commercially available amines and obtained with moderate to good yields (23-81%) and high purities (>95%). With one exception, all derivatives displayed nanomolar to subnanomolar affinity for the TSPO and also high selectivity versus the CBR (K (CBR)/K (TSPO) > 10). Within this series, three compounds showed better K values (0.25, 0.26 and 0.30 nM) than that of DPA-714 (0.91 nM) and CfO-DPA-714 (0.37 nM), and favorable lipophilicity for brain penetration (3.6 < logD < 4.4). Among these three compounds, the N-methyl-N-propyl amide analogue (9) exhibited similar metabolic stability when compared to CfO-DPA-714 in mouse, rat and human microsomes. Therefore, the latter compound stands out as a promising candidate for drug development or for use as a PET probe, once fluorine-18-labelled, for in vivo neuroinflammation imaging.

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TSPO Imaging in Glioblastoma Multiforme: A Direct Comparison Between ¹²³I-CLINDE SPECT, ¹⁸F-FET PET, and Gadolinium-Enhanced MR Imaging

Cited by 40 publications

References 19 publications

TSPO-PET and diffusion-weighted MRI for imaging a mouse model of infiltrative human glioma

TSPO-PET and diffusion-weighted MRI for imaging a mouse model of infiltrative human glioma

Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells

Synthesis and in vitro characterization of novel fluorinated derivatives of the translocator protein 18 kDa ligand CfO-DPA-714

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TSPO Imaging in Glioblastoma Multiforme: A Direct Comparison Between 123I-CLINDE SPECT, 18F-FET PET, and Gadolinium-Enhanced MR Imaging

Cited by 40 publications

References 19 publications

TSPO-PET and diffusion-weighted MRI for imaging a mouse model of infiltrative human glioma

TSPO-PET and diffusion-weighted MRI for imaging a mouse model of infiltrative human glioma

Glioblastoma Exhibits Inter-Individual Heterogeneity of TSPO and LAT1 Expression in Neoplastic and Parenchymal Cells

Synthesis and in vitro characterization of novel fluorinated derivatives of the translocator protein 18 kDa ligand CfO-DPA-714

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Product

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TSPO Imaging in Glioblastoma Multiforme: A Direct Comparison Between ¹²³I-CLINDE SPECT, ¹⁸F-FET PET, and Gadolinium-Enhanced MR Imaging