TSPO PET using 18F-GE-180: a new perspective in neurooncology?
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As early as the 1980s binding sites for the mitochondrial translocator protein (TSPO), which is also referred to as the peripheral benzodiazepine receptor, were identified in glioma cells and brain tumour tissue by Olson et al. . These findings were confirmed years later by immunohistochemical methods . By that time, the feasibility of PET imaging of glioblastoma (GBM) in patients had been demonstrated using the TSPO ligand 11C-PK11195 . Further studies, however, were hampered by partially nonspecific binding and low tumour-to-brain contrast of 11C-PK11195. In recent years, the development of so-called second generation TSPO ligands with lower nonspecific binding characteristics has initiated more preclinical studies exploiting the utility of TSPO imaging for diagnosis of brain tumours [4, 5]. Unfortunately, these new ligands are sensitive to a single-nucleotide polymorphism (rs6971 polymorphism, A147T) which is present in the human, but not the rodent, TSPO gene, resulting in variable binding affinities to the protein . The polymorphism divides the human population into high-, medium- and low-affinity binders depending on the homozygosity or heterozygosity of the allele. To overcome this clear limitation of the existing TSPO ligands, radiochemists around the world are currently working on new ligands.
GE-180 is a novel 18F-labelled so-called third generation TSPO ligand with promising characteristics, although some sensitivity to the polymorphism has also been reported [7, 8, 9]. In several preclinical studies in which TSPO tracers were directly compared with each other, 18F-GE-180 has been proven to be superior to other TSPO ligands. In an ischemia model of the rat, 18F-GE-180 showed a higher signal-to-noise ratio and lower nonspecific binding than 11C-PK11195 . Also, in a mouse model of mild neuroinflammation obtained by injecting low doses of endotoxin into the brain, only 18F-GE-180, and not the second generation tracer 18F-DPA-714 demonstrated a significantly higher binding potential and signal-to-noise ratio than 11C-PK11195 . 18F-GE-180 was also able to pick up neuroinflammation in a mouse model of Alzheimer’s disease, in which another second generation tracer, 18F-PBR06, showed no significant differences compared with wild-type control mice .
The superior imaging quality of 18F-GE-180 appears to be particularly relevant when the inflammatory activity is only slightly pronounced or diffuse neuroinflammation is present, as in neurodegenerative diseases. For imaging of gliomas, a high tumour-to-brain ratio was detected with several TSPO ligands in preclinical studies [5, 13, 14] and in patients using 11C-PK11195  owing to the high expression of TSPO in glioma cells. However, there have been no PET studies directly comparing the imaging properties of different TSPO ligands in glioma-bearing animals and patients. High binding potential to glioma cells and low nonspecific binding to the surrounding brain tissue might allow improved tumour delineation, but discrimination between tumour mass and brain tissue can be critical at the tumour rim where glia-associated microglia/macrophages (GAM), which also express TSPO, are known to be present . Here, a TSPO ligand with high and specific binding characteristics, such as 18F-GE-180, might be particularly beneficial.
In this edition of the EJNMMI, Albert et al.  present the first data on brain tumour imaging with the novel TSPO ligand 18F-GE-180. High uptake of 18F-GE-180 was shown in untreated and pretreated GBM partially extending beyond the contrast enhancement on MRI. After genotyping, no difference in 18F-GE-180 uptake was found between medium-affinity and high-affinity binders, nor in tumours and normal brain, indicating a relatively low sensitivity of 18F-GE-180 to the rs6971 polymorphism. The image quality obtained with TSPO PET using 18F-GE-180 appears to be definitively superior to that obtained with previous TSPO ligands [10, 15]. The conclusions that can be drawn from these data with respect to the identification of tumour extent, however, are limited since no data on regional histology were provided. Furthermore, it cannot be excluded that increased uptake of 18F-GE-180 in pretreated gliomas is partially caused by GAM removing debris in necrotic areas. A previous study using 11C-PK11195 indicated that TSPO is predominantly expressed in neoplastic cells with GAM only partially contributing to the PET signal and no expression in reactive astrocytes . In that study, TSPO was detectable only in a subpopulation of microglia and macrophages, overall accounting for about 16% of GAM. Thus, the data are promising and further studies comparing 18F-GE-180 uptake with histological data and with PET imaging using established tracers for brain tumour imaging such as radiolabelled amino acids or advanced MRI methods are highly recommended .
A recent study by Jensen et al.  compared the uptake of 18F-fluoroethyltyrosine (18F–FET) with TSPO expression as shown by the SPECT tracer 123I-CLINDE in three patients with GBM. There was a considerable discrepancy in the spatial distribution of the two tracers. 123I-CLINDE exhibited low uptake in wide areas of 18F-FET-positive tumour tissue, but intense uptake in normal-appearing brain areas outside abnormal 18F-FET uptake and contrast enhancement on MRI. In the further course of the disease, tumour progression was observed in those brain areas indicating that TSPO expression might be an early imaging biomarker of GBM progression. In any case, the combination of amino acid PET and TSPO imaging using 18F-GE-180 may open up a new window to the further development of neurooncological diagnostics. This is very desirable, as the cost of brain tumour treatment is high and efficient use of these therapies is very important for both the patient and the clinical community.
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Conflicts of interest
This Editorial does not discuss any studies with human participants or animals performed by any of the authors.
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