Review articleThe pre-requisite of a second-generation glioma PET biomarker
Introduction
The search for novel molecular imaging tracers to find the optimal diagnostic biomarker for glioma is hampered by a number of issues. The first part of this article will review these (mainly theoretical) issues, as we feel this is a pre-requisite to the development of novel second-generation PET markers for glioma. The main issues include, but are not limited to, the following: (i) what are the clinical considerations and how will the physicians use the results to direct patient's care? (ii) What are the biological considerations of radiochemists and radiopharmacists for a novel second-generation imaging biomarker? (iii) What do the clinicians, radiochemists and radiopharmacists expect from the regulatory authorities in terms of a quick and effective introduction of a novel second-generation imaging biomarker?
Despite the fact that advanced morphological neuroimaging techniques such as MRI allow in a number of cases to determine whether an anatomical lesion is a tumor or not and whether the tumor is malignant or not, this is not always the case. For instance, a large multiple sclerosis plaque can mimic a low-grade astrocytoma. In case the morphological features clearly indicate the presence of a tumor, the grades of the tumor need to be characterized in order to decide on the optimal therapeutic approach. The differentiation between low-grade and high-grade tumors and the localization of the most malignant part of the tumor within the tumor volume prior to biopsy are of crucial importance. Similarly, an accurate and reliable delineation of the tumor extent in both low-grade and high-grade tumors is a vital question before either invasive or non-invasive therapy (surgical resection or radio- and/or chemotherapy) is attempted. This issue is especially important in tumors involving functionally important cortical regions, such as the motor or language areas, e.g. the eloquent area. The early detection of the malignant transformation of a low-grade tumor into a high-grade form is also decisive. A novel second generation imaging biomarker should also be able to accurately differentiate residual or recurrent tumors from post-therapeutic changes, such as postirradiation necrosis and response to chemotherapy.
The most widely used tumor biomarker, FDG, is a metabolic marker. Indeed, the accumulation of FDG depends on the metabolic function of the cell. Most tumors accumulate FDG because they have increased glucose metabolism. But not all tumors are hypermetabolic and, as such, FDG is not an absolute tumor marker. A specific tumor marker is expected to label those abnormal metabolic functions or products which are characteristic of the given tumor only. Furthermore, this “labeling function” should be parametrically quantifiable. In the case of gliomas, a further requirement for the biomarker is a good blood-brain barrier penetration and an optimal signal-to-noise ratio.
Further practical considerations can be added to this list of requirements. As there are many PET centers without a cyclotron, 18F-labeled compounds have a practical priority over 11C-labeled compounds.
Regarding radiopharmaceutical aspects, the compounds' chemical and biological characteristics, such as lipophilicity, affinity, brain clearance, plasma metabolism, binding to plasma proteins, etc., are of utmost importance, similar to the development of other radiopharmaceuticals [1].
Whereas national regulatory authorities apply clear standards for the development and marketing of novel drugs, the development and marketing process for molecular imaging biomarkers is less regulated, despite recent efforts by international agencies and organizations. The regulatory agencies have to balance two opposite expectations: (i) the need of patient populations and their clinicians to have more potent glioma markers in the very near future, and (ii) the safety of the patients.
Different approaches have been formulated during the past years to meet these considerations. The EANM “Guidelines on Good Radiopharmacy Practice” (http://www.eanm.org/scientific_info/guidelines/gl_radioph_cgrpp.pdf, 2007) and its “Guideline to regulations for radiopharmaceuticals in early phase clinical trials in the EU” [2] were significant steps towards secure and easier administrative procedures of new radiotracer development, while assuring the safety aspects of the development.
Section snippets
Glioma biomarkers in recent clinical practice
More than three decades after its introduction, FDG is still dominating the molecular imaging scene of oncology in general, and that of glioma imaging in particular, as a seemingly “unbeatable champion”. The components of this success are multifold. As a glucose analogue participating in the first step of the metabolism of glucose, FDG is most faithfully mirroring the behavior of glucose as the main energy source of the cell. It can therefore provide us with useful and parametrically measurable
Challengers—2008
Over the past few years, a number of challenger imaging biomarkers have been developed and tested in the field of the molecular imaging of gliomas with PET. These challengers include, among others, radiolabeled analogues of acetate, amino acids (FET), nucleosides (FLT), amines (choline), monoamine neurotransmitter precursors (l-DOPA) and nitroimidazoles (F-miso). Several clinical PET studies have addressed the comparative analysis of these glioma markers in comparison with FDG or the “optimal
Conclusions
Three decades after the introduction of PET into the clinical practice of tumor imaging in general, and brain tumor imaging in particular, FDG is still the “working horse” among the available PET radiotracers. As explained above, there are several reasons for that. FDG is a close analogue of glucose, the major fuel molecule of the body's metabolism. Its alterations reflect faithfully the alterations in regional glucose consumption. In terms of practicality, its automated radiosynthesis is a
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Easy upgrade of the TRACERLab FX C Pro for [<sup>11</sup>C]carboxylation reactions: Application to the routine production of [1-<sup>11</sup>C]acetate
2013, Applied Radiation and IsotopesCitation Excerpt :Applied to methylmagnesium halide and [11C]CO2, which is the most common cyclotron-produced precursor in carbon-11 chemistry, [1-11C]acetate can be easily produced. This radiopharmaceutical is of importance in cardiology for the measurement of myocardial metabolism but also in oncology in different types of tumors (Bengel and Schwaiger, 2002; Borbely et al., 2010; Caroli et al., 2010; Grassi et al., 2012; Oyama et al., 2009). The importance in clinical practice of [1-11C]acetate is underlined by the fact that a monograph is existing in the European Pharmacopeia.
PET radiotracers for molecular imaging in the brain: Past, present and future
2012, NeuroImageCitation Excerpt :18F]FDG has been the tracer of choice for oncologic PET imaging, based on the increased glucose metabolism of most tumors. Despite its recognized limitations in brain tumor imaging due to the high background of normal gray matter, this imaging modality remains the most commonly used glioma tracer nowadays (Borbely et al., 2010). [ 18F]FDG provides a global picture of the tumor, predicting aggressiveness, helping to differentiate recurrent tumor from treatment-related changes and discriminating pharmacosensitive tumors.
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