Development of 18F-labeled positron emission tomography tracers for non-invasive assessment of isocitrate dehydrogenase (IDH) mutations in cerebral gliomas

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After meningiomas, cerebral gliomas are the most common primary brain tumors in adults. Despite aggressive, multidisciplinary treatment (resection, radiotherapy, chemotherapy), especially high-grade gliomas like glioblastomas are still associated with a poor prognosis. As a consequence, intense ongoing research efforts have been aimed at identifying molecules involved in tumor growth that could provide novel targets for personalized treatment approaches in these patients. Studies in large cohorts of glioma patients revealed that >65% of low-grade gliomas and >85% of secondary glioblastomas but only <5% of primary glioblastomas exhibit mutations in the enzyme isocitrate dehydrogenase (IDH), which are associated with increased production of the oncometabolite 2-hydroxyglutarate. As these mutations occur early during tumorigenesis and affect the whole tumor tissue, the mutant enzymes could serve as both, diagnostic biomarkers and potential targets for therapeutic approaches. However, detection of IDH mutations is still mostly achieved through immunohistochemistry and genomic sequencing, which require tissue samples retrieved by e.g. biopsy or during an operation and are thus not suitable for disease progression monitoring or longitudinal studies. Aim of this work is the development of IDH-specific probes for non-invasive assessment of IDH expression in gliomas by positron emission tomography (PET). Our focus will be on the development of brain-permeable radiotracers that selectively address the mutant IDH isoform. To this end, radiofluorination protocols previously developed by the applicants will be used to label different specific inhibitors currently undergoing phase I clinical trials with fluorine-18, a radionuclide with ideal properties for preclinical and clinical PET imaging. Apart from the production of sufficiently accessible radiolabeling precursors, the radiolabeling conditions will be optimized with regard to synthesis duration and radiochemical yields. In parallel, the developed tracers will be evaluated for their affinity, selectivity, stability, brain permeability, pharmacokinetic and pharmacodynamics properties using enzymatic and functional inhibition assays, in vitro cell uptake studies with several tumor cell lines as well as ex vivo and in vivo studies with the same tumor cell lines inoculated into embryonated chicken eggs. For the most promising candidates, the results thus obtained will be validated in an orthotopic glioblastoma model in the rat and their radiosynthesis will be transferred to an automated synthesis module for clinical tracer production.