The proliferation marker FLT which accumulates in malignant tissues due to an enhanced activity of TK1 however often shows relatively low tumor uptakes, favoring F-DOPA for the PET imaging of malignancies.ĭue to its increasing importance for human tumor imaging, the synthesis of F-DOPA becomes a critical measure regarding its dissemination in clinical routine. FDG on the contrary is taken up by the glucose transporter not only by malignant tissues but also by inflamed and healthy tissues exhibiting a high glucose metabolism, resulting in low tumor-to-background ratios in CNS malignancies. F-DOPA, which is transported via the dopamine transporter (DAT) into cells, has thus shown diagnostic advantages in the imaging of high- and low-grade malignancies like neuroendocrine tumors, pheochromocytoma, and pancreatic adenocarcinoma regarding diagnostic efficiency and sensitivity. Among these tracers used for neurooncologic imaging, F-DOPA shows a high uptake in the malignant tissues, thus allowing a very sensitive tumor detection via PET imaging.īeyond glioma imaging, recent studies have also shown the increasing importance of F-DOPA for the visualization of various peripheral tumor entities via PET which can be attributed to the upregulation of amino acid transporters in malignant tissues due to an often increased proliferation. Also other alternatives based on amino acids were developed for the imaging of brain malignancies such as methyl- L-methionine (CH 3-MET), 3′-deoxy-3′- L-fluorothymidine (FLT), or fluoroethyl- L-tyrosine (FET) (Figure 1) which also exhibit the advantage to show a low physiological accumulation in normal cerebral tissue and inflamed lesions compared to FDG, thus giving more favorable results in brain tumor imaging. In the following, numerous studies were conducted establishing F-DOPA as the main diagnostic tool for brain tumor imaging giving more favorable diagnostic results than FDG (Figure 1) due to a significantly lower background accumulation. Incidental findings in a patient undergoing a movement disorder diagnosis resulted in a coincidental discovery of a malignant glioma, indicating the potential applicability of F-DOPA also for glioma imaging. Selected radiotracers applicable in (brain-)tumor imaging. As a diagnostic tool for the investigation of the neuronal dopaminergic metabolism, a high specific activity (SA) of F-DOPA is not mandatory. For example, its uptake in the striatum is increased during dopamine replacement therapies in Parkinson’s disease and modulated by administration of dopamine D 2 receptor antagonist-based antipsychotic compounds. Likewise, the F-DOPA uptake can also be relevant for determining the effects of treatment of the underlying pathophysiology. As DOPA is the precursor of the neurotransmitter dopamine, the extent of accumulation of F-DOPA in the brain reflects the functional integrity of the presynaptic dopaminergic synthesis and visualizes the activity of aromatic amino acid decarboxylase (AADC), which converts F-DOPA to 18F-dopamine. The 18F-radiolabeled nonproteinogenic amino acid 3,4-dihydroxy-6-fluoro- L-phenylalanine (F-DOPA) (Figure 1) has been used for over 30 years to image the presynaptic dopaminergic system in the human brain in order to investigate a number of CNS disorders, in particular schizophrenia and Parkinson’s disease with positron emission tomography (PET). This review summarizes the developments in the field of F-DOPA syntheses using electrophilic synthesis pathways as well as recent developments of nucleophilic syntheses of F-DOPA and compares the different synthesis strategies regarding the accessibility and applicability of the products for human in vivo PET tumor imaging.
The nucleophilic syntheses which were developed recently are able to provide F-DOPA by automated syntheses in very high specific activities, radiochemical yields, and enantiomeric purities. Among these, the no-carrier-added nucleophilic introduction of fluorine-18, especially, has gained increasing attention as it gives F-DOPA in higher specific activities and shorter reaction times by less intricate synthesis protocols. With the application of this tracer in neuroendocrine tumor imaging, improved radiosyntheses have been developed. Recent findings however point to very favorable results of this tracer for the imaging of other malignant diseases such as neuroendocrine tumors, pheochromocytoma, and pancreatic adenocarcinoma expanding its application spectrum. For many years, the main application of F-DOPA has been the PET imaging of neuropsychiatric diseases, movement disorders, and brain malignancies.