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6-[18 F] Fluoro-L-DOPA: a Well-Established Neurotracer with Expanding Application Spectrum and Strongly Improved Radiosyntheses

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6-[18 F] Fluoro-L-DOPA: a Well-Established Neurotracer with Expanding Application Spectrum and Strongly Improved Radiosyntheses Hindawi Publishing Corporation BioMed Research International Volume 2014, Article ID 674063, 12 pages http://dx.doi.org/10.1155/2014/674063 Review Article 6-[18F]Fluoro-L-DOPA: A Well-Established Neurotracer with Expanding Application Spectrum and Strongly Improved Radiosyntheses M. Pretze,1 C. Wängler,2 and B. Wängler1 1 Molecular Imaging and Radiochemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany 2 Biomedical Chemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany Correspondence should be addressed to B. Wangler;¨ [email protected] Received 26 February 2014; Revised 17 April 2014; Accepted 18 April 2014; Published 28 May 2014 Academic Editor: Olaf Prante Copyright © 2014 M. Pretze et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 18 For many years, the main application of [ F]F-DOPA has been the PET imaging of neuropsychiatric diseases, movement disorders, and brain malignancies. 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. With the application of this tracer in neuroendocrine tumor imaging, improved radiosyntheses have been developed. Among these, 18 the no-carrier-added nucleophilic introduction of fluorine-18, especially, has gained increasing attention as it gives [ F]F-DOPA in higher specific activities and shorter reaction times by less intricate synthesis protocols. The nucleophilic syntheses whichwere 18 developed recently are able to provide [ F]F-DOPA by automated syntheses in very high specific activities, radiochemical yields, 18 and enantiomeric purities. This review summarizes the developments in the field of[ F]F-DOPA syntheses using electrophilic 18 synthesis pathways as well as recent developments of nucleophilic syntheses of [ F]F-DOPA and compares the different synthesis strategies regarding the accessibility and applicability of the products for human in vivo PET tumor imaging. 1. Introduction is increased during dopamine replacement therapies in 18 Parkinson’s disease [6] and modulated by administration The F-radiolabeled nonproteinogenic amino acid 3,4- 18 18 of dopamine D2 receptor antagonist-based antipsychotic dihydroxy-6-[ F]fluoro-l-phenylalanine ([ F]F-DOPA) compounds [7, 8]. As a diagnostic tool for the investigation (Figure 1) has been used for over 30 years to image the of the neuronal dopaminergic metabolism, a high specific 18 presynaptic dopaminergic system in the human brain in activity (SA) of [ F]F-DOPA is not mandatory. order to investigate a number of CNS disorders, in particular Incidental findings in a patient undergoing a movement schizophrenia [1, 2] and Parkinson’s disease with positron disorder diagnosis resulted in a coincidental discovery of a emission tomography (PET) [3, 4]. As DOPA is the precur- malignant glioma, indicating the potential applicability of sor of the neurotransmitter dopamine, the extent of accumu- 18 18 [ F]F-DOPA also for glioma imaging [9]. In the following, lation of [ F]F-DOPA in the brain reflects the functional 18 integrity of the presynaptic dopaminergic synthesis [5]and numerous studies were conducted establishing [ F]F-DOPA visualizes the activity of aromatic amino acid decarboxylase asthemaindiagnostictoolforbraintumorimaginggiv- 18 18 18 (AADC), which converts [ F]F-DOPA to F-dopamine. ing more favorable diagnostic results than [ F]FDG [10] 18 Likewise, the [ F]F-DOPAuptakecanalsoberelevant (Figure 1)duetoasignificantlylowerbackgroundaccumula- for determining the effects of treatment of the underlying tion. Also other alternatives based on amino acids were pathophysiology. For example, its uptake in the striatum developed for the imaging of brain malignancies such 2 BioMed Research International OH O O OH HO O OH O N 18 NH F NH2 HO 18 O F O OH 18F []18F FET []18F FLT []18F FDG O O HO HO 11 S H3 C OH NH 18 2 HO F NH2 []18 [11 ] F F-DOPA C CH3-MET Figure 1: Selected radiotracers applicable in (brain-)tumor imaging. 11 11 as [ C]methyl-l-methionine ([ C]CH3-MET) [11–13], synthesis routes and the more recent synthesis improvements 18 18 3 -deoxy-3 -l-[ F]fluorothymidine ([ F]FLT) [14, 15], or via nucleophilic syntheses. The main focus of this work is 18 18 [ F]fluoroethyl-l-tyrosine ([ F]FET) [16–19](Figure 1) to compare the radiochemical yields (RCYs), radiochemical which also exhibit the advantage to show a low physiological purities (RCPs), enantiomeric excess (ee), synthesis times, accumulation in normal cerebral tissue and inflamed lesions reliability, and a potential for automation of the different 18 compared to [ F]FDG, thus giving more favorable results radiosynthesis pathways. in brain tumor imaging. Among these tracers used for 18 neurooncologic imaging, [ F]F-DOPA shows a high uptake 2. Synthesis Routes for the Production of in the malignant tissues, thus allowing a very sensitive tumor [18F]F-DOPA detection via PET imaging. 18 Beyond glioma imaging, recent studies have also shown 2.1. First Attempts to Synthesize [ F]F-DOPA. One of the first 18 18 the increasing importance of [ F]F-DOPA for the visual- fluorine-18-labeled DOPA derivatives was 5-[ F]F-DOPA 18 ization of various peripheral tumor entities via PET [20] [ F]4, synthesized via isotopic exchange by Firnau et al. 6 which can be attributed to the upregulation of amino acid in 1973 [34](Figure 2). In a swimming pool reactor Li(, 4 3 16 3 18 transportersinmalignanttissuesduetoanoftenincreased He) Hand O( H, ) F nuclear reactions were utilized to 18 proliferation [21, 22]. [ F]F-DOPA, which is transported produce fluorine-18 in a mixture of Li2CO3 in H2SO4 and 18 via the dopamine transporter (DAT) into cells, has thus H2O. The resulting [ F]fluoride was subsequently distilled shown diagnostic advantages in the imaging of high- and twice and the diazonium fluoroborate precursor 1 was added low-grade malignancies like neuroendocrine tumors [23– to this solution. After the isotopic exchange reaction has 27], pheochromocytoma [28, 29], and pancreatic adenocarci- occurred, the water was removed and the residue was dried 18 noma [30–32] regarding diagnostic efficiency and sensitivity. over P2O5.Thedriedresidue[ F]2 was redissolved in 18 ∘ [ F]FDG on the contrary is taken up by the glucose trans- dioxane, filtered, and heated to 80 C. After adding xylene, the ∘ porter not only by malignant tissues but also by inflamed solution was further heated to 132 C for the pyrolysis of the 18 18 and healthy tissues exhibiting a high glucose metabolism, diazonium[ F]fluoroborate [ F]2 for 30 min. After solvent 18 resulting in low tumor-to-background ratios [10]inCNS evaporation, HBr (48%) was added to hydrolyze [ F]3 to the 18 18 malignancies. The proliferation marker [ F]FLT which accu- final product 5-[ F]F-DOPA. 18 mulatesinmalignanttissuesduetoanenhancedactivityof The resulting product [ F]4 was obtained in high radio- TK1 however often shows relatively low tumor uptakes [15], chemical purities of >95% but very low specific activities 18 favoring [ F]F-DOPA for the PET imaging of malignancies. between 2.2 and 22 kBq/mol (0.2–2.0 Ci/mg). Further- Due to its increasing importance for human tumor imag- more, the enantiomeric purity of the product was not 18 ing, the synthesis of [ F]F-DOPA becomes a critical measure determined, limiting the applicability of this cumbersome regarding its dissemination in clinical routine. Ideally, the synthesis route. 18 radiotracer should be easily accessible in high radiochemical A significant limitation for the use of 5-[ F]F-DOPA for yields (RCYs) and specific activities (SAs) as well as in short in vivo imaging purposes is the accelerated O-methylation 18 18 18 synthesis times by an automated process. Furthermore, as of 5-[ F]F-DOPA in contrast to 6-[ F]F-DOPA ([ F]7, it was demonstrated that d-amino acids lack a permeability Figure 3). This increased O-methylation rate is caused by the through the blood-brain barrier, an enantioselective synthe- fluorine atom in position 5 in direct vicinity to the hydroxyl 18 sis for [ F]F-DOPA is mandatory [33]. group in position 4 [35]andresultsinasignificantlylower 18 18 The following review outlines the developments in in vivo stability of 5-[ F]F-DOPA ([ F]4, Figure 2). The 18 18 the field of [ F]F-DOPA radiosyntheses via electrophilic same group presented the reaction of [ F]F2 and l-DOPA BioMed Research International 3 O O OO [18F]fluoride, H O (pH 4), O NH 2 O NH O ∘ O O (1) 30 min, 50 C O O O O (2) ,15min 18 P2O5 18 [ F]2 N2BF4 N2BF3 F 1 Dioxane, xylene ∘ 30 min, 132 C O O HO NH2-HBr HBr (48%),H 2,g O NH O ∘ HO O OH 45 min, 146–148 C O O O 18 F [18F]4 18 18F []3F 18 Figure 2: Isotopic exchange reaction pathway for the synthesis of 5-[ F]F-DOPA [34]. R R O O [18 ] , N F F2 N O O 48 CCl4, Freon-11, HBr ( %), (A) O O 10 ∘ min, dry ice 35 min, 135 C [18F]6a: = O Si 5a: = O 18F R H R H 18 5a: = [ F]6b:R=NO R NO2 2 O O OH H H N O N O NH [18F]AcOF, 2 O O ( %), O AcOH, HI 55 O CF3 O CF3 HO ∘ (B) 5 min, r.t. 10 min, 130 C 18 18 O HgOCOCF3 O F HO F 18 18 8 [ F]9 [18F]F-DOPA([ F]7) O O H H O [18 ] , N O N F F2 O , O CDCl3 HCI (6 M), BocO BocO ∘ (C) ∘ 5 min, 80 C 5 min, 5 C ∘ 8 min, 130 C BocO Sn BocO 18F 10 [18F]11 18 18 Figure 3: Examples for different demetallation synthesis routes for production of carrier-added [ F]F-DOPA ([ F]7) via desilylation (A) [42], demercuration (B) [44], and destannylation (C) [95].
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