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See detailProduction at the Curie Level of No-Carrier-Added 6-18F-Fluoro-L-Dopa
Libert, Lionel ULg; Franci, Xavier; Plenevaux, Alain ULg et al

in Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine (2013), 54(7), 1154-1161

6-18F-fluoro-L-dopa (18F-FDOPA) has proven to be a useful radiopharmaceutical for the evaluation of presynaptic dopaminergic function using PET. In comparison to electrophilic synthesis, the no-carrier ... [more ▼]

6-18F-fluoro-L-dopa (18F-FDOPA) has proven to be a useful radiopharmaceutical for the evaluation of presynaptic dopaminergic function using PET. In comparison to electrophilic synthesis, the no-carrier-added (NCA) nucleophilic method has several advantages. These include much higher available activity and specific activity. Recently, we have described an NCA enantioselective synthesis using a chiral phase-transfer catalyst. However, some chemicals were difficult to implement into a commercially available synthesizer, restricting access to this radiopharmaceutical to only a few PET centers. Methods: In this paper, 2 important chemical improvements are proposed to simplify production of 18F-FDOPA, resulting in straightforward automation of the synthesis in a commercially available module. Results: First, a fast, simple, and reliable synthesis of 2-18F-fluoro-4,5-dimethoxybenzyl iodide on a solid phase support was developed. Second, a phase-transfer catalyst alkylation of a glycine derivative at room temperature was used to enable enantioselective carbon–carbon bond formation. After hydrolysis and high-performance liquid chromatography purification, a high enantiomeric excess of 18F-FDOPA (~97%) was obtained using a chiral catalyst available from a biphenyl 3 substrate. The total synthesis time was 63 min, and the decay-corrected radiochemical yield was 36% +/- 3% (n = 8). Conclusion: By exploiting the advantages of this NCA approach, using a starting activity of 185 GBq of NCA 18F-fluoride, high activities of 18F-FDOPA (> 45 GBq) with high specific activity (>753 GBq/mmol) are now available at the end of synthesis for use in clinical investigations. [less ▲]

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See detailQuality controls of no-carrier-added aromatic amino acids such as FDOPA and FTYR produced at curie level
Libert, Lionel ULg; Lemaire, Christian ULg; Giacomelli, Fabrice ULg et al

Poster (2013, May)

Aromatic fluoro amino acids such as 2-[18F]fluoro-L-tyrosine (FTYR) and 6-[18F]fluoro-L-DOPA (FDOPA) are useful radiopharmaceuticals for oncologic studies and evaluation of the presynaptic dopaminergic ... [more ▼]

Aromatic fluoro amino acids such as 2-[18F]fluoro-L-tyrosine (FTYR) and 6-[18F]fluoro-L-DOPA (FDOPA) are useful radiopharmaceuticals for oncologic studies and evaluation of the presynaptic dopaminergic function using positron emission tomography. Recently, a no-carrier-added (nca) enantioselective synthesis of these compounds, based on an multistep PTC approach was automated in a FASTlabTM module from GE . From 185 GBq of [18F]fluoride and after 1 hour of synthesis, more than 37 GBq of FTYR or FDOPA are available . This automated production yields enough doses for many PET studies. A monograph for FDOPA prepared by electrophilic substitution exists , but it is not adapted to the nca nucleophilic synthesis of FDOPA and FTYR, as in this case specific activity, by products and possible impurities are different. A complete quality control (QC) has then be developed in accordance with the guidelines of the European Pharmacopeia (Eur. Ph.). [less ▲]

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See detailAutomated radiosynthesis of [18F]MPPF derivatives for imaging 5-HT1A receptors
Goblet, David ULg; Thonon, David ULg; Plenevaux, Alain ULg et al

Poster (2010, May 30)

TOPIC: Molecular Neuroimaging: from Bench to Bedside Automated radiosynthesis of [18F]MPPF derivatives for imaging 5-HT1A receptors Introduction: Dysfunction of the cerebral serotoninergic system is ... [more ▼]

TOPIC: Molecular Neuroimaging: from Bench to Bedside Automated radiosynthesis of [18F]MPPF derivatives for imaging 5-HT1A receptors Introduction: Dysfunction of the cerebral serotoninergic system is implicated in numerous neurodegenerative disorders such as Alzheimer disease’s, dementia, depression, anxiety, schizophrenia, and Parkinson disease’s. The 5-HT1A serotonin receptors are involved in several physiological functions including sleep, mood, neurogenesis and learning [1]. Consequently, there have been huge efforts in finding ligands for this receptor. [11C]WAY-100635 is a high affinity radioligand used for quantifying serotonin 5-HT1A receptors with positron emission tomography. An 18F-labeled radioligand is advantageous because of higher specific activity and physical/nuclear properties (t1/2= 109 min, 97% of positron decay and positron energy of 635 keV maximum). [18F]MPPF, a selective 5-HT1A antagonist derived from WAY-100635, is currently one of the most successful PET ligand used for 5-HT1A receptor imaging [2]. However the affinity is lower then WAY-100635 and the amount of [18F]MPPF reaching the brain is relatively low since MPPF is a substrate for p-glycoprotein [3]. Methods: In order to improve the brain uptake of the radiotracer, a desmethylated analog has been developed in our lab and preliminary in vitro studies show positive results [4]. Nevertheless, the radiosynthesis take place in two steps as a protecting group removal is needed. A one step procedure with a MPPF derivative could be of very great interest. We have synthesized many MPPF derivatives in our lab (modification on the phenylpiperazine moiety) and developed an automated radiosynthesis procedure for the production of these radiotracers. [18F]MPPF was chosen as the model compound. We used a GE Healthcare FASTlabTM module and made modifications to the [18F]FDG synthesis sequence and cassette. [18F]MPPF was synthesized by coupling of [18F]FBA with the corresponding amine. After coupling, the crude solution was diluted with water and passed through a tC18 cartridge for prepurification. After elution, the [18F]MPPF was purified by semi-preparative HPLC. Results: Total synthesis time, including purification was approximately 100 min. [18F]FBA and [18F]MPPF were obtained at a corrected yield of 55% (n=20) and 25% (n=5) respectively. The radiochemical purity, checked by radio-TLC and UPLC, was >95%. Conclusions: We have developed an automated method for [18F]MPPF and derivatives production using a commercial synthesizer (FASTlabTM from GE Healthcare) and a conventional HPLC system resulting in good yields and high (radio)chemical purity. By simply switching the vial containing the modified amine, an 18F-labeled MPPF derivative could be obtained. Radiosynthesis is still under optimization and the radiotracers synthesized need to be tested as suitable 5-HT1A radioligands. Acknowledgement: This work was supported by the Fondation Rahier. References: [1] Filip M., Bader M. et Al, Pharmacol Rep. 2009 Sep-Oct; 61(5):761-77 [2] Aznavour N, Zimmer L. Et Al, Neuropharmacology. 2007 Mar; 52(3):695-707 [3] Laćan G., Plenevaux A. et Al, Eur J Nucl Med Mol Imaging. 2008 Dec;35(12):2256-66 [4] Defraiteur C., Plenevaux A. et Al., Br J Pharmacol. 2007 Nov; 152(6):952-8 [less ▲]

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See detailLarge Scale Preparation of [18]Fluoromethoxybenzyl Bromides, Key Precursors for 2-[18F]Fluoro-L-Tyrosine and 6-[18F]Fluoro-L-Dopa
Libert, Lionel ULg; Lemaire, Christian ULg; Wouters, Ludovic ULg et al

in Journal of Labelled Compounds & Radiopharmaceuticals (2009, July), 52(S1), 292

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