Abstract :
[en] 6-[18F]fluoro-L-dopa (FDOPA) and 2-[18F]fluoro-L-tyrosine (FTYR) are useful radiopharmaceuticals for evaluation by positron emission tomography (PET) of the dopaminergic function and oncological studies, respectively. In comparison to electrophilic synthesis, the no-carrier-added (nca) nucleophilic preparation of these 2 radiopharmaceuticals, described in 2004 by Lemaire et al, has several advantages such a high batch yield and high specific activity. However, this nca enantioselective synthesis using a chiral phase-transfer catalyst requires some chemicals (i.e. corrosive HBr gas) arduous to handle and store and reactions at low and high temperature (0°C, 200°C) difficult to implement into a commercially available synthesizer. Important chemical improvements, realized during this PhD thesis, having resulted in straightforward automation of FDOPA and FTYR synthesis, in a commercially available FASTLab module (GE healthcare) are presented.
The first significant improvement to the synthesis has consisted in the development of a fast and reliable method suitable for the preparation of (substituted) [18F]fluorobenzyl halides from several [18F]fluorobenzaldehydes. Aromatic nucleophilic substitution of trimethylammonium benzaldehyde triflate and nitro precursors were realized with nca [18F]fluoride. After labeling, [18F]fluorobenzaldehydes were trapped on a Solid Phase Extraction (SPE) cartridge and the subsequent conversion (reduction and halogenation) into benzyl halides was directly realized, on-line, on the support. Reduction of the aldehydes and the following halogenation step were performed with an aqueous solution of NaBH4 and aqueous solutions of concentrated acid (HI, HBr, HCl), respectively. These two near-quantitative reactions proceed at room temperature within 2 minutes at high yields.
The second improvement of the nca synthesis of FDOPA and FTYR has consisted in the enantioselective formation of a new carbon-carbon bond by phase-transfer catalysis in presence of a chiral phase-transfer catalyst (PTC) at RT rather than at 0°C. Seven chiral phase-transfer catalysts with a potential high enantioselectivity, at room temperature, for the asymmetric alkylation of a N-(diphenylmethylene)glycine tert-butyl ester have been prepared. Two of these catalysts affords high enantiomeric excess in FDOPA and FTYR (e.e. ≥ 95%) at room temperature and even at 75°C (e.e. ≥ 90%). One is readily available from a cinchona alkaloid and the other one from a biphenyl substrate.
The third improvement concerned the hydrolysis step (200°C, 20 min). Different starting precursors with more labile protective groups than the methoxy were synthesized and evaluated. Among these compounds, the isopropyl ether protective group seems the more advantageous.
By exploiting the advantages of the improvements to the chemistry described in this work and the potential of the nca approach, the synthesis of FDOPA and FTYR was automated in a FASTlab module with GMP single use cassettes. After 100 min of bombardment (167 GBq) and 63 min of synthesis, more than 50 GBq (1,35 Ci) of 6-[18F]fluoro-L-dopa (e.e. ≥ 96,3%) with a specific activity in excess of 0.75 TBq/µmol are routinely produced. For FTYR, slightly higher yield was obtained. With such reliable production, 6-[18F]fluoro-L-dopa and 2-[18F]fluoro-L-tyrosine are now available for clinical investigation.
