Abstract
1107
Objectives: Arylsulfonamides are increasingly used as functional groups in drugs for their enhanced biological activity and in-vivo stability. Reports of [18F]-pyridinylsulfonamides as PET radiopharmaceuticals are sparse. Our aim was to develop and optimise the [18F]radiolabelling of a series of substituted-sulfonyl nicotinamides as novel synthons for PET radiopharmaceuticals.
Methods: [18F]-fluoride nucleophilic heteroaromatic substitution reactions were undertaken and optimised on a series of pyridin-3-yl-sulfonyl glycinate esters, exemplified by the model compound tert-butyl ((6-chloropyridin-3-yl)sulfonyl)glycinate. Aliquots of [18F]fluoride, produced on a GE PETtrace cyclotron were trapped on a QMA cartridge and eluted with various bases into a reactor vial, followed by azeotropic drying using acetonitrile at 95oC. Radiochemical optimisation included using anhydrous DMSO, DMF and Dimethylacetamide (DMA) as solvents. For each of these solvents (1.0 mL), different bases including tetrabutylammonium hydrogen carbonate (TBAHCO3), tetraethylammonium hydrogen carbonate (TEAHCO3), cesium hydrogen carbonate, cesium carbonate, potassium oxalate and potassium carbonate were examined at different temperatures (100-160oC) for 10 min and different concentrations of the pyridinyl-sulfonamide precursor (1-10 mg). Radiolabelling was also conducted on the corresponding free carboxylic acid analogue. All reaction mixtures were analysed by HPLC and products were collected to determine the radiochemical yields.
Results: High [18F]fluoride incorporation (non-decay corrected (n.d.c.) yields) was achieved following nucleophilic substitution of the 6-chloro leaving group of the ((pyridin-3-yl)sulfonyl)glycinate in 1 mL of DMF (17%), DMSO (32%) and DMA (31%) at 150oC for 10 min, using 10 mg of precursor and tetrabutyl ammonium hydrogen carbonate (0.14M, 800 μl (4:1, acetonitile:water)) as the base. Extending the reaction time in DMSO to 20 min did not result in an increase in radiochemical yield (31%), whilst raising the reaction temperature to 160oC provided only slightly improved yields (35%). A decrease in radiochemical yield was seen when reducing the precursor to 5.0 mg (24%) and 2.0 mg (21%) in DMSO. Lower radiochemical yields were also seen when the 18F-fluorination reactions were conducted at 135oC for 10 min (20%) or 150oC for 5 mins (16%) in DMSO with the radiochemical yield dropping to < 5% below 120oC. The yields for different bases in DMSO were tetraethylammonium hydrogen carbonate (28%), cesium hydrogen carbonate (22%), cesium carbonate (18%), potassium oxalate (16%) and potassium carbonate (12%). Reactions on the corresponding carboxylic acid (6-chloropyridin-3-yl)sulfonyl)glycine) precursor at 130oC and 150oC produced two unidentified products in 42% radiochemical yield.
Conclusions: [18F]-pyridinylsulfonamide glycine esters can be synthesised with good radiochemical yield (30-35%) n.d.c. in > 98% radiochemical purity within 10 minutes of reaction time at temperatures ranging from 135-160oC using a variety of bases and solvents. The sulfonamide functional group offers considerable scope for the development of phenyl- and pyridinyl-sulfonamide-based PET radiopharmaceuticals. Further studies involving different leaving groups and counterions are in progress.