Radiosynthesis of 3-(3-[18F]fluoropropoxy)-4-(benzyloxy)-N-[(1-dimethylaminocyclopentyl)methyl]-5-methoxybenzamide, a potential PET radiotracer for the glycine transporter GlyT-2

The recently described selective and potent GlyT2 antagonist, 4-benzyloxy-3, 5-dimethoxy-N-[(1-dimethylaminocyclopentyl) methyl]benzamide (IC50 = 16 nM) provided an important additional tool to further characterize GlyT2 pharmacology. In order to identify an effective PET radioligand for in vivo assessment of the GlyT-2 transporter, 3-(3-[F-18]fluoropropoxy)-4-(benzyloxy)-N-((1-dimethylaminocyclopentyl) methyl)-5-methoxybenzamide ([F-18]3), a novel analog of 4-benzyloxy-3,5-dimethoxy-N-[(1-dimethylaminocyclopentyl) methyl]benzamide was synthesized using a one-pot, two-step method. The NCA radiotluorination of 1,3-propanediol di-p-tosylate in the presence of K2CO3 and Kryptofix-222 in acetonitrile gave 81% 3-[18F]fluoropropyl tosylate, which was subsequently coupled with 4-benzyloxy-3-hydroxy-5-methoxy-N-[(1-dimethylaminocyclopentyl) methyl]benzamide in the same reaction vessel. Solvent extraction and HPLC (Eclipse XDB-C8 column, 80/20/0.1 MeOH/H2O/Et3N, 3.0 ml/min) gave [F-18]3 in 98.5% radiochemical purity. The radiochemical yield was determined to be 14.0-16.2% at EOS, and the specific activity was 1462 +/- 342 GBq/mu mol. The time of synthesis and purification was 128 min. The final product was prepared as a sterile saline solution suitable for in vivo use. Copyright (c) 2006 John Wiley & Sons, Ltd.