LBT-999 (8-((E)-4-fluoro-but-2-enyl)-3-beta-p-tolyl-8-aza-bicyclo[3.2.1]octane-2-beta-carboxylicacid methyl ester) is a recently developed cocaine derivative belonging to a new generation of highly selective dopamine transporter (DAT) ligands (KD: 9 nM for the DAT and IC50 > 1000 nM for the serotonin and norepinephrine transporter). Initial fluorine-18-labelling of LBT-999 was based on the robust and reliable two-step radiochemical pathway often reported for such tropane derivatives, involving first the preparation of (E)-1-[18F]fluoro-4-tosyloxybut-2-ene followed by a N-alkylation reaction with the appropriate nor-tropane moiety. In the present work, a simple one-step fluorine-18-labelling of LBT-999 is reported, based on a chlorine-for-fluorine nucleophilic aliphatic substitution, facilitating as expected both automation and final high-performance liquid chromatography (HPLC) purification. The process involves: (A) reaction of K[18F]F–Kryptofix®222 with the chlorinated precursor (3.5–4.5 mg) at 165°C for 10 min in DMSO (0.6 mL) followed by (B) C-18 PrepSep cartridge pre-purification and finally (C) semi-preparative HPLC purification on a Waters Symmetry® C-18. Typically, 3.70–5.92 GBq of [18F]LBT-999 (> 95% chemically and radiochemically pure) could be obtained with specific radioactivities ranging from 37 to 111 GBq/µmol within 85–90 min (HPLC purification and Sep-Pak-based formulation included), starting from a 37.0 GBq [18F]fluoride batch (overall radiochemical yields: 10–16%, non-decay-corrected). Copyright © 2007 John Wiley & Sons, Ltd.