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The vesicular acetylcholine transporter (VAChT) is a reliable biomarker for assessing cholinergic dysfunction associated with dementia. We recently reported three new potent and selective carbon-11 labeled VAChT radiotracers. Herein, we report the resolution with a Chiralcel OD column of three additional fluorine containing VAChT ligands in which a fluoroethoxy or fluoroethylamino moiety was substituted for the methoxy group. An in vitro competitive binding assay showed that (-)-7 had high potency for VAChT (K i-VAChT = 0.31 ± 0.03 nM) and excellent selectivity for VAChT versus σ receptors (K i-σ 1  = 1870 ± 250 nM, K i-σ 2  = 5480 ± 140 nM). Three different radiolabeling approaches were explored; the radiosynthesis of (-)-[ 18 F]7 was successfully accomplished via a stepwise two-pot, three-step method with moderate yield (11 ± 2%) and high radiochemical purity (&gt;98%). PET imaging studies in a nonhuman primate indicated that (-)-[ 18 F]7 rapidly entered the brain and accumulated in the VAChT-enriched striatum. The uptake of (-)-[ 18 F]7 in the target striatal area peaked at 10 min and displayed improved clearance kinetics compared to the VAChT tracer [ 18 F]VAT, which has been approved by the Food and Drug Administration (FDA) for first-in-man studies. These studies justify further investigation of (-)-[ 18 F]7 and exploration of the structure-activity relationships of these fluoroethoxy and fluoroethylamino analogs.

organic and biomolecular chemistry

Synthesis, resolution, and in vitro evaluation of three vesicular acetylcholine transporter ligands and evaluation of the lead fluorine-18 radioligand in a nonhuman primate