Exploration of Sulfur‐Containing Analogues for Imaging Vesicular Acetylcholine Transporter in the Brain

Sixteen new sulfur‐containing compounds targeting the vesicular acetylcholine transporter (VAChT) were synthesized and assessed for in vitro binding affinities. Enantiomers (−)‐(1‐(3‐hydroxy‐1,2,3,4‐tetrahydronaphthalen‐2‐yl)piperidin‐4‐yl)(4‐(methylthio)phenyl)methanone [(−)‐8] and (−)‐(4‐((2‐fluoroethyl)thio)phenyl)(1‐(3‐hydroxy‐1,2,3,4‐tetrahydronaph‐thalen‐2‐yl)piperidin‐4‐yl)methanone [(−)‐14 a] displayed high binding affinities, with respective Ki values of 1.4 and 2.2 nm for human VAChT, moderate and high selectivity for human VAChT over σ1 (≈13‐fold) and σ2 receptors (>420‐fold). Radiosyntheses of (−)‐[11C]8 and (−)‐[18F]14 a were achieved using conventional methods. Ex vivo autoradiography and biodistribution studies in Sprague–Dawley rats indicated that both radiotracers have the capacity to penetrate the blood–brain barrier, with high initial brain uptake at 5 min and rapid washout. The striatal region had the highest accumulation for both radiotracers. Pretreating the rats with the VAChT ligand (−)‐vesamicol decreased brain uptake for both radiotracers. Pretreating the rats with the σ1 ligand YUN‐122 (N‐(4‐benzylcyclohexyl)‐2‐(2‐fluorophenyl)acetamide) also decreased brain uptake, suggesting these two radiotracers also bind to the σ1 receptor in vivo. The microPET study of (−)‐[11C]8 in the brain of a non‐human primate showed high striatal accumulation that peaked quickly and washed out rapidly. Although preliminary results indicated these two sulfur‐containing radiotracers have high binding affinities for VAChT with rapid washout kinetics from the striatum, their σ1 receptor binding properties limit their potential as radiotracers for quantifying VAChT in vivo. Let's image: New sulfur‐containing analogues have high potency for the vesicular acetylcholine transporter (VAChT). The radiosyntheses of two lead radiotracers are straightforward and effective. Rodent studies demonstrated the tracers can enter the brain with high accumulation in the striatum. PET studies indicated the lead 11C tracer has rapid washout kinetics from the macaque brain. Although moderate σ1 receptor binding affinity limited the in vivo mapping of VAChT, structure–activity relationship data may provide information for future explorations of new VAChT radioligands.