To identify the ligands for σ1 receptors that are potent and selective, analogues of prezamicol and trozamicol scaffolds of carbonyl-containing vesicular acetylcholine transporter (VAChT) inhibitors were explored. Of the 23 analogues synthesized and tested, 5 displayed very high affinity for σ1 (Ki = 0.48-4.05 nM) and high selectivity for σ1 relative to σ2 receptors (σ1/σ2 selectivity of >749-fold). Four of the five compounds (14a, 14b, 14c, and 14e) showed very low affinity for VAChT (Ki > 290 nM), and the fifth compound (14g) showed moderate affinity for VAChT (Ki = 44.2 nM). The compound [1′-(4- fluorobenzyl)-3′-hydroxy[1,4′]bipiperidinyl-4-yl]-(4-fluorophenyl) methanone (14a) displayed very high affinity and selectivity for σ1 receptor (Ki = 0.48 nM, σ1/ σ2 > 3600). All four of these most promising compounds (14a, 14b, 14c, and 14e) can be radiosynthesized with fluorine-18 or carbon-11, which will allow further evaluation of their properties as PET probes for imaging σ1 receptor in vivo.