Wang_2011_J.Med.Chem_54_5362

To identify the ligands for sigma(1) 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 sigma(1) (K(i) = 0.48-4.05 nM) and high selectivity for sigma(1) relative to sigma(2) receptors (sigma(1)/sigma(2) selectivity of >749-fold). Four of the five compounds (14a, 14b, 14c, and 14e) showed very low affinity for VAChT (K(i) > 290 nM), and the fifth compound (14g) showed moderate affinity for VAChT (K(i) = 44.2 nM). The compound [1'-(4-fluorobenzyl)-3'-hydroxy[1,4']bipiperidinyl-4-yl]-(4-fluorophenyl)methanon e (14a) displayed very high affinity and selectivity for sigma(1) receptor (K(i) = 0.48 nM, sigma(1)/sigma(2) > 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 sigma(1) receptor in vivo.