HALOGENATED 4-(PHENOXYMETHYL)PIPERIDINES AS POTENTIAL RADIOLABELED PROBES FOR SIGMA-1 RECEPTORS - IN-VIVO EVALUATION OPROPEN-2-YL)-4-[(4-CYANOPHENOXY)METHYL]PIPERIDINE

Several halogenated 4-(4-phenoxymethyl)piperidines were synthesized as potential sigma receptor ligands. The affinity and selectivity of the se compounds were determined using in vitro receptor binding assays, a nd their log P values were estimated using HPLC analysis. The effect o f various N-substituents on the sigma-1 and sigma-2 dissociation const ants was examined. These substituents included fluoroalkyl, hydroxyalk yl, iodopropenyl, and selected ortho-, meta-, and para-substituted ben zyl groups. Also determined were the effects of various moieties on th e phenoxy ring; specifically 4-iodo, 4-bromo, 4-nitro, 4-cyano, 3-brom o, and pentafluoro substituents were examined. The ranges in the disso ciation constants of these compounds for sigma-1 and sigma-2 receptors were 0.38-24.3 and 3.9-361 nM, respectively. The ratio of K-i (sigma- 2/sigma-1) ranged from 1.19 to 121. One of the most promising of the i odinated ligands, opropen-2-yl)-4-[(4-cyanophenoxy)methyl]piperidine ( 4), was labeled with I-123 and studied in vivo in adult male rats. Hig h uptake and good retention of radioactivity was observed in the brain and many other organs known to possess sigma receptors. Blocking stud ies revealed high specific binding of [I-123]-4 to sigma receptors in the brain, lung, kidney, heart, muscle, and other organs known to poss ess these sites. These results indicate that [I-123]-4 and other halog enated 4-(phenoxymethyl)piperidines of this series may provide useful probes for in vivo tomographic studies of sigma receptors.