Halogenated 4-(Phenoxymethyl)piperidines as Potential Radiolabeled Probes for σ-1 Receptors:  In Vivo Evaluation of [123I]-1-(Iodopropen-2-yl)-4-[(4-cyanophenoxy)methyl]piperidine

• Published in: Journal of medicinal chemistry 1997-05, Vol.40 (11), p.1657-1667
• Main Authors: Waterhouse, Rikki N, Mardon, Karine, Giles, Katrina M, Collier, T. Lee, O'Brien, Joanne C
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Contrast media. Radiopharmaceuticals; Medical sciences; Pharmacology. Drug treatments
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960720+

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