Halogenated 4-(phenoxymethyl)piperidines as potential radiolabeled probes for sigma-1 receptors: in vivo evaluation of [123I]-1-(iodopropen-2-yl)-4-[(4-cyanophenoxy)methyl]pip eri dine

Journal of Medicinal Chemistry
Rikki N WaterhouseJ C O'Brien

Abstract

Several halogenated 4-(4-phenoxymethyl)piperidines were synthesized as potential sigma 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 sigma-1 and sigma-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 sigma-1 and sigma-2 receptors were 0.38-24.3 and 3.9-361 nM, respectively. The ratio of Ki (sigma-2/sigma-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]piperidi ne (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 sigma receptors. Blocking studies revealed high specific binding of [123I]-4...Continue Reading

Citations

Sep 23, 2003·Nuclear Medicine and Biology·Mitchell QuinlivanMichael Kassiou
Mar 21, 2006·Nuclear Medicine and Biology·Catherine HouMei-Ping Kung
Apr 8, 2010·Human Psychopharmacology·Ian Hindmarch, Kenji Hashimoto
Dec 15, 2005·International Journal of Clinical Practice·J L Carrasco, C Sandner
Sep 23, 2003·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Benjamin SolomonRodney Hicks
Nov 29, 2013·Journal of Labelled Compounds & Radiopharmaceuticals·Samuel D BanisterMichael Kassiou
Feb 28, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Matthew R HightH Charles Manning
Apr 17, 2008·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Michelle L JamesMichael Kassiou

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