Synthesis and Binding Characteristics of Potential SPECT Imaging Agents for σ-1 and σ-2 Binding Sites

Xiao shu He, Wayne D. Bowen, Kan Sam Lee, Wanda Williams, Daniel R. Weinberger, Brian R. de Costa

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


2-, 3-, and 4-iodophenyl derivatives of the high-affinity σ ligand N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (1) were synthesized in two to four steps starting from N-methyl-2-(1-pyrrolidinyl)ethylamine. These compounds were evaluated for their capacity to label both σ1 and σ2 subtypes in vitro. σ-1 binding affinity was determined by measuring competition with [3H]-(+)-pentazocine binding to guinea pig brain membranes while σ2 binding was evaluated through competition with [3H]DTG binding to rat liver membranes in the presence of excess dextrallorphan. The binding data revealed that N-[2-(3-iodophenyl)ethyl]-N-methyl-2-(1-pyrrohdinyl)ethylamine (2) and N-[2-(4-iodophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (3) displayed almost identical binding affinity at σ1 sites to the parent compound 1. This suggests that the 3- or 4-iodo group can effectively substitute for the 3,4-dichloro substituents of 1. In this series of compounds, Ki's at the σ1 site varied from 2.0 nM for N-(4-iodobenzyl)-N-methyl-2-(1-pyrrolidinyl)ethylamine (6) to 26.6 nM for N-(2-iodobenzyl)-N-methyl-2-(1-pyrrolidinyl)ethylamine (4). Ki's for σ2 site ranged from 8.1 nM for 1 to 220 nM for N-(3-bromobenzyl)-N-methyl-2-(1-pyrrolidinyl)ethylamine (11) while the σ21 ratio varied from 1.8 for 4 to 25 for 11. Comparing halogen substitution, the trend Cl = I > Br > F was observed for binding affinity at σ1 sites; no such trend was observed at σ2 sites. On the basis of the binding data, compounds 2 and 3 were selected for labeling with 123I. Thus, treatment of the corresponding 3- and 4-(tributylstannyl) intermediates (7 and 8) with Na123I in the presence of excess CH3CO3H furnished [123I]-2 and [123I]-3 in up to 70% radiochemical yield. Preliminary in vitro binding with [123I]-3 indicated up to 97% specific binding with guinea pig brain membranes.

Original languageEnglish (US)
Pages (from-to)566-571
Number of pages6
JournalJournal of medicinal chemistry
Issue number5
StatePublished - Jan 1 1993
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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