Synthesis and binding characteristics of potential SPECT imaging agents for .sigma.-1 and .sigma.-2 binding sites

Abstract

2-, 3-, and 4-idophenyl derivatives of the high-affinity sigma 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 sigma 1 and sigma 2 subtypes in vitro. sigma-1 binding affinity was determined by measuring competition with [3H]-(+)-pentazocine binding to guinea pig brain membranes while sigma 2 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-pyrrolidinyl)ethylamine (2) and N-[2-(4-iodophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (3) displayed almost identical binding affinity at sigma 1 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 sigma 1 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 sigma 2 site ranged from 8.1 nM for 1 to 220 nM for N-(3-bromobenzyl)-N-methyl-2-(1-pyrrolidinyl)ethylamine (11) while the sigma 2/sigma 1 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 sigma 1 sites; no such trend was observed at sigma 2 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.

Differentiation of σ ligand‐activated receptor subtypes that modulate NMDA‐evoked [3H]‐noradrenaline release in rat hippocampal slices

“…a a receptor distinct from the al and a2 receptors. BD-1008 is considered to be a selective and high affinity ligand for both al and a2 sites He et al, 1993). In the present experiments, it produced no effect on NMDA-evoked release of [3H]-NA but partially inhibited the modulation by (+)-pentazocine and DTG.…”

Cytotoxic effects of sigma ligands: sigma receptor-mediated alterations in cellular morphology and viability

“…However, C6 glioma cells also contain a high density of sigma-2 receptors , in addition to an as yet uncharacterized lowaffinity binding site for [3H]( +)-pentazocine that does not appear to be present in brain tissue (Vilner et al, 1992 and unpublished observations). We have also identified a unique sigma-like binding site for the iodinated aryl ethylene diamine [1251]SH344, which has properties that differ in some ways from either sigma-1 or sigma-2 sites (Lee et al, 1992 and unpublished observations;He et al, 1993). It is possible, therefore, that any of these other sigma-like sites, alone or in combination with sigma-l sites labeled by ['H]( +)-pentazocine, could mediate the observed morphological and cytotoxic effects.…”

“…Fetal bovine serum, horse serum, and nerve growth factor were purchased from Advanced Biotechnologies, Inc. (Columbia, MD). Novel sigma ligands based on the aryl ethylene diamine pharmacophore were synthesized as described previously (Radesca et al, 199 1;de Costa et al, 1992ade Costa et al, ,b, 1993He et al, 1993). Morphine, naltrexone, and levallorphan were obtained from NIDA.…”

“…We have reported the synthesis and characterization of a novel class of sigma ligands based on the aryl ethylene diamine pharmacophore (Radesca et al, 199 1;Bowen et al, 1992;de Costa et al, 1992ade Costa et al, ,b, 1993He et al, 1993). These compounds exhibit high affinity and selectivity for sigma receptors.…”

“…Neuroleptics lacking sigma affinity and ligands for other receptors failed to produce this effect. We have synthesized and characterized an extensive series of novel compounds based on N-[arylethyll-N-alkyl-2-( 1 -pyrrolidinyl)ethylamine for binding affinity and selectivity at sigma sites (Radesca et al, 199 1;Bowen et al, 1992;de Costa et al, 1992ade Costa et al, ,b, 1993He et al, 1993). Here, we extend our studies on C6 glioma cells to compounds of the aryl ethyl(pyrrolidinyl)cyclohexylamine, aryl ethylene diamine, and aryl alkyl piperazine series (see Materials and Methods), and also investigate the actions of several additional neuroleptics, prototypic sigma ligands, and non-sigma compounds.…”