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

X. S. He, W. D. Bowen, Sam Lee Kan Sam Lee, W. Williams, Daniel Weinberger, B. R. De Costa

Research output: Contribution to journalArticle

Abstract

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-pyrrolidinyl)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, K(i)'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). K(i)'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
Volume36
Issue number5
StatePublished - 1993
Externally publishedYes

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Single-Photon Emission-Computed Tomography
Binding Sites
Membranes
Guinea Pigs
Pentazocine
Halogens
Brain
ethylamine
Ligands
Liver
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

He, X. S., Bowen, W. D., Kan Sam Lee, S. L., Williams, W., Weinberger, D., & De Costa, B. R. (1993). Synthesis and binding characteristics of potential SPECT imaging agents for σ-1 and σ-2 binding sites. Journal of Medicinal Chemistry, 36(5), 566-571.

Synthesis and binding characteristics of potential SPECT imaging agents for σ-1 and σ-2 binding sites. / He, X. S.; Bowen, W. D.; Kan Sam Lee, Sam Lee; Williams, W.; Weinberger, Daniel; De Costa, B. R.

In: Journal of Medicinal Chemistry, Vol. 36, No. 5, 1993, p. 566-571.

Research output: Contribution to journalArticle

He, XS, Bowen, WD, Kan Sam Lee, SL, Williams, W, Weinberger, D & De Costa, BR 1993, 'Synthesis and binding characteristics of potential SPECT imaging agents for σ-1 and σ-2 binding sites', Journal of Medicinal Chemistry, vol. 36, no. 5, pp. 566-571.
He, X. S. ; Bowen, W. D. ; Kan Sam Lee, Sam Lee ; Williams, W. ; Weinberger, Daniel ; De Costa, B. R. / Synthesis and binding characteristics of potential SPECT imaging agents for σ-1 and σ-2 binding sites. In: Journal of Medicinal Chemistry. 1993 ; Vol. 36, No. 5. pp. 566-571.
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abstract = "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-pyrrolidinyl)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, K(i)'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). K(i)'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 σ2/σ1 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.",
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T1 - Synthesis and binding characteristics of potential SPECT imaging agents for σ-1 and σ-2 binding sites

AU - He, X. S.

AU - Bowen, W. D.

AU - Kan Sam Lee, Sam Lee

AU - Williams, W.

AU - Weinberger, Daniel

AU - De Costa, B. R.

PY - 1993

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N2 - 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-pyrrolidinyl)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, K(i)'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). K(i)'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 σ2/σ1 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.

AB - 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-pyrrolidinyl)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, K(i)'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). K(i)'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 σ2/σ1 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.

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