Synthesis and binding characteristics of potential SPECT imaging agents for sigma-1 and sigma-2 binding sites.
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.
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
X S
XS
He
W D
WD
Bowen
K S
KS
Lee
W
W
Williams
D R
DR
Weinberger
B R
BR
de Costa
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D001966:Bromine; D002462:Cell Membrane / Q000378:metabolism; D002712:Chlorides; D005029:Ethylenediamines / Q000138:chemical synthesis* / Q000378:metabolism; D005461:Fluorine; D006168:Guinea Pigs; D007455:Iodine; D007457:Iodine Radioisotopes; D007462:Iodobenzenes / Q000138:chemical synthesis / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D010423:Pentazocine / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000378:metabolism; D011817:Rabbits; D017480:Receptors, sigma / Q000378:metabolism*; D013329:Structure-Activity Relationship; D015899:Tomography, Emission-Computed, Single-Photon
D002712:Chlorides; D005029:Ethylenediamines; D007457:Iodine Radioisotopes; D007462:Iodobenzenes; D008024:Ligands; D011759:Pyrrolidines; D017480:Receptors, sigma; C081339:N-(2-(4-iodophenyl)ethyl)-N-methyl-2-(1-pyrrolidinyl)ethylamine; D005461:Fluorine; D007455:Iodine; D010423:Pentazocine; D001966:Bromine