SYNTHESIS AND BINDING CHARACTERISTICS OF POTENTIAL SPECT IMAGING AGENTS FOR SIGMA-1 AND SIGMA-2 BINDING-SITES

2-,3-, and 4-iodophenyl 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 sigma1 and sigma2 subtypes in vitro. Sigma-1 binding affinity was determined by measuring competition with [H-3]-(+)-pentazocine binding to guinea pig brain membranes while sigma2 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-(l-pyrrolidinyl)ethylamine (3) displayed almost identical binding affinity at sigma1 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 al 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-(l-pyrrolidinyl)ethylamine (4). K(i)'s for a2 site ranged from 8.1 nM for 1 to 220 nM for N-(3-bromobenzyl)-N-methyl-2-(1-pyrrolidinyl)ethylamine (11) while the sigma2/a, 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 sigma1 sites; no such trend was observed at sigma2 sites. On the basis of the binding data, compounds 2 and 3 were selected for labeling with I-123. Thus, treatment of the corresponding 3- and 4-(tributylstannyl) intermediates (7 and 8) with (NaI)-I-123 in the presence of excess CH3CO3H furnished [I-123]-2 and [I-123]-3 in up to 70% radiochemical yield. Preliminary in vitro binding with [I-123]-3 indicated up to 97% specific binding with guinea pig brain membranes.