Abstract
The sigma-2 receptor/transmembrane protein 97 (σ2R/TMRM97) is a promising biomarker of tumor proliferation and a target for cancer therapy. [3H]DTG has been used to evaluate σ2R/TMEM97 binding affinity in compound development studies. However, [3H]DTG has equal and moderate binding affinities to both sigma 1 receptor (σ1R) and σ2R/TMEM97. Furthermore, co-administration with the σ1R masking compound (+)-pentazocine may cause bias in σ2R/TMEM97 binding affinity screening experiments. We have developed a radioiodinated ligand, [125I]RHM-4, which has high affinity and selectivity for σ2R/TMEM97 versus σ1R. In this study, a head-to-head comparison between [3H]DTG and [125I]RHM-4 on the binding affinity and their effectiveness in σ2R/TMEM97 compound screening studies was performed. The goal of these studies was to determine if this radioiodinated ligand is a suitable replacement for [3H]DTG for screening new σ2R/TMEM97 compounds. Furthermore, to delineate the binding properties of [125I]RHM-4 to the σ2R/TMEM97, the structure of RHM-4 was split into two fragments. This resulted in the identification of two binding regions in the σ2R, the “DTG” binding site, which is responsible for binding to the σ2R/TMEM97, and the secondary binding site, which is responsible for high affinity and selectivity for the σ2R/TMEM97 versus the σ1R. The results of this study indicate that [125I]RHM-4 is an improved radioligand for in vitro binding studies of the σ2R/TMEM97 versus [3H]DTG.
Funder
the Department of Radiology at the University of Pennsylvania, the Ministry of Science and Technology, Taiwan
Chang Gung Memorial Hospital
Healthy Aging Research Center
Subject
Drug Discovery,Pharmaceutical Science,Molecular Medicine
Cited by
2 articles.
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