Screening of σ₂ Receptor Ligands and In Vivo Evaluation of ¹¹C-Labeled 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline for Potential Use as a σ₂ Receptor Brain PET Tracer

Abstract

In this study, a panel of 46 compounds containing five different scaffolds known to have high σ2 receptor affinity were screened. 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)­butan-2-yl]-1,2,3,4-tetrahydroisoquinoline [(±)-7] (K i for σ1 = 48.4 ± 7.7 nM, and K i for σ2 = 0.59 ± 0.02 nM) and its desmethyl analogue, (±)-8 (K i for σ1 = 108 ± 35 nM, and K i for σ2 = 4.92 ± 0.59 nM), showed excellent binding affinity and subtype selectivity for σ2 receptors. In vitro cell binding indicated that σ2 receptor binding of [11C]-(±)-7 and [11C]-(±)-8 was dependent on TMEM97 protein expression. In PET studies, the peak brain uptake of [11C]-(±)-7 (8.28 ± 2.52%ID/cc) was higher than that of [11C]-(±)-8 (4.25 ± 0.97%ID/cc) with specific distribution in the cortex and hypothalamus. Brain uptake or tissue binding was selectively inhibited by ligands with different σ2 receptor binding affinities. The results suggest [11C]-(±)-7 can be used as a PET radiotracer for imaging the function of σ2 receptors in central nervous system disorders.

Exploration of Diazaspiro Cores as Piperazine Bioisosteres in the Development of σ2 Receptor Ligands

“…Evaluation of the compounds in the in vitro radioligand binding studies was conducted using a two-step process. An initial screen for σ1 and σ2 receptor affinity was conducted using three different concentrations of the displacer (10 nM, 100 nM, 1μM), as described previously [ 34 ]. Compounds displaying ≥ 50% displacement of radioligand binding in σ1 and σ2 assays ( Table 1 ) were chosen for full competition studies using 10 different concentrations of the displacer.…”

Computational Chemistry for the Identification of Lead Compounds for Radiotracer Development

“…The design of new radiotracers that meet these criteria is incredibly difficult, time consuming, and costly. However, computer-aided drug design (CADD) approaches, including virtual screening (VS) and ligand optimization, have been utilized to increase the efficiency of identifying and optimizing novel compounds into lead radiotracers [ 1 , 2 , 3 , 4 ].…”

Characterization of CM-398, a Novel Selective Sigma-2 Receptor Ligand, as a Potential Therapeutic for Neuropathic Pain

“…In guinea pig brain membranes, coincubation with phenytoin was used to reportedly increase the binding affinity of putative sigma-1 receptor agonists while slightly decreasing the affinity of putative sigma-1 receptor antagonists [ 18 ]. In contrast, reliable functional in vitro assays for sigma-2 receptor ligands are still in development [ 20 ], potentially one day resolving this knowledge gap, but leaving confirmation of the function of this selective sigma-2 receptor ligand currently out of reach. This question is important, as some recent reports suggest that sigma-2 receptor activation may produce analgesia.…”