Current development of sigma-2 receptor radioligands as potential tumor imaging agents

Development of a Highly Specific 18F-Labeled Radioligand for Imaging of the Sigma-2 Receptor in Brain Tumors

“…Over the years, a number of radioligands targeting the σ 2 receptors have been developed for tumor imaging. 6,7,30,31 One radiotracer, N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-fluoroethyl)-5-methylbenzamide ([ 18 F]ISO-1), has entered clinical trials for PET imaging of σ 2 receptors in tumors. 19,20 However, its affinity for the σ 2 receptors (K i (σ 2 ) = 6.95−28.2 nM) and subtype selectivity (K i (σ 1 )/K i (σ 2 ) = 4−48) are relatively low and thus could be improved further.…”

“…Over the years, a number of radioligands targeting the σ 2 receptors have been developed for tumor imaging. ,,, One radiotracer, N -(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2­(1 H )-yl)­butyl)-2-(2-fluoroethyl)-5-methylbenzamide ([ 18 F]­ISO-1), has entered clinical trials for PET imaging of σ 2 receptors in tumors. , However, its affinity for the σ 2 receptors ( K i (σ 2 ) = 6.95–28.2 nM) and subtype selectivity ( K i (σ 1 )/ K i (σ 2 ) = 4–48) are relatively low and thus could be improved further. − In our previous work, we developed a series of σ 2 receptor ligands with the 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or 5,6-dimethoxyisoindoline pharmacophore. ,− Among these ligands, [ 18 F]­SYB4 was found to display excellent biological profiles including nanomolar affinity, high subtype selectivity, high brain uptake, good specific binding, and appropriate kinetics in the brain. − Recently, 1-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2­(1 H )-yl)­butyl)-3-methyl-1 H -benzo­[ d ]­imidazol-2­(3 H )-one (CM398) was reported as a σ 2 receptor ligand with high affinity ( K i (σ 2 ) = 0.43 nM) and subtype selectivity ( K i (σ 1 ) = 560 nM, K i (σ 1 )/ K i (σ 2 ) = 1302). , In the current work, we used SYB4 and CM398 as lead compounds to design and develop suitable 18 F-labeled radioligands for imaging the σ 2 receptor in brain tumors. The design concept is presented in Figure .…”

Synthesis of Aminoethyl‐Substituted Piperidine Derivatives as σ1 Receptor Ligands with Antiproliferative Properties

“…[5,[25][26][27][28][29][30] Several human tumor cells express an even higher amount of σ 2 receptors, which represents the rationale to develop σ 2 receptor-based anticancer drugs and imaging tools. [31][32][33] In literature, a large number of structurally diverse ligands interacting with the σ 1 receptor is reported. [24.28] Recently, the aminoethyl substituted 1,3-dioxane 1 revealing low nanomolar σ 1 affinity (K i = 19 nM) and high antiallodynic activity in vivo (mouse capsaicin assay), which indicates σ 1 antagonistic activity, was reported.…”

“…Moreover, the high density of σ 1 receptors in tumor tissue can be exploited for the development of novel diagnostic tools to image tumor cells, to evaluate the treatment with anticancer drugs and to increase the understanding of tumor physiology and pathophysiology [5,25–30] . Several human tumor cells express an even higher amount of σ 2 receptors, which represents the rationale to develop σ 2 receptor‐based anticancer drugs and imaging tools [31–33] …”

Development of tumor-targeting aza-vesamicol derivatives with high affinity for sigma receptors for cancer theranostics

“…22,23 Therefore, radiolabeled ligands of the sigma-2 receptor have been developed as imaging probes. 24 Moreover, some radioligands exhibiting high affinity for both sigma receptor subtypes (sigma-1 and sigma-2 receptors) have been reported, given the fact that their use could enhance the extent of tumor-targeting compared to radioligands that are selective for a single subtype of the sigma receptors. 25,26 2-(4-Phenylpiperidino)cyclohexanol (vesamicol, Fig.…”