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Review
. 2023 Jul 27;24(15):12025.
doi: 10.3390/ijms241512025.

The Sigma Receptors in Alzheimer's Disease: New Potential Targets for Diagnosis and Therapy

Tao Wang  1   2 , Hongmei Jia  1
Affiliations
Review

The Sigma Receptors in Alzheimer's Disease: New Potential Targets for Diagnosis and Therapy

Tao Wang et al. Int J Mol Sci. .

Abstract

Sigma (σ) receptors are a class of unique proteins with two subtypes: the sigma-1 (σ1) receptor which is situated at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), and the sigma-2 (σ2) receptor, located in the ER-resident membrane. Increasing evidence indicates the involvement of both σ1 and σ2 receptors in the pathogenesis of Alzheimer's disease (AD), and thus these receptors represent two potentially effective biomarkers for emerging AD therapies. The availability of optimal radioligands for positron emission tomography (PET) neuroimaging of the σ1 and σ2 receptors in humans will provide tools to monitor AD progression and treatment outcomes. In this review, we first summarize the significance of both receptors in the pathophysiology of AD and highlight AD therapeutic strategies related to the σ1 and σ2 receptors. We then survey the potential PET radioligands, with an emphasis on the requirements of optimal radioligands for imaging the σ1 or σ2 receptors in humans. Finally, we discuss current challenges in the development of PET radioligands for the σ1 or σ2 receptors, and the opportunities for neuroimaging to elucidate the σ1 and σ2 receptors as novel biomarkers for early AD diagnosis, and for monitoring of disease progression and AD drug efficacy.

Keywords: Alzheimer’s disease; diagnosis; neuroimaging; positron emission tomography; sigma-1 receptor; sigma-2 receptor; therapeutic strategy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of representative σ1 and σ2 ligands with therapeutic potential in clinical trials.
Figure 2
Figure 2
Chemical structures of σ1 receptor radioligands investigated in primates (* chiral center of the compound).
Figure 3
Figure 3
Chemical structures of potential radioligands for neuroimaging of σ2 receptors.
See this image and copyright information in PMC

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