Sigma-2 Receptors: An Emerging Target for CNS PET Imaging Studies

The sigma-2 (σ2) receptor represents one of the most poorly understood proteins in cell biology. Although this receptor was identified through in vitro binding studies over 30 years ago, the molecular identity of this protein was not unambiguously determined until 2017. It is now known that the σ2 receptor is a protein called TMEM97 and that this protein forms a trimeric complex with PGRMC1 and the LDL receptor to increase the rate of internalization of lipoproteins. There is overwhelming data demonstrating that the σ2 receptor is an important biomarker of tumor cell proliferation, which is consistent with the lipoprotein uptake mechanism associated with this protein. In the CNS, σ2 receptor antagonists block Aβ1-42 oligomer synaptic dysfunction in transgenic mouse models of Alzheimer’s disease and have shown promise in animal models of traumatic brain injury and alcohol abuse. These results clearly indicate that this protein is an important therapeutic target for the treatment of a variety of CNS conditions. These observations highlight the importance of having high affinity σ2-selective radiotracers for imaging this protein in vivo with PET.