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sigma-1 stains in mouse brain

Sigma-1 Receptor Imaging

Sigma receptors are characterized as sigma-1 and -2 receptors (S1R, S2R) and are found at significant levels in the brain.  S1R has been shown to be involved with a wide range of biological processes and chronic disease states, such as pain reception, neuropsychiatric diseases, vascular diseases, and cancer.  A ligand-gated membrane chaperone protein, SIR is Ca2+ sensitive and resides in the mitochondria-associated endoplasmic reticulum.  The subcellular location has driven the proposal of its function as a interorganelle-signaling modulator.  Numerous tracers targeting S1R exist, however the affinity and selectivity needed to fully elucidate the role of the receptor has not been achieved to distinguish S1R from S2R and vesicular acetylcholine transporters.   A radiotracer should bind to its target with high affinity and selectivity in order to provide insight about the distribution, expression levels, and functional role of the receptor. 

FTC146 in human scan

Imaging Pain with [18F]FTC-146

Sigma receptors are characterized as sigma-1 and -2 receptors (S1R, S2R) and are found at significant levels in the brain. S1R has been implicated in a range of biological processes and chronic disease states for neuropsychiatry and cancer.

We previously reported the synthesis of a new S1R PET radioligand, [18F]FTC-146.  Following our recent eIND and IRB approvals, first-in-human studies have begun to assess the ligand’s biodistribution and radiation dosimetry in healthy controls and patients suffering with pain. The promising clinical results illustrate the high potential of using [18F]FTC-146 as a tool to investigate the role of S1R in human health and disease. 

Binge Eating Disorder

Sigma-1 receptors (S1R) are widely distributed throughout the brain where they interact with ion channels and neurotransmitters involved in learning, memory, and the development of compulsive behavior. It has previously been shown that S1R agonists facilitate the reinforcing effects of ethanol and induce binge-like drinking, while S1R antagonists block excessive drinking in genetic and environmental models of alcoholism as well as prevent cocaine self-administration in a drug abusing rat model. Similarly, researchers have reported that S1R protein levels increased in rat anterior cingulate cortex but not in other brain regions when the animals engaged in compulsive binge-eating behavior. S1R antagonism was also shown to dose-dependently prevent binge-eating in these rats which suggests that S1Rs may play an important role in the mediation of the reinforcing and rewarding effects caused by a highly palatable diet.

Our preliminary data show that18 F-FTC-146 PET-MR imaging of S1Rs can differentiate between normal (n = 1) vs. binge-eating mice (n = 2). After we have demonstrated clinical feasibility with our mice studies and established tracer kinetics modeling, we will translate and explore the utility of clinical-grade18 F-FTC-146 for PET-MR imaging. For example, changes in S1R density or DHEA occupancy of S1Rs in the human prefrontal and/or anterior cingulate cortex can be compared between healthy vs. binge-eating human subjects. Thus, we hypothesize that PET-MR imaging with our highly selective S1R radioligand (18F-FTC-146) will be a useful strategy for studying the potential role of S1Rs for treating BED.