Sigma-1 Receptor Imaging in the Brain: Cerebral sigma-1 receptors and cognition: Small-animal PET studies using 11C-SA4503

The sigma-1 receptor is a unique orphan receptor, strongly expressed in neurons and glia. Sigma-1 receptors are involved in several central nervous system (CNS) disorders like depression, anxiety, psychosis, schizophrenia, Parkinson’s disease, Alzheimer’s disease, addiction and neuropathic pain. Several CNS drugs like haloperidol, donepezil, rimcazole, fluvoxamine, sertraline and clorgyline have moderate to high sigma-1 receptor affinity. Pharmaceutical companies currently involved in R&D and clinical trials of sigma-1 drugs include Anavex Life Sciences Corp., M’s Science Corp. and Laboratorios del Dr. Esteve S.A.
The studies presented in this thesis demonstrated the usefulness of 11C-SA4503 and microPET to evaluate sigma-1 receptors in the rat brain. Decreased and increased binding of the tracer to sigma-1 receptors was estimated in normal aging brain and spontaneous pituitary tumor respectively. REM sleep deprivation was found to cause reduced sigma-1 expression in the brain, while treatment with cutamesine (SA4503) was shown to overcome REM sleep deprivation induced cognitive deficits. The receptor occupancy by agonist drugs, donepezil and cutamesine, at doses effective in behavioral studies of cognition could be estimated using 11C-SA4503. The kinetics of the drug cutamesine in plasma and brain could be modeled using classical and non-linear mixed effects modeling (NONMEM) for the cold drug and its radioactive form (11C-SA4503) respectively.
In conclusion, the sigma-1 agonist tracer 11C-SA4503 has potential uses in the study of various disorders, both of the CNS and periphery, as well as in the evaluation of potential treatments and drug effects.