The development of radiotracers for imaging sigma (s) receptors in the central nervous system (CNS) using positron emission tomography (PET) † Samuel D. Banister, a,b Miral Manoli, b,c and Michael Kassiou a,b,c * Sigma (s) receptors are unique mammalian proteins, distributed in the central nervous system and elsewhere, which are increas- ingly implicated in the pathophysiology of virtually all major central nervous system disorders. The heterogeneous but wide distribution of s 1 in the brain has prompted the development of selective radiotracers for imaging these sites using positron emission tomography (PET). To date, some 50 carbon-11-labelled and fluorine-18-labelled candidate PET radioligands targeting s receptors have been reported. The historical development of selective s 1 receptor ligands as potential PET imaging agents, as well as the radiochemistry and application of the most recently developed examples, is described herein. Keywords: sigma receptors; CNS; carbon-11; fluorine-18 Introduction Sigma (s) receptors are unique mammalian proteins, widely dis- tributed in the central and peripheral nervous systems (CNS and PNS, respectively) as well as peripheral organs, which are increas- ingly implicated in the pathophysiology of numerous major CNS disorders 1,2 including affective disorders, 3–5 psychosis and schizophrenia, 6 and drug addiction. 1 Consistent with their roles in motor function and higher cognition, s receptors have also been implicated in movement disorders, such as Parkinson’ s dis- ease, and disorders of memory, including Alzheimer’ s disease. Numerous s receptor ligands have shown promise in animal models of CNS disease, many have been patented, and several have been evaluated in clinical trials. 7–9 Two s receptor subtypes, s 1 and s 2 , have been defined, dif- fering in size, distribution, and ligand selectivity profiles. 10 The s 1 receptor has been cloned from numerous mammalian tissue sources, including human brain, and shares no homology with any known mammalian protein. 11 The primary subcellular loca- tion of s 1 receptors is the mitochondria-associated endoplasmic reticulum membrane, where s 1 receptors act as molecular cha- perones for type 3 inositol-1,4,5-triphosphate receptors, thereby regulating endoplasmic reticulum–mitochondria Ca 2+ signalling under conditions of cellular stress. 12,13 However, s 1 receptors are also known to translocate along the continuous endoplasmic reticular network to the nuclear envelope and the plasma membrane, accounting for their ability to modulate plasma membrane-bound K + , Ca 2+ , and Cl  channels 14–20 and to main- tain intracellular Ca 2+ levels through multiple mechanisms. 21 Consistent with their diverse pharmacology, s 1 receptors pos- sess a complex neuromodulatory role within the CNS, altering the neurotransmission of the cholinergic, 22–25 dopaminergic, 26 glutamatergic, 27–37 and serotonergic systems. 38,39 The s 2 receptor is relatively less well defined than the s 1 sub- type, and much of its pharmacology remains unelucidated. The s 2 receptor has not been cloned and little is known about its sequence and structure. Photoaffinity labelling studies have suggested that the s 2 receptor is approximately 21.5 kDa in size, smaller than the 25 kDa s 1 receptor. 40,41 As demonstrated by various fluorescent probes, the subcellular localization of s 2 receptors appears similar to that of s 1 receptors; high levels are found in mitochondria, endoplasmic reticulum, and plasma membrane. 42 The overexpression of s 2 receptors in tumour cells suggests a prominent role in cell proliferation, 43,44 and high densities of both s 1 and s 2 receptors have been reported in a diversity of human tumour cell lines. 45,46 Furthermore, s 2 receptors have been implicated in cell death via apoptotic and non-apoptotic processes. 47,48 a Brain and Mind Research Institute, The University of Sydney, NSW 2050, Australia b School of Chemistry, The University of Sydney, NSW 2006, Australia c Discipline of Medical Radiation Sciences, The University of Sydney, NSW 2006, Australia *Correspondence to: Michael Kassiou, Brain and Mind Research Institute, The University of Sydney. 100 Mallett St, Camperdown, NSW 2050, Australia. E-mail: michael.kassiou@sydney.edu.au † This article is published in Journal of Labelled Compounds and Radiopharma- ceuticals as a special issue on ‘Carbon-11 and Fluorine-18 Chemistry Devoted to Molecular Probes for Imaging the Brain with PET’, edited by Frédéric Dollé, Service Hospitalier Frédéric Joliot, Institut d’Imagerie BioMédicale, CEA, 4 Place du Général Leclerc, F-91406 Orsay, France. Copyright © 2013 John Wiley & Sons, Ltd. J. Label Compd. Radiopharm 2013, 56 215–224 Special Issue Review Received 3 May 2012, Revised 19 November 2012, Accepted 20 November 2012 Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/jlcr.3010 215