1-([4-methoxy-C]-3,4-Dimethoxyphenethyl)-4-(3-phenylpropyl)piperazinephenoxy)

1-([4-methoxy-C]-3,4-Dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine ([C]SA4503) is a radioligand developed for positron emission tomography (PET) imaging of the sigma (σ) receptors. [C]SA4503 is a potent σ receptor agonist labeled with C, a positron emitter with a physical half-life () of 20.4 min (1). σ receptors are functional, membrane-bound proteins distributed in the central nervous system (CNS) and peripheral organs (2). The CNS σ receptors are unique binding sites related to higher brain functions (3). They are distinct from opiate and phencyclidine binding sites. There are at least two subtypes of σ receptors: σ and σ receptors. The precise mechanism of the functional response of these receptors is not entirely known. These receptors appear to be involved in numerous pharmacologic and physiologic functions, and they also modulate a number of central neurotransmitter systems, including noradrenergic, glutamatergic, and dopaminergic systems. Phencyclidine and derivatives, cocaine and derivatives, some neuroleptics, atypical antipsychotic agents, and other chemically unrelated compounds can bind to the σ receptor sites. Studies have shown that these receptors may play a role in the pathogenesis of psychiatric disorders (4, 5). These receptors are also expressed on a number of human and murine tumors (6). The σ receptor subtypes have a molecular weight of ≈25 kDa, and through the process of cloning they have shown a 30% sequence homology with the yeast C89-C7 sterol isomerase (2, 7, 8) The σ receptor subtypes have a molecular weight of ≈21.5 kDa and have not been cloned. The σ receptors are thought to be involved in certain neuropsychiatric disorders, and the σ receptors are also implicated in malignant neoplastic diseases. Because of these effects, σ receptor ligands may be useful for detection and treatment in neurology and oncology. Matsuno et al. (9) developed a potent σ agonist, 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)-piperazine dihydrochloride (SA4503), which is undergoing phase II clinical trials as a therapeutic agent for functional recovery after stroke. SA4503 is highly selective for σ receptors versus σ receptors (9). Small modifications in the SA4503 structure appear to have profound effects on the σ/σ receptor affinity and selectivity (10). SA5403 can be labeled with C for PET studies of σ receptors, and studies have shown specific localization of [C]SA4503 in animals and humans (1, 11, 12).