1-(3,4-[C]Dimethoxyphenethyl)-4-[3-(3,4-dichlorophenyl)propyl]piperazinephenoxy)

1-(3,4-[C]Dimethoxyphenethyl)-4-[3-(3,4-dichlorophenyl)propyl]piperazine ([C]SA6298) is a radioligand developed for positron emission tomography (PET) imaging of the sigma (σ) receptors. [C]SA6298 is a potent σ receptor agonist labeled with C, a positron emitter with a physical half-life () of 20.4 min (1). The σ receptors are functional, membrane-bound proteins that are 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. A σ receptor subtype has also been proposed (4). The precise mechanism of the functional response of these receptors is not entirely known. These receptors appear to be involved in numerous pharmacological and physiological 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 (5, 6). These receptors are also expressed on a number of human and murine tumors (7). 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, 8, 9) The σ receptor subtypes have a molecular weight of ≈21.5 kDa and they have not been cloned. The σ receptors are thought to be involved in certain neuropsychiatric disorders, and the σ receptors are 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. (10) 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 (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). SA6298 is an analog of SA4503 with a higher but less selective affinity [inhibition constant (IC) for σ = 6.9 nM; σ/σ = 22] for σ receptors than SA4503 (IC for σ = 17.4 nM; σ/σ = 103) (10, 13, 14). Kawamura et al. (13) evaluated the potential of [C]SA6298 as a PET σ receptor ligand.