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Cheng KT1.


Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2007 Jun 07 [updated 2008 Feb 06].

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National Center for Biotechnology Information, NLM, NIH, Bethesda, MD, Email:


1-(4-[18F]Fluoromethoxy-3-methoxyphenethyl)-4-(3-phenylpropyl)piperazine ([18F]FM-SA4503) is a radioligand developed for positron emission tomography (PET) imaging of the sigma (σ) receptors (1). It is a potent σ1 receptor agonist labeled with 18F, a positron emitter with a physical half-life (t½) of 109.8 min. The 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: σ1 and σ2 receptors. 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 (4, 5). The σ1 receptor subtypes appear to play a role in motor function and potassium channels (2). The σ2 receptor subtypes are implicated in CNS disorders and malignant neoplastic diseases. Because of these effects, σ receptor ligands may be useful for detection and treatment in neurology and oncology. Matsuno et al. (6) developed 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)-piperazine dihydrochloride (SA4503), a potent σ1 agonist that is in phase II clinical trials as a therapeutic agent for functional recovery after stroke. SA4503 is highly selective for σ1 receptors (Inhibition Concentration (IC50) = 4.63–6.67 nM) versus σ2 receptors (1, 6). Small modifications in the SA4503 structure appear to have profound effects on the σ12 receptor affinity and selectivity (7). SA5403 has been labeled with 11C for PET studies of σ receptors in monkeys and humans (8-10). However, the equilibrium state of the receptor–ligand binding in monkeys could not be measured with [11C]SA4503 because of the short t½ of 11C. In an effort to overcome this problem, Elsinga et al. (7) synthesized [18F]fluoroethyl analog of SA45043 ([18F]FE-SA4503), which has a longer physical t½, so that the equilibrium state of receptor–ligand binding can be studied. However, [18F]FE-SA4503 is a non–subtype-selective σ receptor ligand. Kawamura et al. (1) synthesized [18F]FM-SA4503 as a selective σ1 receptor ligand.

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