Background

[PubMed]

1-(3,4-[¹¹C]Dimethoxyphenethyl)-4-[3-(3,4-dichlorophenyl)propyl]piperazine ([¹¹C]SA6298) is a radioligand developed for positron emission tomography (PET) imaging of the sigma (σ) receptors. [¹¹C]SA6298 is a potent σ₁ receptor agonist labeled with ¹¹C, a positron emitter with a physical half-life (t_½) 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: σ₁ and σ₂ receptors. A σ₃ 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 σ₁ 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 σ₂ receptor subtypes have a molecular weight of ≈21.5 kDa and they have not been cloned. The σ₁ receptors are thought to be involved in certain neuropsychiatric disorders, and the σ₂ 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 σ₁ 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 σ₁ receptors versus σ₂ receptors (10). SA5403 can be labeled with ¹¹C for PET studies of σ receptors, and studies have shown specific localization of [¹¹C]SA4503 in animals and humans (1, 11, 12). SA6298 is an analog of SA4503 with a higher but less selective affinity [inhibition constant (IC₅₀) for σ₁ = 6.9 nM; σ₁/σ₂ = 22] for σ₁ receptors than SA4503 (IC₅₀ for σ₁ = 17.4 nM; σ₁/σ₂ = 103) (10, 13, 14). Kawamura et al. (13) evaluated the potential of [¹¹C]SA6298 as a PET σ₁ receptor ligand.

Synthesis

[PubMed]

Fujimura et al. (14) reported the preparation of SA6298 from phenylpropylamine. Kawamura et al. (13) designed the radiosynthesis of [¹¹C]SA6298 based on the precursor desmethyl SA6298 (SA11726), which was obtained commercially. [¹¹C]SA6298 was prepared by methylation of SA11726 with [¹¹C]CH₃I. Briefly, [¹¹C]CH₃I was produced with an automated system and trapped in 0.2 ml of N,N-dimethylformamide containing 0.2 mg of SA11726 and 1−4 mg of sodium hydride (NaH). The mixture of SA11726 and NaH was preheated at 80ºC for 2−5 min before [¹¹C]CH₃I was added. The mixture of [¹¹C]CH₃I, SA11726 and NaH was heated at 120ºC for 1 min. The solution was then diluted with a solvent, and [¹¹C]SA6298 was isolated by a reversed-phase chromatography. The isolated product was purified by a high-performance liquid chromatography (HPLC). The decay-corrected radiochemical yield (based on [¹¹C]CH₃I) was 38.9 ± 5.2%, and the specific activity (n = 5) was 52.8 ± 16.8 TBq/mmol (453.6 Ci/mmol). The radiochemical purity was >97%.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Fujimura et al. (14) used guinea pig brain homogenate and [³H](+)-pentazocine to determine the affinity of SA8298 to σ receptors. The IC₅₀ to σ₁ receptors was 6.9 nM, and the σ₁/σ₂ ratio was 22. Kawamura et al. (13) determined that the octanol/phosphate buffered saline partition coefficient of [¹¹C]SA6298 was logP_7.4= 3.82.

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

References

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Kawamura K. , Ishiwata K. , Tajima H. , Ishii S. , Matsuno K. , Homma Y. , Senda M. In vivo evaluation of [(11)C]SA4503 as a PET ligand for mapping CNS sigma(1) receptors. Nucl Med Biol. 2000; 27 (3):255–61. [PubMed: 10832082]

2.

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6.

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Vilner B.J. , John C.S. , Bowen W.D. Sigma-1 and sigma-2 receptors are expressed in a wide variety of human and rodent tumor cell lines. Cancer Res. 1995; 55 (2):408–13. [PubMed: 7812973]

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Mach R.H. , Gage H.D. , Buchheimer N. , Huang Y. , Kuhner R. , Wu L. , Morton T.E. , Ehrenkaufer R.L. N-[18F]4'-fluorobenzylpiperidin-4yl-(2-fluorophenyl) acetamide ([18F]FBFPA): a potential fluorine-18 labeled PET radiotracer for imaging sigma-1 receptors in the CNS. Synapse. 2005; 58 (4):267–74. [PubMed: 16206186]

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Hanner M. , Moebius F.F. , Flandorfer A. , Knaus H.G. , Striessnig J. , Kempner E. , Glossmann H. Purification, molecular cloning, and expression of the mammalian sigma1-binding site. Proc Natl Acad Sci U S A. 1996; 93 (15):8072–7. [PMC free article: PMC38877] [PubMed: 8755605]

10.

Matsuno K. , Nakazawa M. , Okamoto K. , Kawashima Y. , Mita S. Binding properties of SA4503, a novel and selective sigma 1 receptor agonist. Eur J Pharmacol. 1996; 306 (1-3):271–9. [PubMed: 8813641]

11.

Kawamura K. , Kubota K. , Kobayashi T. , Elsinga P.H. , Ono M. , Maeda M. , Ishiwata K. Evaluation of [11C]SA5845 and [11C]SA4503 for imaging of sigma receptors in tumors by animal PET. Ann Nucl Med. 2005; 19 (8):701–9. [PubMed: 16444997]

12.

van Waarde A. , Buursma A.R. , Hospers G.A. , Kawamura K. , Kobayashi T. , Ishii K. , Oda K. , Ishiwata K. , Vaalburg W. , Elsinga P.H. Tumor imaging with 2 sigma-receptor ligands, 18F-FE-SA5845 and 11C-SA4503: a feasibility study. J Nucl Med. 2004; 45 (11):1939–45. [PubMed: 15534066]

13.

Kawamura K. , Ishiwata K. , Tajima H. , Ishii S. , Shimada Y. , Matsuno K. , Homma Y. , Senda M. Synthesis and in vivo evaluation of [11C]SA6298 as a PET sigma1 receptor ligand. Nucl Med Biol. 1999; 26 (8):915–22. [PubMed: 10708305]

14.

Fujimura K. , Matsumoto J. , Niwa M. , Kobayashi T. , Kawashima Y. , In Y. , Ishida T. Synthesis, structure and quantitative structure-activity relationships of sigma receptor ligands, 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl) piperazines. Bioorg Med Chem. 1997; 5 (8):1675–83. [PubMed: 9313869]