Background

[PubMed]

Sigma receptor (SR) subtypes 1 (Sig-1R) and 2 (Sig-2R) and are known to be present primarily in the central nervous system and the peripheral tissues. Both receptor subtypes have a different distribution in the two types of tissues, and the exact biological function of these receptors is not known (1). Of the two receptor subtypes, only the Sig-1R has been cloned, expressed, and purified (2). The Sig-2R is known to be overexpressed in various malignant tumors and is believed to promote cell proliferation, indicating that these receptors may play a role in the development of some cancers (3). As a consequence, the Sig-2R have been suggested to be biomarkers for tumor cell proliferation (4) and could be targeted for the development of different anti-cancer drugs (5) or imaging agents for tumors that overexpress Sig-2R (3, 5). Several clinical trials have been approved by the United States Food and Drug Administration for the evaluation of drugs that target the Sig-2R for the imaging and treatment of different clinical conditions. In addition, Sig-2R ligands have been used in preclinical studies to chemosensitize tumors to low doses of anti-cancer drugs that are otherwise toxic when given at high doses to animals bearing mammalian cell line tumors (6, 7).

Investigators have developed and characterized several SR ligands, but most of them are either selective only for the Sig-1R or have similar affinity for both SR subtypes, therefore limiting their use as anti-cancer drugs that target the Sig-2R or as detection and imaging agents for this receptor (3, 7). In an effort to develop a ligand with high specificity for Sig-2R, Tu et al. synthesized a series of ¹⁸F-labeled benzamide analogs and evaluated these radiolabeled compounds with positron emission tomography (PET) and computed tomography (CT) imaging of mice bearing allograft tumors expressing the receptor (3). Among the various compounds tested, N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-[¹⁸F]-fluoroethoxy)-5-methylbenzamide (designated [¹⁸F]3c) and another analog, N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-[¹⁸F]-fluoroethoxy)-5-iodo-3-methoxybenzamide (designated [¹⁸F]3f), were determined to be most suitable for the detection of solid tumors expressing Sig-2R with the use of PET and CT imaging. This chapter describes the in vitro characterization and in vivo biodistribution of [¹⁸F]3c and the PET/CT imaging with [¹⁸F]3c. The in vitro and in vivo characterization of [¹⁸F]3f are described in a separate chapter in MICAD (www.micad.nih.gov) (8).

Synthesis

[PubMed]

The synthesis and ¹⁸F-labeling of 3c has been described by Tu et al. (3). The total time of synthesis to obtain [¹⁸F]3c was ~2 h with a decay-corrected yield of ~35%. The radiochemical purity of the labeled compound was >99% as determined with analytical high-performance liquid chromatography with a specific activity of >74.07 TBq/mmol (2,000 Ci/mmol). The entire procedure, including purification, was completed in approximately 2 h. The stability and conditions used to store [¹⁸F]3c were not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

In vitro receptor binding studies with [¹⁸F]3c were performed by Tu et al. (3) using membranes isolated from liver homogenates as described elsewhere (9). The affinity of 3c for the two SR subtypes was determined by competition studies using [³H](+)-pentazocine (for Sig-1R) and [³H]1,3-di(2-tolyl)guanidine in the presence of unlabeled (+)-pentazocine (for Sig-2R). The affinity of 3c, as determined with Scatchard plot analysis, was reported to be 330 ± 25 and 6.95± 1.63 nM for Sig-1R and Sig-2R, respectively, with a Sig-1R/Sig-2R ratio of 48. For comparison, the affinity of 3f was reported to be 2,150 ± 410 and 0.26 ± 0.07 nM, respectively for the two receptor subtypes, with a Sig-1R/Sig-2R ratio of 8,190.

Animal Studies

Human Studies

[PubMed]

No references are currently available.

Supplemental Information

[Disclaimers]

No information is currently available.

NIH Support

Some studies reported in this chapter were supported by National Institutes of Health grants CA-102869 and P41RR0954.

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Chopra, A., [18F]Labeled N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-fluoroethoxy)-5-iodo-3-methoxybenzamide ([18F]3f). Molecular Imaging and Contrast agent Database (MICAD) [database online]. National Library of Medicine, NCBI, Bethesda, MD, USA. Available from www​.micad.nih.gov, 2004 -to current.

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