Skip to main content
SpringerLink
Log in

Evaluation of [11C]SA5845 and [11C]SA4503 for imaging of sigma receptors in tumors by animal PET

  • Original Article
  • Published:
Annals of Nuclear Medicine Aims and scope Submit manuscript

Abstract

Sigma receptors are expressed in a wide variety of tumor cell lines, and are expressed in proliferating cells. A radioligand for the visualization of sigma receptors could be useful for selective detection of primary tumors and their metastases, and for non-invasive assessment of tumor proliferative status. To this end we evaluated two sigma receptor ligands, [11C]SA5845 and [11C]SA4503. In an in vitro study, AH109A hepatoma showed moderate densities of sigma1 and sigma2 receptors, and VX-2 carcinoma showed a high density of sigma2 receptors: Bmax (fmol/mg protein) for sigma1 vs. sigma2, 1,700 vs. 1,200 for AH109A hepatoma and 800 vs. 10,000 for VX-2 carcinoma. In a cell growth assay in vitro, neither SA5845 nor SA4503 (<10 μM) showed any inhibitory effect on proliferation of the AH109A hepatoma cells. In rats, the uptake of [11C]SA5845 and [11C]SA4503 in AH109A tissues was accumulated over the first 60 minutes; however, the uptake of both tracers increased by co-injection with haloperidol as a sigma receptor ligand. On the other hand, in the PET studies of rabbits, the uptake of [11C]SA5845 in the VX-2 carcinoma was relatively higher than that of [11C]SA4503, because of a much higher density of sigma2 receptors compared to sigma1 receptors in the VX-2 tissue, and the uptake of both tracers in the VX-2 tissue was decreased by carrier-loading and pre-treatment with haloperidol ([11C]SA5845, 53% and 26%, respectively; [11C]SA4503, 41% and 22%, respectively at 30 minutes after injection). Therefore, [11C]SA5845 and [11C]SA4503 may be potential ligands for PET imaging of sigma receptor-rich tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Reference

  1. Walker JM, Bowen WD, Walker FO, Matsumoto RR, de Costa B, Rice KC. Sigma receptors: biology and function.Pharmacol Rev 1990; 42:355–402.

    PubMed  CAS  Google Scholar 

  2. Su TP, London ED, Jaffe JH. Steroid binding at σreceptors suggests a link between endocrine, nervous, immune systems.Science 1988; 240:219–221.

    Article  PubMed  CAS  Google Scholar 

  3. Wolfe SA Jr, Culp SG, De Souza EB. σ-receptors in endocrine organs: identification, characterization, and autoradiogaphic localization on rat pituitary, adrenal, testis and ovary.Endocrinology 1989; 124:1160–1172.

    PubMed  CAS  Google Scholar 

  4. Hellewell SB, Bruce A, Feinstein G, Orringer J,. Williams W, Bowen WD. Rat liver and kidney contain high densities of σ1 and σ2 receptors: characterization by ligand binding and photoafflnity labeling.Eur J Pharmacol 1994; 268:9–18.

    Article  PubMed  CAS  Google Scholar 

  5. Bern WT, Thomas GE, Mamone JY, Homan SM, Levy BK, Johnson FE, et al. Overexpression of preceptors in nonneural human tumors.Cancer Res 1991; 51:6558–6562.

    Google Scholar 

  6. Vilner BJ, John CS, Bowen WD. Sigma-1 and sigma-2 receptors are expressed in a wide variety of human and rodent tumor cell lines.Cancer Res 1995; 55:408–413.

    PubMed  CAS  Google Scholar 

  7. Brent PJ, Pang GT. σ binding site ligands inhibit cell proliferation in a mammary and colon carcinoma cell lines and melanoma cells in culture.Eur J Pharmacol 1995; 278:151–160.

    Article  PubMed  CAS  Google Scholar 

  8. Wheeler KT, Wang LM, Wallen CA, Childers SR, Cline JM, Keng PC, et al. Sigma-2 receptors as a biomarker of proliferation in solid tumours.Br J Cancer 2000; 82:1223–1232.

    Article  PubMed  CAS  Google Scholar 

  9. Mach RH, Smith CR, Al Nabulsi I, Whirrett BR, Childers SR, Wheeler KT. Sigma-2 receptors as potential biomarkers of proliferation in breast cancer.Cancer Res 1997; 57:156–161.

    PubMed  CAS  Google Scholar 

  10. Zamora PO, Moody TW, John CS. Increased binding to sigma sites of N-[l′(2-piperidinyl)ethyl]-4-[I-125]-iodobenzamide (I-125-PAB) with onset of tumor cell proliferation.Life Sci 1998; 63:1611–1618.

    Article  PubMed  CAS  Google Scholar 

  11. Crawford KW, Bowen WD. Sigma-2 receptor agonists activate a novel apoptotic pathway and potentiate antineoplastic drugs in breast tumor cell lines.Cancer Res 2002; 62:313–322.

    PubMed  CAS  Google Scholar 

  12. Crawford KW, Coop A, Bowen WD. σ2 Receptors regulate changes in sphingolipid levels in breast tumor cells.Eur J Pharmacol 2002; 443:207–209.

    Article  PubMed  CAS  Google Scholar 

  13. Wilson AA, Dannals RF, Ravert HT, Sonders MS, Weber E, Wagner HN Jr. Radiosynthesis of sigma receptor ligands for positron emission tomography:11C- and18F-labeled guanidines.J Med Chem 1991; 34:1867–1870.

    Article  PubMed  CAS  Google Scholar 

  14. Musachio JL, Scheffel U, Stathis M, Ravert HT, Mathews WB, Dannals RF. (+)-[C-l l]-cis-N-benzyl-nonnetazocine: a selective ligand for sigma receptorsin vivo. Life Sci 1994; 55:PL225–232.

    Article  PubMed  CAS  Google Scholar 

  15. Dence CS, John CS, Bowen WD, Welch MJ. Synthesis and evaluation of [18F] labeled benzamides: High affinity sigma receptor ligands for PET imaging.Nucl Med Biol 1997; 24:333–340.

    Article  PubMed  CAS  Google Scholar 

  16. Shiue CY, Shiue GG, Zhang SX, Wilder S, Greenberg JH, Benard F, et al. N-(N-Benzylpiperidin-4-yl)-2-[l8F]fluorobenzamide: a potential ligand for PET imaging of sigma receptors.Nucl Med Biol 1997; 24:671–676.

    Article  PubMed  CAS  Google Scholar 

  17. Waterhouse RN, Collier TL.In vivo evaluation of [l8F]l-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine: a selective sigma-1 receptor radioligand for PET.Nucl Med Biol 1997; 24:127–134.

    Article  PubMed  CAS  Google Scholar 

  18. Ishiwata K, Noguchi J, Ishii S, Hatano K, Ito K, Nabeshima T, et al. Synthesis of [11C]NE-100 labeled in two different positions as a PET a receptor ligand.Nucl Med Biol 1998; 25:195–202.

    Article  PubMed  CAS  Google Scholar 

  19. Kawamura K, Ishiwata K, Tajima H, Ishii S, Shimada Y, Matsuno K, et al. Synthesis andin vivo evaluation of [11C]SA6298 as a PET sigma1 receptor ligand.Nucl Med Biol 1999; 26:915–922.

    Article  PubMed  CAS  Google Scholar 

  20. Mach RH, Huang Y, Buchheimer N, Kuhner R, Wu L, Morton TE, et al. [18F]N-(4′-fluorobenzyl)-4-(3-bromophenyl) acetamide for imaging the sigma receptor status of tumors: comparison with [18F]FDG, and [125I]IUDR.Nucl Med Biol 2001; 28:451–458.

    Article  PubMed  CAS  Google Scholar 

  21. Barbieri F, Sparatore A, Alama A, Novelli F, Bruzzo C, Sparatore F. Novel sigma binding site ligands as inhibitors of cell proliferation in breast cancer.Oncol Res 2003; 13:455–461.

    PubMed  Google Scholar 

  22. Casellas P, Galiegue S, Bourrie B, Ferrini JB, Jbilo O, Vidal H. SR31747A: a peripheral sigma ligand with potent antitumor activities.Anticancer Drugs 2004; 15:113–118.

    Article  PubMed  CAS  Google Scholar 

  23. Kawamura K, Elsinga PH, Kobayashi T, Ishii S, Wang WF, Matsuno K, et al. Synthesis and evaluation of11C- and18F-labeled 1 -[2-(4-alkoxy-3-methoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazines as sigma receptor ligands for positron emission tomography studies.Nucl Med Biol 2003; 30:273–284.

    Article  PubMed  CAS  Google Scholar 

  24. Kawamura K, Ishiwata K, Tajima H, Ishii S, Matsuno K, Homma Y, et al.In vivo evaluation of [11C]SA4503 as a PET ligand for mapping CNS sigma1 receptors.Nucl Med Biol 2000; 27:255–261.

    Article  PubMed  CAS  Google Scholar 

  25. Kawamura K, Ishiwata K, Shimada Y, Kimura Y, Kobayashi T, Matsuno K, et al. Preclinical evaluation of [11C]SA4503: radiation dosimetry,in vivo selectivity and PET imaging of sigma1 receptors in the cat brain.Ann Nucl Med 2000; 14:285–292.

    Article  PubMed  CAS  Google Scholar 

  26. Kawamura K, Kimura Y, Tsukada H, Kobayashi T, Nishiyama S, Kakiuchi T, et al. An increase of sigma receptors in the aged monkey brain.Neurobiol Aging 2003; 24:745–752.

    Article  PubMed  CAS  Google Scholar 

  27. Ishiwata K, Tsukada H, Kawamura K, Kimura Y, Nishiyama S, Kobayashi T, et al. Mapping of CNS sigma1 receptors in the conscious monkey: Preliminary PET study with [11C]SA4503.Synapse 2001; 40:235–237.

    Article  PubMed  CAS  Google Scholar 

  28. Matsuno K, Nakazawa M, Okamoto K, Kawashima Y, Mita S. Binding properties of SA4503, a novel and selective σ1 receptor agonist.Eur J Pharmacol 1996; 306:271–279.

    Article  PubMed  CAS  Google Scholar 

  29. Fujimura K, Matsumoto J, Niwa M, Kobayashi T, Kawashima Y, In Y, et al. Synthesis, structure and quantitative structure-activity relationships of σreceptor ligands, 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)pipera-zines.Bioorg Med Chem 1997; 5:1675–1683.

    Article  PubMed  CAS  Google Scholar 

  30. Mishina M, Ishiwata K, Ishii K, Kitamura S, Kimura Y, Kawamura K, et al. Function of sigma1 receptors in Parkinson’s disease.Acta Neurol Scand 2005; 112:103–107.

    Article  PubMed  CAS  Google Scholar 

  31. Elsinga PH, Kawamura K, Kobayashi T, Tsukada H, Senda M, Vaalburg W, et al. Synthesis and evaluation of [18F]fiuoroethyl SA4503 as a PET ligand for the sigma receptor.Synapse 2002; 43:259–267.

    Article  PubMed  CAS  Google Scholar 

  32. Elsinga PH, Tsukada H, Harada N, Kakiuchi T, Kawamura K, Vaalburg W, et al. Evaluation of [18F]fluorinated sigma receptor ligands in the conscious monkey brain.Synapse 2004; 52:29–37.

    Article  PubMed  CAS  Google Scholar 

  33. van Waarde A, Buursma AR, Hospers GAP, Kawamura K, Kobayashi T, Ishii K, et al. Tumor imaging with two sigma receptor ligands, [18F]FE-SA5845 and [11C]SA4503: a feasibility study.J Nucl Med 2004; 45:1939–1945.

    Google Scholar 

  34. Kubota K, Ishiwata K, Kubota R, Yamada S, Takahashi J, Abe Y, et al. Feasibility of fluorine-18-fluorophenylalanine for tumor imaging compared with carbon-11-l-methionine.J Nucl Med 1996; 37:320–325.

    PubMed  CAS  Google Scholar 

  35. Ono M, Hirata A, Kometani T, Miyagawa M, Ueda S, Kinoshita H, et al. Sensitivity to gefitinib (‘Iressa’, ZD1839) in non-small cell lung cancer cell lines correlates with dependence on the epidermal growth factor (EGF) receptor/ extra cellular signal-regulated kinase 1/2 and EGF receptor/ Akt pathway for proliferation.Mol Cancer Ther 2004; 3:465–472.

    PubMed  CAS  Google Scholar 

  36. Ishiwata K, Kawamura K, Wang WF, Furumoto S, Kubota K, Pascali C, et al. Evaluation of O-[11C]methyl-l-tyrosine and O-[18F]fiuoromethyl-l-tyrosine as tumor imaging tracers by PET.NuclMedBiol 2004; 31:191–198.

    CAS  Google Scholar 

  37. Moody TW, Leyton J, John C. Sigma ligands inhibit the growth of small cell lung cancer cells.Life Sci 2000; 66:1979–1986.

    Article  PubMed  CAS  Google Scholar 

  38. Leitner ML, Hohmann AG, Patrick SL, Walker JM. Regional variation in the ratio of sigma1 to sigma2 binding in rat brain.Eur J Pharmacol 1994; 259:65–69.

    Article  PubMed  CAS  Google Scholar 

  39. Waterhouse RN, Collier TL.In vivo evaluation of [18F]l-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine: a selective sigma-1 receptor radioligand for PET.Nucl Med Biol 1997; 24:127–134.

    Article  PubMed  CAS  Google Scholar 

  40. Georg A, Friedl A. Characterization of specific binding sites for [3H]-l,3-di-o-tolyl-guanidine (DTG) in the rat glioma cell line C6-BU-1.Glia 1992; 6:258–263.

    Article  PubMed  CAS  Google Scholar 

  41. Shiue C, Shiue GG, Benard F, Visonneau S, Santoli D, Alavi AA. N-(N-Benzylpiperidin-4-yl)-2-[18F]fluorobenzamide: a potential ligand for PET imaging of breast cancer.Nucl Med Biol 2000; 27:763–767.

    Article  PubMed  CAS  Google Scholar 

  42. John CS, Vilner BJ, Schwartz AM, Bowen WD. Characterization of sigma receptor binding sites in human biopsied solid breast tumors.J Nucl Med 1996; 37 (Suppl): 267P (abstract).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Naka-cho 1-1, 173-0022, Itabashi-ku, Tokyo, JAPAN

    Kiichi Ishiwata & Kazunori Kawamura

  2. SHI Accelerator Service, Tokyo, Japan

    Kazunori Kawamura

  3. Department of Radiology, International Medical Center of Japan, Tokyo, Japan

    Kazuo Kubota

  4. M’s Science Co., Ltd., Kobe, Japan

    Tadayuki Kobayashi

  5. PET-center, Croningen University Hospital, Groningen, The Netherlands

    Philip H. Elsinga

  6. Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Mayumi Ono

  7. Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

    Minoru Maeda

Authors
  1. Kiichi Ishiwata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazunori Kawamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kazuo Kubota
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tadayuki Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Philip H. Elsinga
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mayumi Ono
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Minoru Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kazunori Kawamura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ishiwata, K., Kawamura, K., Kubota, K. et al. Evaluation of [11C]SA5845 and [11C]SA4503 for imaging of sigma receptors in tumors by animal PET. Ann Nucl Med 19, 701–709 (2005). https://doi.org/10.1007/BF02985120

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02985120

Key words

Search

Navigation