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σ2 Receptors: Regulation of Cell Growth and Implications for Cancer Diagnosis and Therapeutics

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Sigma Receptors

Summary

σ Receptors are expressed in the brain, as well as in many other tissues throughout the body. While much is being learned regarding functions of these receptors in the central nervous system, less is known regarding functions in the periphery. The nearly ubiquitous expression across tissues suggests a global function. Upregulation of σ2 receptors in rapidly proliferating cells, down regulation in quiescent cells, and the ability of σ2 agonists to inhibit cell proliferation and induce apoptosis suggest a role of σ2 receptors in cell growth control. This is further supported by the ability of σ2 receptors to modulate several signaling pathways known to regulate proliferation and cell survival. Current evidence suggests that σ2 receptors may be useful targets for development of antineoplastic agents that will be effective against drug-resistant tumors. They can also be targeted by noninvasive imaging agents that will be able to detect many types of tumors,monitor their growth, and perhaps detect and treat tumors at metastatic sites. Further exploration with respect to elucidation of σ2 receptor structure, delineation of endogenous ligands, mechanisms of cell growth control, and development of selective receptor probes as agonists and imaging agents is clearly warranted.

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References

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

    PubMed  CAS  Google Scholar 

  2. Quirion R, Bowen WD, Itzhak Y, Junien JL, Musacchio JM, Rothma RB, Su TP, Tam SW, Taylor DP. A proposal for the classification of sigma binding sites. Trends Pharmacol Sci 1992, 13: 85–86.

    Article  PubMed  CAS  Google Scholar 

  3. Bowen WD. Biochemical pharmacology of sigma receptors. in: Aspects of Synaptic Transmission Vol. 11: Acetylcholine, Sigma Receptors, CCK and Eicosanoids, Neurotoxins. (T.W. Stone, ed.), Taylor and Francis, London, U.K., 1993, pp. 113–136.

    Google Scholar 

  4. Bowen WD. Sigma receptors: Recent advances and new clinical potentials. Pharmaceutica Acta Helvetiae 2000, 74: 211–218.

    Article  PubMed  CAS  Google Scholar 

  5. Su TP, Hayashi T. Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction. Curr Med Chem 2003, 10: 2073–2080.

    Article  PubMed  CAS  Google Scholar 

  6. Guitart X, Codony X, Monroy X. Sigma receptors: biology and therapeutic potential. Psychopharmacology 2004, 174: 301–319.

    Article  PubMed  CAS  Google Scholar 

  7. Maurice T. Neurosteroids and sigma-1 receptors, biochemical and behavioral relevance. Pharmacopsychiatry 2004, 37(Suppl3): S171–182.

    Article  PubMed  CAS  Google Scholar 

  8. Hellewell SB, Bowen WD. A sigma-like binding site in rat pheochromocytoma (PC12) cells: Decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form fkom that in guinea pig brain. Brain Res 1990, 527:244–253.

    Article  PubMed  CAS  Google Scholar 

  9. Hanner M, Moebius FF, Flandorfer A, Knaus HG, Striessnig J, Kempner E, Glossmann H. Purification, molecular cloning, and expression of the mammalian sigma,-binding site. Proc Natl Acad Sci USA 1996, 93: 8072–8077.

    Article  PubMed  CAS  Google Scholar 

  10. Prasad PD, Li HW, Fei YJ, Ganapathy ME, Fujita T, Plumley LH, Yang-Feng TL, Leibach FH, Ganapathy V. Exon-intron structure, analysis of promoter region, and chromosomal localization of the human type 1 sigma receptor gene. J Neurochem 1998, 70:443–451.

    Article  PubMed  CAS  Google Scholar 

  11. Hellewell SB, Bruce A, Feinstein G, Orringer J, Williams W, Bowen WD. Rat liver and kidney contain high densities of sigma-1 and sigma-2 receptors: Characterization by ligand binding and photoaffinity labeling. Eur J Pharmacol Mol Pharmacol Sect 1994, 268:9–18.

    Article  CAS  Google Scholar 

  12. Su, TP, London, ED, Jaffe JH. Steroid binding at sigma receptors suggests a link between endocrine, nervous, and immune systems. Science 1988, 240:219–221.

    Article  PubMed  CAS  Google Scholar 

  13. Patterson TA, Connor M, Chavkin C. Recent evidence for endogenous substance(s) for sigma receptors. in: The Sigma Receptors, Neuroscience Perspectives Series. (Y. Itzhak, ed)., Academic Press, London, 171–189, 1994.

    Google Scholar 

  14. Bowen WD, de Costa BR, Hellewell SB, Walker JM, Rice KC. [3H](+)-Pentazocine: A potent and highly selective benzomorphan-based probe for sigma-1 receptors. Mol Neuropharmacol 1993, 3: 117–126.

    CAS  Google Scholar 

  15. Wolfe Jr SA, Culp SG, De Souza, EB. Sigma receptors in endocrine organs: Identification, characterization, and autoradiographic localization in rat pituitary, adrenal, testis, and ovary. Endocrinology 1989, 124:1160–1172.

    Article  PubMed  CAS  Google Scholar 

  16. Thomas GE, Szucs M., Mamone JY, Bem WT, Rush MD, Johnson FE, Coscia CJ. Sigma and opioid receptors in human brain tumors. Life Sci 1990, 46:1279–1286.

    Article  PubMed  CAS  Google Scholar 

  17. Bem WT, Thomas GE, Mamone JY, Homan SM, Levy BK, Johnson FE, Coscia CJ. Overexpression of sigma receptors in nonneural human tumors. Cancer Res 1990, 51:6558–6562.

    Google Scholar 

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

    Google Scholar 

  19. Vilner BJ, Bowen WD. Characterization of sigma-like binding sites of NB41A3, S-20Y, and N1E-115 neuroblastomas, C6 glioma, and NG108-15 neuroblastoma-glioma hybrid cells: Further evidence for sigma-2 receptors. In: Multiple Sigma and PCP Receptor Ligands: Mechanisms for Neuromodulation and Neuroprotection? J.-M. Kamenka and E.F. Domino, eds. NPP Books, Ann Arbor, MI, 1992, pp. 341–353.

    Google Scholar 

  20. 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 

  21. Ganapathy ME, Prasad PD, Huang W, Seth P, Leibach FH, Ganapathy V. Molecular and ligand-binding characterization of the sigma-receptor in the Jurkat human T lymphocyte cell line. J Pharmacol Exp Ther 1999, 289:251–260.

    PubMed  CAS  Google Scholar 

  22. 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 

  23. Al-Nalbusi I, Mach RH, Wang LM, Wallen CA, Keng PC, Sten K, Childers SR, Wheeler KT. Effect of ploidy, recruitment, environmental factors, and tamoxifen treatment on the expression of sigma-2 receptors in proliferating and quiescent tumor cells. British J Cancer 1999, 81:925–933.

    Article  Google Scholar 

  24. Wheeler KT, Wang LM, Wallen CA, Childers SR, Cline JM, Keng PC, Mach RH. Sigma-2 receptors as a biomarker of proliferation in solid tumors. Br J Cancer 2000, 82:1223–1232.

    Article  PubMed  CAS  Google Scholar 

  25. Vilner BJ, de Costa BR, Bowen WD. Cytotoxic effects of sigma ligands: Sigma receptor-mediated alterations in cellular morphology and viability. J Neurosci 1995, 15:117–134.

    PubMed  CAS  Google Scholar 

  26. de Costa BR, Radesca L, Di Paolo L, Bowen WD. Synthesis, characterization and biological evaluation of a novel class of N-(arylethy1)-N-alkyl-2-(1-pyrrolidinyl)ethylamines: Structural requirements and binding affinity at the sigma receptor. J Med Chem 1992, 35:38–47.

    Article  PubMed  Google Scholar 

  27. Bowen WD, Walker JM, de Costa BR, Wu R, Tolentino PJ, Finn D, Rothman RB, Rice KC. Characterization of the enantiomers of cis-N-[2-(3,4-dichlorophenyl)ethyl]-Nmethyl-2-(1-pyrrolidinyl)cyclohexylamine (BD737 and BD738): Novel compounds with high affinity, selectivity, and biological efficacy at sigma receptors. J Pharmacol Exp Ther 1992, 262:32–40.

    PubMed  CAS  Google Scholar 

  28. Vilner BJ, Bowen WD. Sigma-2 receptor agonists induce apoptosis in rat cerebellar granule cells and human SK-N-SH neuroblastoma cells. Soc Neurosci Abst 1997, 23:2319, #905.6.

    Google Scholar 

  29. Bowen WD, Vilner BJ, Williams W, Bandarage UK, Kuehne ME. Novel ibogaine analogs as selective sigma-2 receptor probes: Ligand binding and functional assays. Soc Neurosci Abst 1997, 23:2319, #905.7.

    Google Scholar 

  30. Bowen WD. Sigma receptors and iboga alkaloids. Alkaloids Chem Biol 2001, 56:173–191.

    PubMed  CAS  Google Scholar 

  31. Bertha CM, Vilner BJ, Mattson MV, Bowen WD, Becketts K, Xu H, Rothman RB, Flippen-Anderson JL, Rice KC. (E)-8 Benzylidene derivatives of 2-methyl-5-(3-hydroxypheny1)morphans: Highly selective ligands for the sigma-2 receptor subtype. J Med Chem 1995, 38:4776–4785.

    Article  PubMed  CAS  Google Scholar 

  32. Bowen WD. Bertha CM Vilner BJ, Rice KC. CB-64D and CB-184: Ligands with high sigma-2 receptor affinity and subtype selectivity. Eur J Pharmacol 1995, 278:257–260.

    Article  PubMed  CAS  Google Scholar 

  33. 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 

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

    Article  PubMed  CAS  Google Scholar 

  35. Brent PJ, Pang G, Little G, Dosen PJ, Van Helden F. The sigma receptor ligand, reduced haloperidol, induces apoptosis and increases intracellular-free calcium levels [ca2+li in colon and mammary adenocarcinoma cells. Biochem Biophys Res Commun 1996, 219:219–226.

    Article  PubMed  CAS  Google Scholar 

  36. Casellas P, Galiegue S, Bourrrie B, Ferrini JB, Jbilo 0, Vidal H. SR31747A: a peripheral sigma ligand with potent antitumor activities. Anticancer Drugs 2004, 15:113–118.

    Article  PubMed  CAS  Google Scholar 

  37. Renaudo A, Watry V, Chassot AA, Ponzio G, Ehrenfeld J, Soriani 0. Inhibition of tumor cell proliferation by sigma ligands is associated with K+ channel inhibition and p27kip1 accumulation. J Pharmacol Exp Ther 2004, 311:1105–1114.

    Article  PubMed  CAS  Google Scholar 

  38. Colabufo NA, Berardi F, Contino M, Niso M, Abate C, Perrone R, Tortorella V. Antiproliferative and cytotoxic effects of some sigmaz agonists and sigma, antagonists in tumor cell lines. Naunyn Schmiedeberg Arch Pharmacol2004, 370: 106–113.

    Article  CAS  Google Scholar 

  39. Spruce BA, Campbell LA, McTavish N, Cooper MA, Appleyard MV, O’Neill M, Howie J, Samson J, Watt S, Murray K, McLean D, Leslie NR, Safrany ST, Ferguson MJ, Peters JA, Prescott AR, Box G, Hayes A, Nutley B, Raynaud F, Downes CP, Lambert JJ, Thompson AM, Eccles S. Small molecule antagonists of the sigma-1 receptor cause selective release of the death program in tumor and self-reliant cells and inhibit tumor growth in vitro and in vivo. Cancer Res 2004, 64:4875–4886.

    Article  PubMed  CAS  Google Scholar 

  40. Aydar E, Palmer CP, Djamgoz MB. Sigma receptors and cancer: possible involvement of ion channels. Cancer Res 2004, 645029–5035.

    Article  PubMed  CAS  Google Scholar 

  41. Berridge MJ, Bootman MD Lipp P. Calcium-a life and death signal. Nature 1998, 395:645–648.

    Article  PubMed  CAS  Google Scholar 

  42. McConkey DJ, Orrenius S. The role of calcium in the regulation of apoptosis. J Leuk Biol 1996, 59:775–783.

    CAS  Google Scholar 

  43. Khal CR, Means AR. Regulation of cell cycle progression by calciurn/calmodulindependent pathways. Endocrine Rev 2003, 24:719–736.

    Article  CAS  Google Scholar 

  44. Demaurex N, Distelhorst C. Apoptosis-the calcium connection. Science 2003, 300:65–67.

    Article  PubMed  CAS  Google Scholar 

  45. Vilner BJ, Bowen WD. Modulation of cellular calcium by sigma-2 receptors: Release from intracellular stores in human SK-N-SH neuroblastoma cells. J Pharmacol Exp Ther 2000, 292:900–911.

    PubMed  CAS  Google Scholar 

  46. Vilner BJ, Bowen WD. Relationship of sigma-2 receptor-mediated increases in intracellular calcium to induction of morphological changes and apoptosis in human SKN-SH neuroblastoma cells. Soc Neurosci Abst 1998, 24: 1594, #627.6.

    Google Scholar 

  47. Kolesnick RN, Kronke M. Regulation of ceramide production and apoptosis. Ann Rev Physiol 1998, 60:643–665.

    Article  CAS  Google Scholar 

  48. Ogretmen B, Hannun YA. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer 2004, 4:604–616.

    Article  PubMed  CAS  Google Scholar 

  49. Obeid LM, Hannun YA. Ceramide: a stress signal and mediator of growth suppression and apoptosis. J Cell Biochem 1995, 58:191–198.

    Article  PubMed  CAS  Google Scholar 

  50. Galardi S, Kishikawa K, Kamibayashi C, Mumby MC, Hannun YA. Purification and characterization of ceramide-activated protein phosphatases. Biochem 1998. 37:11232–11238.

    Article  Google Scholar 

  51. Chalfant CE, Kishikawa K, Bielawska A, Hannun YA. Analysis of ceramide-activated protein phosphatases. Methods Enzymol2000, 312:420–428.

    Article  PubMed  CAS  Google Scholar 

  52. Zinda MJ, Vlahos CJ, Lai MT. Ceramide induces the dephosphosphorylation and inhibition of constitutively activated Akt in PTEN negative U87mg cells. Biochem Biophys Res Commun 2001, 280:1107–1115.

    Article  PubMed  CAS  Google Scholar 

  53. Ruvolo PP, Clark W, Mumby M., Gao F, May WS. A functional role for the B56 a-subunit of protein phosphatases 2A in ceramide-mediated regulation of Bc12 phosphorylation status and function. J Biol Chem 2002, 277:22847–22852.

    Article  PubMed  CAS  Google Scholar 

  54. Laethem R, Hannun Y, Jayadev S, Sexton CJ, Strum JC, Sundseth R, Smith GK. Increases in neutral, Mg2+-dependent and acidic, Mg2+-independent sphingomyelinase activities precede commitment to apoptosis and are not a consequence of caspase-3-like activity in Molt-4 cells in response to thymidylate synthase inhibition by GW1843. Blood 1998, 91:4350–4360.

    PubMed  CAS  Google Scholar 

  55. Mathiasen IS, Lademann U, Jaattela M. Apoptosis induced by vitamin D compounds in breast cancer cells is inhibited by bcl-2 but does not involve known caspases or p53. Cancer Res 1999, 59:4848–4856.

    PubMed  CAS  Google Scholar 

  56. Crawford KW, Coop A, Bowen WD. Sigma-2 receptors regulate changes in sphingolipid levels in breast tumor cells. Eur J Pharmacol2002, 443:207–209.

    Article  PubMed  CAS  Google Scholar 

  57. Bowen WD, Crawford KW, Huang S, Walker JW. Activation of sigma-2 receptors causes changes in ceramide levels in neuronal and non-neuronal cell lines. Soc Neurosci Abst 2000, 26:601, #226.11.

    Google Scholar 

  58. Bowen WD, Crawford KW, Coop A. Sigma-2 receptors may activate sphingolipidceramide N-deacylase (SCDase) as a mechanism to regulate cell growth. Soc Neurosci Abst 2001, 27:948, #364.1.

    Google Scholar 

  59. Ito M, Kurita T, Kita K. A novel enzyme that cleaves the N-acyl linkage of ceramides in various glycosphingolipids as well as sphingomyelin to produce their lyso forms. J Biol Chem 1995, 270:24370–24374.

    Article  PubMed  CAS  Google Scholar 

  60. Kita K, Kurita T, Ito M. Characterization of the reversible nature of the reaction catalyzed by sphingolipid ceramide N-deacylase: A novel form of reverse hydrolysis reaction. Eur J Biochem 2001, 268592–602.

    Article  PubMed  CAS  Google Scholar 

  61. Stoica BA, Movsesyan VA, Lea PM 4th, Faden AI. Ceramide-induced neuronal apoptosis is associated with dephosphorylation of Akt, BAD, FKHR, GSK3beta, and induction of the mitochondrial-dependent intrinsic caspase pathway. Mol Cell Neurosci 2003, 22:365–382.

    Article  PubMed  CAS  Google Scholar 

  62. Spiegel S, Culliver 0, Edsall LC, Kohama T, Menzeleev R, Olah Z, Olivera, A, Pirianov, G, Thomas DM, Tu Z, Van Brocklyn JR, Wang F. Sphingosine-I-phosphate in cell growth and cell death. Ann NY Acad Sci 1998, 845: 11–18.

    Article  PubMed  CAS  Google Scholar 

  63. Spiegel S, Milstien S. Functions of a new family of sphingosine-1-phosphate receptors. Biochim Biophys Acta 2000, 1484: 107–116.

    PubMed  CAS  Google Scholar 

  64. Myer zu Heringdorf D, van Koppen, CJ, Jakobs KH. Molecular diversity of sphingolipid signalling. FEBS Lett 1997, 410:34–38.

    Article  Google Scholar 

  65. Xu Y. Sphingosylphosphorylcholine and lysophosphatidylcholine: G protein-coupled receptors and receptor-mediated signal transduction. Biochim Biophys Acta 2002, 1582:81–88.

    PubMed  CAS  Google Scholar 

  66. Meyer zu Heringdorf D, Himmel HM, Jakobs KH. Sphingosylphosphorylcholinebiological functions and mechanisms of action. Biochim Biophys Acta 2002, 1582:178–189.

    PubMed  CAS  Google Scholar 

  67. Mao C, Kim SH, Almenoff JS, Rudner XL, Kearney DM, Kindman LA. Molecular cloning and characterization of SCaMPER, a sphingolipid Ca2+ release-mediating protein from endoplasmic reticulum. Proc Natl Acad Sci USA 1996, 93:1993–1996.

    Article  PubMed  CAS  Google Scholar 

  68. Stein WD, Bates SE, Fojo T. Intractable cancers: the many faces of multidrug resistance and the many targets it presents for therapeutic attack. Curr Drug Targets 2004, 5:333–346.

    Article  PubMed  CAS  Google Scholar 

  69. Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol 2005, 205:275–292.

    Article  PubMed  CAS  Google Scholar 

  70. Mathiasen IS, Jaattela M. Triggering caspase-independent cell death to combat cancer. Trends Mol Med 2002, 8:212–220.

    Article  PubMed  CAS  Google Scholar 

  71. Broker LE, Kruyt FA, Giaccone G. Cell death independent of caspases: a review. Clin Cancer Res 2005, 11:3155–3162.

    Article  PubMed  Google Scholar 

  72. Selivanova G. Mutant p53: the loaded gun. Curr Opin Investig Drugs 2001, 2:1136–1141.

    PubMed  CAS  Google Scholar 

  73. Gasco M, Crook T. p53 members and chemoresistance in cancer: what we know and what we need to know. Drug Resist Update 2003, 6:323–328.

    Article  CAS  Google Scholar 

  74. Ryan KM, Vousden KH. Characterization of structural p53 mutants which show selective defects in apoptosis but not cell cycle arrest. Mol Cell Biol 1998, 18:3692–3698.

    PubMed  CAS  Google Scholar 

  75. Wallace-Brodeur RR, Lowe SW. Clinical implications of p53 mutations. Cell Mol Life Sci 1999, 55:64–75.

    Article  PubMed  CAS  Google Scholar 

  76. Cohen GM. Caspases. The executioners of apoptosis. Biochem J 1997, 326:l–16.

    Google Scholar 

  77. Prokop A, Wieder T, Sturm I, Essmann F, Seeger K, Wuchter C, Ludwig WD, Henze G, Dorken B, Daniel PT. Relapse in childhood acute lymphoblastic leukemia is associated with a decrease of the BaxIBcl-2 ratio and loss of spontaneous caspase-3 processing in vivo. Leukemia 2000, 14:1606–1613.

    Article  PubMed  CAS  Google Scholar 

  78. Teitz T, Lahti JM, Kidd VJ. Aggressive childhood neuroblastomas do not express caspase-8: an important component of programmed cell death. J Mol Med 2001, 79:428–436.

    Article  PubMed  CAS  Google Scholar 

  79. Baumler C, Duan F, Onel K, Rapaport B, Jahnwar S, Offit K, Elkon KB. Differential recruitment of caspase 8 to cFlip confers sensitivity or resistance to Fas-mediated apoptosis in a subset of familial lymphoma patients. Leuk Res 2003, 27:841–851.

    Article  PubMed  CAS  Google Scholar 

  80. Linn SC, Honkoop AH, Hoekman K, van der Valk P, Pinedo HM, Giaccone G. p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer. Br J Cancer 1996, 74:63–68.

    PubMed  CAS  Google Scholar 

  81. Bowen WD, Jin B, Blann E, Vilner BJ, Lyn-Cook BD. Sigma receptor ligands modulate expression of the multidrug resistance gene in human and rodent brain tumor cell lines. Proc Am Assoc Cancer Res 1997, 38:479, #3206.

    Google Scholar 

  82. John CS, Bowen WD, Saga T, Kinuya S, Vilner BJ, Baumgold J, Paik CH, Reba RC, Neumann RD, Varma VM, McAfee JG. A malignant melanoma imaging agent: Synthesis, characterization, in vitro binding and biodistribution of iodine-125-(2-piperidinylaminoethy1)4-iodobenzamide. J Nucl Med 1993, 34:2169–2175.

    PubMed  CAS  Google Scholar 

  83. John CS, Baumgold J, Vilner BJ, McAfee JG, Bowen WD. [125I]N-(2-Piperidinylaminoethy1)4-iodobenzamide and related analogs as sigma receptor imaging agents: High affinity binding to human malignant melanoma and rat C6 glioma cell lines. J Labelled Compd Radiopharm 1994, 33:242–244.

    Google Scholar 

  84. John CS, Vilner BJ, Gulden ME, Efange SMN, Langason RB, Moody TW, Bowen WD. Synthesis and pharmacological characterization of 4-[125I]BP: A high affinity sigma receptor ligand for potential imaging of breast cancer. Cancer Res 1995, 55:3022–3027.

    PubMed  CAS  Google Scholar 

  85. 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 

  86. John CS, Gulden ME, Li JH, Bowen WD, McAfee JG, Thakur ML. Synthesis, in vitro binding, and tissue distribution of radioiodinated 2-[125I]N-(N-benzylpiperidin-4-yl)-2-iodo benzamide, 2-[125I]BP: A potential sigma receptor marker for human prostate tumors. Nucl Med Biol 1998, 25:189–194.

    Article  PubMed  CAS  Google Scholar 

  87. John CS, Bowen WD, Fisher SJ, Lim BB, Geyer BC, Vilner BJ, Wahl RL. Synthesis, in vitro pharmacologic characterization, and preclinical evaluation of N-[2-(1′-piperidinyl)ethyl]-3-[125I]iodo-4-methoxybenzamide (P[125I]MBA) for imaging breast cancer. Nucl Med Biol 1999, 26:377–382.

    Article  PubMed  CAS  Google Scholar 

  88. John CS, Vilner BJ, Geyer BC, Moody T, Bowen WD. Targeting sigma receptorbinding benzamides as in vivo diagnostic and therapeutic agents for human prostate tumors. Cancer Res 1999, 59:4578–4583.

    PubMed  CAS  Google Scholar 

  89. John CS, Gulden ME, Vilner BJ, Bowen WD. Synthesis, in vitro validation and in vivo pharmacokinetics of [125I]N-[2-(4-iodophenyl)ethyl]-N-methyl-2-(lpiperidiny1) ethylamine: A high affinity ligand for imaging sigma receptor positive tumors. Nucl Med Biol 1996, 23:761–766.

    Article  PubMed  CAS  Google Scholar 

  90. John CS, Lim BB, Vilner BJ, Bowen WD. Substituted N-(9-benzy1)-N-methyl-2-(1′-piperidiny1)ethylamine (BME) and its analogs as new sigma receptor markers: Synthesis, characterization, and in vivo evaluation. J Labelled Compd Radiopharm 1999, 42(Suppl 1):S411–S413.

    Google Scholar 

  91. Van Waarde A, Buursma AR, Hospers GA, Kawamura K., Kobayashi T, Ishii K, Oda K, Ishiwata K, Vaalburg W, Elsinga PH. Tumor imaging with two sigma receptor ligands, 18F-FE-SA5845 and 11C-SA4503: a feasibility study. J Nucl Med 2004, 45:1939–1945.

    PubMed  Google Scholar 

  92. John CS, Lim BB, Vilner BJ, Geyer BC, Bowen WD. Substituted halogenated arylsulfonamides: A new class of sigma receptor binding tumor imaging agents. J Med Chem 1998, 41:2445–2450.

    Article  PubMed  CAS  Google Scholar 

  93. John CS, Lim BB, Geyer BC, Vilner BJ, Bowen WD. 99mTc-Labeled sigma-receptorbinding complex: Synthesis, characterization, and specific binding to human ductal breast carcinoma (T47D) cells. Bioconjugate Chem 1997, 8:304–309.

    Article  CAS  Google Scholar 

  94. Caveliers V, Everaert H, John CS, Lahoutte T, Bossuyt A. Sigma receptor scintigraphy with N-[2-(l′-piperidinyl)ethyl]-3-(123)I-iodo-4-methoxybenzamide of patients with suspected primary breast cancer: first clinical results. J Nucl Med 2002, 43:1647–1649.

    PubMed  CAS  Google Scholar 

  95. Michelot JM, Moreau MF, Veyre AJ, Bonafous JF, Bacin FJ, Madelmont JC, Bussiere F, Souteyrand PA, Mauclaire LP, Chossat FM, et al. Phase II scintigraphic clinical trial of malignant melanoma and metastases with iodine-123-N-(2-diethylaminoethyl 4-iodobenzamide). J Nucl Med 1993, 34: 1260–1266.

    PubMed  CAS  Google Scholar 

  96. Nicholl C, Mohammed A, Hull WE, Bubeck B, Eisenhut M. Pharmacokinetics of iodine-123-IMBA for melanoma imaging. J Nucl Med 1997, 38:127–133.

    PubMed  CAS  Google Scholar 

  97. Mach RH, Huang Y, Buchheimer N, Kuhner R, Wu L, Morton TE, Wang L, Ehrenkaufer RL, Wallen CA, Wheeler KT. [18F]N-(4′-fluorobenzyl)-4-(3-bromophenyl) acetamide for imaging the sigma receptor staus of tumors: comparison with [18F]FDG and [125I]IUDR. Nucl Med Biol2001, 28:451–458.

    Article  PubMed  CAS  Google Scholar 

  98. Choi SR, Yang B, Plossl K, Chumpradit S, Wey SP, Acton PD, Wheeler K, Mach RH, Kung HF. Development of a Tc-99m labeled sigma-2 receptor-specific ligand as a potential breast tumor imaging agent. Nucl Med Biol2001, 28:657–666.

    Article  PubMed  CAS  Google Scholar 

  99. Mach RH, Huang Y, Freeman RA, Wu L, Vangveravong S, Luedtke RR. Conformationally-flexible benzarnide analogues as dopamine Dj and sigma2 receptor ligands. Bioorg Med Chem Lett 2004, 14:195–202.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Molecular Pharmacology, Physiology & Biotechnology, Division of Biology and Medicine, Brown University, Providence, RI 02912, USA

    Dr. Wayne D. Bowen

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  1. National Institute on Drug Abuse, Bethesda, MD

    Tsung-Ping Su

  2. University of Mississippi, University, MS

    Rae R. Matsumoto

  3. Brown University, Providence, RI

    Wayne D. Bowen

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Bowen, W.D. (2007). σ2 Receptors: Regulation of Cell Growth and Implications for Cancer Diagnosis and Therapeutics. In: Su, TP., Matsumoto, R.R., Bowen, W.D. (eds) Sigma Receptors. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-36514-5_11

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