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Characterization and evaluation of two novel fluorescent sigma-2 receptor ligands as proliferation probes.

Abstract
We synthesized and characterized two novel fluorescent sigma-2 receptor selective ligands, SW120 and SW116, and evaluated these ligands as potential probes for imaging cell proliferation. Both ligands are highly selective for sigma-2 receptors versus sigma-1 receptors. SW120 and SW116 were internalized into MDA-MB-435 cells, and 50% of the maximum fluorescent intensity was reached in 11 and 24 minutes, respectively. In vitro studies showed that 50% of SW120 or SW116 washed out of cells in 1 hour. The internalization of SW120 was reduced ≈30% by phenylarsine oxide, an inhibitor of endocytosis, suggesting that sigma-2 ligands are internalized, in part, by an endocytotic pathway. Subcellular localization studies using confocal and two-photon microscopy showed that SW120 and SW116 partially colocalized with fluorescent markers of mitochondria, endoplasmic reticulum, lysosomes, and the plasma membrane, suggesting that sigma-2 receptors localized to the cytoplasmic organelles and plasma membrane. SW120 did not colocalize with the nuclear dye 4',6-diamidino-2-phenylindole. In vivo studies showed that the uptake of SW120 in solid tumors and peripheral blood mononuclear cells of mice positively correlated with the expression level of the cell proliferation marker Ki-67, suggesting that sigma-2 fluorescent probes may be used to image cell proliferation in mice.
AuthorsChenbo Zeng, Suwanna Vangveravong, Lynne A Jones, Krzysztof Hyrc, Katherine C Chang, Jinbin Xu, Justin M Rothfuss, Mark P Goldberg, Richard S Hotchkiss, Robert H Mach
JournalMolecular imaging (Mol Imaging) Vol. 10 Issue 6 Pg. 420-33 (Dec 2011) ISSN: 1536-0121 [Electronic] England
PMID22201533 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Fluorescent Dyes
  • Ligands
  • Receptors, sigma
  • sigma-2 receptor
Topics
  • Animals
  • Cell Growth Processes (physiology)
  • Cell Line, Tumor
  • Cell Tracking (methods)
  • Female
  • Fluorescent Dyes (chemistry, pharmacokinetics)
  • Humans
  • Leukocytes, Mononuclear (metabolism)
  • Ligands
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Microscopy, Fluorescence, Multiphoton
  • Molecular Probe Techniques
  • Neoplasms, Experimental (metabolism)
  • Receptors, sigma (metabolism)

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