Abstract
σ Receptors have been detected in many tissues and are highly expressed in several tumour cell lines from various tissues. In particular, σ2 receptor subtype is considered to be a potential biomarker for rapid proliferating tumour cells. It was demonstrated that σ2 receptor agonists and σ1 receptor antagonists displayed cytotoxic effect and cell proliferation inhibition in several tumour cell lines such as neuroblastoma, glioma and sarcoma. In the last years several σ ligands have been radiolabelled for obtaining a potential radiotracer suitable in PET technique and among them [ 11 C]-PB28, our cyclohexylpiperazine derivative, [ 11 C]-SA4503, and [ 11 C]-I derivative. Recently, we synthesized PB167, a potent σ receptor ligand that bears between the tetralin nucleus and cyclohexylpiperazine moiety a spacer longer than compound PB28. Moreover, PB167 displayed low Papp (12 x 10 -6 cm/sec) and high clogP (6.19). For this purpose, EMT-6 cells (murine mammary sarcoma) have been selected and subcutaneously implanted in the nape of the neck of mice. In this work we reported both the recognition of σ receptors in EMT-6 cells and PB167 σ receptor affinity evaluation in EMT-6 cells. The biodistribution of [ 11 C]-PB167 will be reported in the next work in the future.
Highlights
The evidenced high level of expression for σ receptors in tumour cells and their involvement in cell proliferation and apoptosis encouraged the development of several σ ligands in order to obtain a molecular probe for in-vivo diagnostic imaging techniques such as Positron Emission Tomography (PET) and Single Photon Emission Computerized Tomography (SPECT).[10,11,12,13,14,15]
In order to define the presence of both σ receptor subtypes in EMT-6 cells, saturation binding analysis with radioligands have been performed
As depicted in figure 3, both σ1 and σ2 receptors have been detected in high density (Bmax = 826 ± 50 fmol/mg of protein and 740 ± 30 fmol/mg of protein, respectively)
Summary
In the last years sigma (σ) receptors have been defined as a distinct class of receptors and classified into σ1 and σ2 subtypes.[1] σ Receptors have been detected in many tissues and are highly expressed in several tumour cell lines from various tissues.[2,3] In particular, σ2 receptor subtype is considered to be a potential biomarker for rapid proliferating tumour cells.[4,5]It was demonstrated that σ2 receptor agonists and σ1 receptor antagonists displayed cytotoxic effect and cell proliferation inhibition in several tumour cell lines such as neuroblastoma, glioma and sarcoma.[6,7,8] these agents induced apoptosis with p53- and caspase-independent mechanism in breast cancer cell lines.[9]. It was demonstrated that σ2 receptor agonists and σ1 receptor antagonists displayed cytotoxic effect and cell proliferation inhibition in several tumour cell lines such as neuroblastoma, glioma Several σ ligands have been suggested as potential radiotracers for PET study but the results demonstrated that these ligands are unable to recognize σ receptors by PET and the possible explanation of these failures involves P-glycoprotein (P-gp) activity.
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