Skip to content
2000
Volume 21, Issue 6
  • ISSN: 1573-4064
  • E-ISSN: 1875-6638

Abstract

Introduction

Development of theranostics agents targeted towards particular receptors can effectively help in the management of cancer. The overexpression of the sigma-2 receptor (S2R) in tumors establishes it as a prominent biomarker for cancer cells.

Methods

Radiotheranostics rely on the design of specific molecules having versatility in applications of diagnosis and therapy by merely changing the radioisotope. We have designed a novel radiotheranostic S2R-targeted ligand using cyclohexylpiperazine and performed docking studies to narrow down the potential efficacious ligand. The potential molecule with G-score = -7.0 kcal/mol, was then synthesized using a three steps reaction including conjugation of 2-(4-cyclohexylpiperazine-1-yl)ethyl(CYX) with DTPA chelator. Subsequently, the molecule has been radiolabelled with 99mTc using stannous chloride as a reducing agent, and a radiolabellieng efficiency of 95.0 ± 0.59% for 99mTc-CYX-DTPA. As proof of concept, the molecule has been evaluated for its binding affinity and specificity using sigma receptors isolated from the liver membrane homogenates of mice. The binding affinity was found to be K = 12.84 ± 0.395 nM; B = 0.5258 ± 0.001 fmol/mg, indicating a high affinity for the receptors.

Results

In addition, the molecule was also assessed for biocompatibility using haemolysis analysis and cytotoxicity on HEK cells and MDA-MB-23, wherein the molecule showed no significant cytotoxicity up to 72 h on HEK cells and 32.42% cytotoxicity on MDA-MB-231 cells.

Conclusion

The future work will concentrate on the demonstration of targeting and site-specific accumulation of the molecule along with its suitability for theranostics applications.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/mc/10.2174/0115734064329861250122113332
2025-02-27
2025-09-02

  • From This Site

    /content/journals/mc/10.2174/0115734064329861250122113332
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. ChandiraR.M. PrabakaranM. JaykarB. VenkateswarluB.S. PalanisamyP. BRCA mutation: A review of breast cancer.J. Drug Deliv. Ther.201994750758
     [Google Scholar]
  2. FallicaA.N. PittalàV. ModicaM.N. SalernoL. RomeoG. MarrazzoA. HelalM.A. IntagliataS. Recent advances in the development of sigma receptor ligands as cytotoxic agents: A medicinal chemistry perspective.J. Med. Chem.202164127926796210.1021/acs.jmedchem.0c02265 34076441
     [Google Scholar]
  3. ShaghaghiZ. AlvandiM. GhanbarimasirZ. FarzipourS. EmamiS. Current development of sigma-2 receptor radioligands as potential tumor imaging agents.Bioorg. Chem.202111510516310.1016/j.bioorg.2021.105163 34289426
     [Google Scholar]
  4. CantoneroC. CamelloP.J. AbateC. BerardiF. SalidoG.M. RosadoJ.A. RedondoP.C. NO1, a new sigma 2 receptor/tmem97 fluorescent ligand, downregulates soce and promotes apoptosis in the triple negative breast cancer cell lines.Cancers202012225710.3390/cancers12020257 31973006
     [Google Scholar]
  5. ThejerB.M. InfantinoV. SantarsieroA. PappalardoI. AbatematteoF.S. TeakelS. Van OosterumA. MachR.H. DenoraN. LeeB.C. RestaN. BagnuloR. NisoM. ContinoM. MontschB. HeffeterP. AbateC. CahillM.A. Sigma-2 receptor ligand binding modulates association between TSPO and TMEM97.Int. J. Mol. Sci.2023247638110.3390/ijms24076381 37047353
     [Google Scholar]
  6. AbateC. NisoM. LacivitaE. MosierP.D. ToscanoA. PerroneR. Analogues of σ receptor ligand 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) with added polar functionality and reduced lipophilicity for potential use as positron emission tomography radiotracers.J. Med. Chem.20115441022103210.1021/jm1013133 21229979
     [Google Scholar]
  7. ColabufoN.A. AbateC. ContinoM. IngleseC. NisoM. BerardiF. PerroneR. PB183, a sigma receptor ligand, as a potential PET probe for the imaging of prostate adenocarcinoma.Bioorg. Med. Chem. Lett.20081861990199310.1016/j.bmcl.2008.01.109 18276137
     [Google Scholar]
  8. PatiM.L. NisoM. SpitzerD. BerardiF. ContinoM. RigantiC. HawkinsW.G. AbateC. Multifunctional thiosemicarbazones and deconstructed analogues as a strategy to study the involvement of metal chelation, Sigma-2 (σ2) receptor and P-gp protein in the cytotoxic action: In vitro and in vivo activity in pancreatic tumors.Eur. J. Med. Chem.201814435937110.1016/j.ejmech.2017.12.024 29287249
     [Google Scholar]
  9. LiuC.C. YuC.F. WangS.C. LiH.Y. LinC.M. WangH.H. AbateC. ChiangC.S. Sigma-2 receptor/TMEM97 agonist PB221 as an alternative drug for brain tumor.BMC Cancer201919147310.1186/s12885‑019‑5700‑7 31109310
     [Google Scholar]
  10. ChenX. CuiM.C. Deuther-ConradW. TuY.F. MaT. XieY. JiaB. LiY. XieF. WangX. SteinbachJ. BrustP. LiuB.L. JiaH.M. Synthesis and biological evaluation of a novel 99mTc cyclopentadienyl tricarbonyl complex ([(Cp-R)99mTc(CO)3]) for sigma-2 receptor tumor imaging.Bioorg. Med. Chem. Lett.201222206352635710.1016/j.bmcl.2012.08.083 22995625
     [Google Scholar]
  11. EberhardtJ. Santos-MartinsD. TillackA.F. ForliS. AutoDock vina 1.2.0: New docking methods, expanded force field, and python bindings.J. Chem. Inf. Model.20216183891389810.1021/acs.jcim.1c00203 34278794
     [Google Scholar]
  12. TrottO. OlsonA.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.J. Comput. Chem.201031245546110.1002/jcc.21334 19499576
     [Google Scholar]
  13. MorrisG.M. HueyR. LindstromW. SannerM.F. BelewR.K. GoodsellD.S. OlsonA.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility.J. Comput. Chem.200930162785279110.1002/jcc.21256 19399780
     [Google Scholar]
  14. AlonA. LyuJ. BrazJ.M. TumminoT.A. CraikV. O’MearaM.J. WebbC.M. RadchenkoD.S. MorozY.S. HuangX.P. LiuY. RothB.L. IrwinJ.J. BasbaumA.I. ShoichetB.K. KruseA.C. Structures of the σ2 receptor enable docking for bioactive ligand discovery.Nature2021600789075976410.1038/s41586‑021‑04175‑x 34880501
     [Google Scholar]
  15. JhaP. ChaturvediS. KaulA. PantP. AnjuA. PalS. JainN. MishraA.K. Design, physico-chemical and pre-clinical evaluation of a homo-bivalent 99m Tc-(BTZ) 2 DTPA radioligand for targeting dimeric 5-HT 1A/5-HT 7 receptors.New J. Chem.20184218150321504310.1039/C8NJ00089A
     [Google Scholar]
  16. ChaudharyV. ChaturvediS. WadhwaA. ChaudharyR. GautamD. SharmaD. KumarR. MishraA.K. Design, development and bio-evaluation of a novel radio-ligand 99mTc-THQ-DTPA as a sigma 2 receptor specific breast tumor imaging agent.Bioorg. Med. Chem.20249711751510.1016/j.bmc.2023.117515 38043245
     [Google Scholar]
  17. Anju; Chaturvedi, S.; Chaudhary, V.; Pant, P.; Jha, P.; Kumaran, S.S.; Hussain, F.; Kumar Mishra, A. 5-HT1A targeting PARCEST agent DO3AM-MPP with potential for receptor imaging: Synthesis, physico-chemical and MR studies.Bioorg. Chem.202110610448710.1016/j.bioorg.2020.104487 33339667
     [Google Scholar]
/content/journals/mc/10.2174/0115734064329861250122113332
Loading
A Step Towards Development and Bio-evaluation of a Novel Radio-ligand 99mTc-CYX-DTPA Targeting Sigma 2 Receptors
Med. Chem. 21, 582 (2025); https://doi.org/10.2174/0115734064329861250122113332
/content/journals/mc/10.2174/0115734064329861250122113332
/content/journals/mc/10.2174/0115734064329861250122113332
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher's website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): 2-(4-cyclohexylpiperazine-1-yl)ethyl; diethylenetriaminepentaacetic; haemolysis analysis; HEK cells; MDA-MB-231; Sigma-2 receptor; SPECT Imaging

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test