Skip to main content
Log in

Preliminary studies of 99mTc-PQQ-NMDAR binding and effect of specificity binding by mannitol

  • Published:
Journal of Radioanalytical and Nuclear Chemistry Aims and scope Submit manuscript

Abstract

Pyrroloquinoline quinone (PQQ) is a powerful neuroprotectant that specifically binds to brain NMDA receptors and inhibits excitotoxicity. Imaging this binding reaction in the brain remains a long sought goal in this field of study, and one of the primary challenges remaining is enabling soluble labeled PQQ to pass the blood–brain barrier (BBB). Previously, our group successfully labeled PQQ with Technetium-99m (99mTc), a metastable nuclear isomer used in radioactive isotope medical tests. In this work, we determined the specific binding of 99mTc-PQQ and NMDAR by radioligand receptor assay. Ebselen (EB) and MK-801 both effectively inhibited 99mTc-PQQ binding. We then investigated methods of opening the BBB using mannitol to enable entry to the brain by 99mTc-PQQ. Our results showed that 7.5 mL/kg of 20 % mannitol effectively opened the BBB and 20 min was the optimum treatment time. Competition studies showed that mannitol did not affect the specific binding between 99mTc-PQQ and NMDA receptors. Using this method, the amount of 99mTc-PQQ uptake and retention was increased most significantly in the hippocampus and cortex, and re-opening the BBB did not affect binding. Together, our results demonstrate that the use of mannitol to open the BBB may contribute significantly to improving image quality by increasing the uptake amount of a water-soluble agent in brain.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Stites TE, Mitchell AE, Rucker RB (2000) Physiological importance of quinoenzymes and the O-quinone family of cofactors. J Nutr 130:719–727

    CAS  Google Scholar 

  2. McIntire WS (1998) Newly discovered redox cofactors: possible nutritional, medical, and pharmacological relevance to higher animals. Annu Rev Nutr 18:145–177

    Article  CAS  Google Scholar 

  3. Davidson VL (2001) Pyrroloquinoline quinone (PQQ) from methanol dehydrogenase and tryptophan tryptophylquinone (TTQ) from methylamine dehydrogenase. Adv Protein Chem 58:95–140

    Article  CAS  Google Scholar 

  4. Anthony C (2001) Pyrroloquinoline quinone (PQQ) and quinoprotein enzymes. Antioxid Redox Signal 3:757–774

    Article  CAS  Google Scholar 

  5. Zhang P, Xu YP, Sun JX et al (2009) Protection of pyrroloquinoline quinone against methylmercury-induced neurotoxicity via reducing oxidative stress. Free Radical Res 43(3):224–233

    Article  CAS  Google Scholar 

  6. Rucker R, Chowanadisai W, Nakano M (2009) Potential physiological importance of pyrroloquinoline quinone. Altern Med Rev 14(3):268–277

    Google Scholar 

  7. Ganapathy PS, White RE, Ha Y et al (2011) The role of N-methyl-d-aspartate receptor activation in homocysteine-induced death of retinal ganglion cells. Invest Ophthalmol Vis Sci 52(8):5515–5524

    Article  CAS  Google Scholar 

  8. Ohnuma T, Arai H (2011) Significance of NMDA receptor-related glutamatergic amino acid levels in peripheral blood of patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 35(1):29–39

    Article  CAS  Google Scholar 

  9. Tsai GE, Lin PY (2010) Strategies to enhance N-methyl-d-aspartate receptor-mediated neurotransmission in schizophrenia, a critical review and meta-analysis. Curr Pharm Des 16(5):522–537

    Article  CAS  Google Scholar 

  10. Yang JH, Wada A, Yoshida K et al (2010) Brain-specific Phgdh deletion reveals a pivotal role for l-serine biosynthesis in controlling the level of d-serine, an N-methyl-d-aspartate receptor co-agonist, in adult brain. J Biol Chem 285(53):41380–41390

    Article  CAS  Google Scholar 

  11. Frasca A, Aalbers M, Frigerio F et al (2011) Misplaced NMDA receptors in epileptogenesis contribute to excitotoxicity, neurobiology of disease. Neurobiol Dis 43(2):507–515

    Article  CAS  Google Scholar 

  12. Sobrio F, Gilbert G, Perrio C et al (2010) PET and SPECT imaging of the NMDA receptor system: an overview of radiotracer development. Mini Rev Med Chem 10(9):870–886

    Article  CAS  Google Scholar 

  13. Hansell C (2008) Nuclear medicine’s double hazard. Nonprolif Rev 15:185–208

    Article  Google Scholar 

  14. Eckelman WC (2009) Unparalleled contribution of technetium-99m to medicine over 5 decades. JACC Cardiovasc Imaging 2:364–368

    Article  Google Scholar 

  15. Kong YY, Zhou XQ, Cao GX et al (2010) Preparation of 99mTc-PQQ and preliminary biological evaluation for the NMDA receptor. J Radioanal Nucl Chem 286(1):93–101

    Google Scholar 

  16. Pardridge WM (2005) The blood-brain barrier: bottleneck is brain drug development. J Am Soc Exp Neuro Ther 2:3–14

    Google Scholar 

  17. Brown RC, Egleton RD, Davis TP (2004) Mannitol opening of the blood–brain barrier: regional variation in the permeability of sucrose, but not 86Rb+ or albumin. Brain Res 1014:221–227

    Article  CAS  Google Scholar 

  18. Chi OZ, Hunter C, Liu X et al (2008) Effects of VEGF on the blood-brain barrier disruption caused by hyperosmolarity. Pharmacology 82:187–192

    Article  CAS  Google Scholar 

  19. Reynolds IJ, Sharma TA (1999) The use of ligand binding in assays of NMDA receptor function. Methods Mol Biol 128:93–102

    CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (30770602) and the Natural Science Foundation of Jiangsu Province, China (BK2010157, BK2011167).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xingqin Zhou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhou, X., Kong, Y., Cao, G. et al. Preliminary studies of 99mTc-PQQ-NMDAR binding and effect of specificity binding by mannitol. J Radioanal Nucl Chem 295, 335–343 (2013). https://doi.org/10.1007/s10967-012-1860-5

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10967-012-1860-5

Keywords

Navigation