Preparation of 123-iodine labeled glucosamine derivative and investigation of its biological properties

Search and synthesis of glucose derivatives for nuclear medicine is of great current interest. Being a promising analogue of glucose, D-glucosamine iodine labeled glucose derivatives can be applied in rheumatoid arthritis radionuclide diagnostics and therapy as a radiopharmaceutical.

The purpose of the study. Synthesis of a new iodine labeled D-glucosamine derivative; development of the iodine-123 labeling method and the obtained glucose derivative biostudy.

Materials and methods. Synthesis of 2-N-(6-iodohexanoyl)-D-glucosamine was carried out through established techniques in organic chemistry. Infrared spectroscopy and nuclear magnetic resonance spectroscopy were used to establish the test compound structure. Isotope change between iodine-127 and iodine-123 of glucosamine derivative was conducted using the heating of mix of the compound and Na123I in acetone. The radio-TLC method was applied to estimate the radiochemical purity of 2-N- (6-iod-123-hexanoyl) -D-glucosamine. The safe application and test of drug pharmacokinetic parameters study was performed on intact Wistar male rats.

Results. An original 2-N-(6-iodohexanoyl)-D-glucosamine synthesis method was proposed. According to the method, an intermediate synthesis succimide-1-yl 6-iodohexanoate was obtained by the cyclohexanone oxidative cleavage reaction. The radiochemical purity of 2-N-(6-iodo-123-hexanoyl)-D-glucosamine was more than 97%.

Conclusion. 2-N-(6-iodohexanoyl)-D-glucosamine was synthesized and iodine-123 labeled. When investigating the proposed radiopharmaceutical safety and pharmacokinetics, it was shown the drug lacks acute toxicity through intravenous injection and is excreted renally by glomerular filtration.

1. Wahl L.R. Targeting glucose transporters for tumor imaging. “Sweet” idea, “Sour” result. J. Nucl. Med. 1996; 37: 1038–1041.

2. Hamacher K., Coenen H.H., Stocklin G. Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro2-deoxy-D-glucose using aminopolyether supported nucleophilic substitution. J. Nucl. Med. 1986; 27: 235–238.

3. Krasikova R.N. Automated radiochemical technologies for providing clinical PET studies. Neuroimmunology. 2011; 9 (1-2): 4–12 (in Russ.).

4. Chernov V.I., Medvedeva A.A., Sinilkin I.G., Zelchan R.V., Bragina O.D., Skuridin V.S. Experience of developing innovative radiopharmaceuticals in Tomsk Research Institute of Oncology. Siberian Oncological Journal. 2015; Appendix 2: 45–47 (in Russ.).

5. Chernov V.I., Bragina O.D., Sinilkin I.G. et al. Radionuclide teranostic of malignancies. Vestnik rentgenologii and radiologii. 2016; 97 (5): 306–313 (in Russ.).

6. Chernov V.I., Bragina O.D., Sinilkin I.G. et al. Radioimmunotherapy: current state of the problem. Voprosi oncologii. 2016; 62 (1): 24–30 (in Russ.).

7. Yang D.J., Kim C.G., Schechter N.R., Azhdarinia A., Yu D.F., Oh C.S., Bryant J.L., Won J.J., Kim E.E., Podoloff D.A. 2-Amino-2-deoxy-glucose conjugated cobalt ferrite magnetic nanoparticle (2DG-MNP) as a targeting agent for breast cancer cells. Radiology. 2003; 226 (2): 465–473. DOI: 10.1148/radiol.2262011811.

8. Chen Y., Huang Z.W., He L., Zheng S.L., Li J.L., Qin D.L. Synthesis and evaluation of a technetium-99m-labeled diethylentriaminepentaacetate-deoxyglucose complex 99mTc-DTPA-DG as a potential imaging modality for tumors. Appl. Radiat. Isot. 2006; 64 (3): 342–347. DOI: 10.1016/j.apradiso.2005.08.004.

9. Chen X.J., Li L., Liu F., Liu B.L. Synthesis and biological evaluation of technetium-99m-labeled deoxyglucose derivatives as imaging agents for tumor. Bioorg. Med. Chem. Lett. 2006; 16 (21): 5503–5505. DOI: 10.1016/j.bmcl.2006.08.050.

10. Chernov V.I., Sinilkin I.G., Choynzonov E.C., Chijevskaya S.Y., Titskaya A.A., Zelchan R.V., Bragina O.D., Lyapunov AY, Skuridin VS. Comparative evaluation of 99mTc-Al2O3 and 99mTc-fitat nanocolloids for sentinel lymph nodes visualization in patients with cancer of larynx and hypopharynx. Eur. J. Nucl. Med. Mol. I. 2015; 42: 704.

11. Skuridin V., Golovkov V., Garapatskiy A., Semenov A., Makarova E., Varlamova N., Minin S., Chernov V., Lishmanov Y. Development on complex radiopharmaceuticals by 123I for radionuclide diagnosis of metabolic disorders and dysfunction of the myocardial autonomic nervous system. European journal of nuclear medicine and molecular imaging. Annual Congress of the European-Association-of-Nuclear-Medicine (EANM). Gothenburg, Sweden: Oct. 18–22, 2014, 41: 430.

12. Gambini J.P., Cabral P., Alonso O., Savio D., Figueroa S.D., Zhang X., Ma L., Deutscher L., Quinnd T.P. Evaluation of 99mTc-glucarate as a breast cancer imaging agent in a xenograft animal model. Nucl. Med. Biol. 2011; 38 (2): 255–260. DOI: 10.1016/j.nucmedbio.2010.08.002.

13. Nadeem Q., Khan I.U., Javed M., Mahmood Z., Dar U.K., Ali M., Hyder S.W., Murad S. Synthesis, characterization and bioevaluation of technetium-99m labeled N-(2Hydroxybenzyl)-2-amino-2-deoxy-D-glucose as a tumor imaging agent. Pak. J. Pharm. Sci. 2013; 26 (2): 353–357.

14. Schechter N.R., Erwin W.D., Yang D.J., Kim E.E., Munden R.F., Forster K.; Taing L.C., Cox J.D., Macapinlac H.A., Podoloff D.A. Radiation dosimetry and biodistribution of 99m Tc-ethylene dicysteine-deoxyglucose in patients with non-small-cell lung cancer. Eur. J. Nucl. Med. Mol. I. 2009; 36 (10): 1583–1591. DOI: 10.1007/s00259-009-1135-8.

15. Yang D., Yukihiro M., Yu D.F., Ito M., Oh C.S., Kohanim S., Azhdarinia A., Kim C.G., Bryant J., Kim E.E., Podoloff D. Assessment of Therapeutic Tumor Response Using 99mTc-Ethylenedicysteine-Glucosamine. Cancer Biother. Radio. 2004; 19 (4): 443–456. DOI: 10.1089/ cbr.2004.19.443.

16. Semenov A.S., Skuridin V.S. Obtaining radionuclide labeled glucose derivatives for diagnosis in oncology. Bulletin of the Tomsk Polytechnic University. Physics. 2013; 56 (4/2): 264–267 (in Russ.).

17. McAlindon T.E., LaValley M.P., Gulin J.P., Felson D.T. Glucosamine and chondroitin for the treatment of osteoarthrosis – A systematic quality assessment and meta-analysis. Journal of the American Medical Association. 2000; 283 (11): 1469–1475. DOI: 10.1001/jama.283.11.1469.

18. Adam M.J., Fisher C.L., Orvig C., Ewart C., Patrick B.O. Cyclopentadienyltricarbonyl rhenium(I) and technetium(I) complexes containing pendant glucose derivatives. J. Labelled Compd. Rad. 2005; 48: 236.

19. Ardestani M.S., Arabzadeh A.J., Heidari Z., Hosseinzadeh A., Ebrahimi H., Hashemi E., Mosayebnia M., Shafiee-Alavidjeh M., Alavi A., Babaei M.H., Rahmim A., Ebrahimi S.E.S., Amanlou M. Novel and facile methods for the synthesis of DTPA-mono-amide: a new completely revised strategy in radiopharmaceutical chemistry. J. Radioanal. Nucl. Ch. 2010; 283 (2): 447–455. DOI: 10.1007/s10967-009-0414-y.

20. Liu L.Q., Zhao M.C., Wang Z., Qin Y.Y., Wang X.B. Synthesis and biological evaluation of novel technetium-99m-labeled HYNIC-D-glucose as a potential tumor imaging agent. J. Radioanal. Nucl. Ch. 2014; 301 (3): 731–737. DOI: 10.1007/s10967-014-3207-x.

21. Wang Y., Zhu J.J., Song X.Q., Wang X.B., Yang J.G., Zhang J.B. Synthesis and evaluation of 99mTc–2-[(3-carboxy-1oxopropyl)amino]-2-deoxy-D-glucose as a potential tumor imaging agent. Bioorg. Med. Chem. Lett. 2014; 24 (16): 3882–3885. DOI: 10.1016/j.bmcl.2014.06.051.

22. Lin X., Chao X.Y., Zhang J.B., Jin Z.H., Zhang Y.Y. Preparation and biodistribution of a 99mTc tricarbonyl complex with deoxyglucose dithiocarbamate as a tumor imaging agent for SPECT. Bioorg. Med. Chem. Lett. 2014; 24 (16): 3964–3967. DOI: 10.1016/j.bmcl.2014.06.037.

23. Yusubov M.S., Zdan- kin V.V., Larkina M.S. et al. Method of producing omega-iodo-aliphatic carboxylic acids and esters thereof. Patent № 2494087. 2013; 27.09.2013 (in Russ.).

24. Codina G.E., Bogorodskaya G.E. Chemical engineering radiopharmaceuticals: a manual. M.: FGU center named after them. A.I. Burnazyan of FMBA of Russia, 2010, 392 (in Russ.).

25. Skuridin V.S. Methods and technologies for obtaining radiopharmaceuticals: textbook. Tomsk: Publishing house of Tomsk Polytechnic University. 2007, 47 (in Russ.).