An optimized formulation for [99mTc]Tc radiolabeling of zoledronic acid as bone imaging agent

Document Type : Original Article

Authors

1 Faculty of Energy Engineering and Physics, Amirkabir University of Technology, Tehran, Iran

2 Radiation Applications Research School, Nuclear Science and Technology Research Institute, Tehran, Iran

Abstract

Introduction: The aim of this study was to develop an optimized formulation for labeling a third-generation bisphosphonate, zoledronic acid with [99mTc] Tc to achieve the best formulation in preparing an ideal skeletal radiotracer.  Radio-complex yield and purity, stability, biodistribution and imaging in normal rat were investigated.  
Methods: The samples containing different amounts of zoledronic acid, ascorbic acid and stannous chloride were prepared and labeled with [99mTc]technetium pertechnetate. TLC methods were used to determine the radiochemical purity. The stability was determined in saline and human serum solutions. Lipophilicity was calculated by measuring radio-complex that was divided between organic and aqueous phases. In vitro bone affinity was studied through hydroxyapatite binding assays. Considering the decomposition of radioactivity, biodistribution of radio-complex was assessed based on the percentage of injected activity per gram of organ (% IA/g).
Results: [99mTc]Tc-zoledronic acid was prepared easily with high yield while 100 µg, 0.34 µmol of zoledronic acid as a ligand and 100 µg, 0.44 µmol SnCl2 as a reducing agent were used. Radiochemical purity of radio-complex was more than 99% with specific activity of 8050 MBq/µmol. The radio-complex showed rapid blood washout along with high bone uptake value (4.53 ± 0.14 % IA/g at 2 h post injection).
Conclusion: Under optimized condition, [99mTc]Tc-zoledronic acid was prepared with high purity and stability together with high bone affinity and rapid blood clearance, make this radio-complex an ideal agent with great potential for skeletal imaging.

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References

  1. Jung A, Bisaz S, Fleisch H. The binding of pyrophosphate and two diphosphonates by hydroxyapatite crystals. Calcif Tissue Res. 1973 Mar 30;11(4):269-80.
  2. Sietsema WK, Ebetino FH, Salvagno AM, Bevan JA. Antiresorptive dose-response relationships across three generations of bisphosphonates. Drugs Exp Clin Res. 1989;15(9):389-96. 
  3. Rogers MJ, Xiong X, Brown RJ, Watts DJ, Russell RG, Bayless AV, Ebetino FH. Structure-activity relationships of new heterocycle-containing bisphosphonates as inhibitors of bone resorption and as inhibitors of growth of Dictyostelium discoideum amoebae. Mol Pharmacol. 1995 Feb;47(2):398-402.
  4. Neves M, Gano L, Pereira N, Costa MC, Costa MR, Chandia M, Rosado M, Fausto R. Synthesis, characterization and biodistribution of bisphosphonates Sm-153 complexes: correlation with molecular modeling interaction studies. Nucl Med Biol. 2002 Apr;29(3):329-38.
  5. Smith MR. Osteoclast targeted therapy for prostate cancer: bisphosphonates and beyond. Urol Oncol. 2008 Jul-Aug;26(4):420-5.
  6. Reginster J, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, Lund B, Ethgen D, Pack S, Roumagnac I, Eastell R. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int. 2000;11(1):83-91.
  7. Tanabe S, Zodda JP, Deutsch E, Heineman WR. Effect of pH on the formation of Tc(NaBH4)-MDP radiopharmaceutical analogues. Int J Appl Radiat Isot. 1983 Dec;34(12):1577-84. 
  8. Meyer JL, Nancollas GH. The influence of multidentate organic phosphonates on the crystal growth of hydroxyapatite. Calcif Tissue Res. 1973 Dec 31;13(4):295-303. 
  9. Libson K, Deutsch E, Barnett BL. Structural characterization of a 99Tc-bisphosphonate complex. Implications for the chemistry of 99mTc skeletal imaging agents.  J Am Chem Soc. 1980;102(7):2476-78.
  10. Love C, Din AS, Tomas MB, Kalapparambath TP, Palestro CJ. Radionuclide bone imaging: an illustrative review. Radiographics. 2003 Mar;23(2):341-58.
  11. Asikoglu M, Durak FG. The rabbit biodistribution of a therapeutic dose of zoledronic acid labeled with Tc-99m. Appl Radiat Isot. 2009 Sep 1;67(9):1616-21.
  12. Erfani M, Tabatabaei M, Doroudi A, Shafiei M. Radiolabeling of zoledronic acid with 188Re as a new palliative agent radiotracer in treatment of bone tumors. J Radioanal Nucl Chem. 2018 May;316:491-500.
  13. Bahrami-Samani A, Anvari A, Jalilian AR, Shirvani-Arani S, Yousefnia H, Aghamiri MR, Ghannadi-Maragheh M. Production, quality control and pharmacokinetic studies of 177Lu-EDTMP for human bone pain palliation therapy trials. Iran J Pharm Res. 2012;11(1):137.
  14. Nikzad M, Jalilian AR, Shirvani-Arani S, Bahrami Samani A, Golchobian H. Development of 166Ho-zoledronate as a bone marrow ablative agent. Pharm Biomed Res. 2016 Feb 10;2(1):14-22.
  15. Qiu L, Cheng W, Lin J, Zhang S, Luo S. A novel (99m)Tc-labeled diphosphonic acid as potential bone seeking agent: synthesis and biological evaluation. Curr Radiopharm. 2013 Mar;6(1):28-35.
  16. Lin J, Qiu L, Cheng W, Luo S, Ye W. Preparation and in vivo biological investigations on a novel radioligand for bone scanning: technetium-99m-labeled zoledronic acid derivative. Nucl Med Biol. 2011 Jul;38(5):619-29.
  17. Wu C, Yang S, Sun Z, Han X, Ye Y, Liu S. Characterization of the attenuation of breast cancer bone metastasis in mice by zoledronic acid using (99m)Tc bone scintigraphy. Pathol Oncol Res. 2014 Jul;20(3):747-54.
  18. El-Demerdash FM, Yousef MI, Zoheir MA. Stannous chloride induces alterations in enzyme activities, lipid peroxidation and histopathology in male rabbit: antioxidant role of vitamin C. Food Chem Toxicol. 2005 Dec;43(12):1743-52.
  19. Yousef MI. Protective role of ascorbic acid to enhance reproductive performance of male rabbits treated with stannous chloride. Toxicology. 2005 Feb 1;207(1):81-9.

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