Preparation and biological study of 68Ga-DOTA-alendronate

Document Type : Original Article


1 Tehran University of Medical Sciences, Faculty of Pharmacy, Tehran, Iran

2 Nuclear Science and Technology Research Institute (NSTRI), Tehran, Iran


Objective(s): In line with previous research on the development of conjugated bisphosphonate ligands as new bone-avid agents, in this study, DOTA conjugated alendronate (DOTA-ALN) was synthesized and evaluated after labeling with gallium-68 (68Ga).
Methods: DOTA-ALN was synthesized and characterized, followed by 68Ga-DOTA-ALN preparation, using DOTA-ALN and 68GaCl3 (pH: 4-5) at 92-95°C for 10 min. Stability tests, hydroxyapatite assay, partition coefficient calculation,
biodistribution studies, and imaging were performed on the developed agent in normal rats.
Results: The complex was prepared with high radiochemical purity (>99% as depicted by radio thin-layer chromatography; specific activity: 310-320GBq/mmol) after solid phase purification and was stabilized for up to 90 min with a logP value of -2.91. Maximum ligand binding (65%) was observed in the presence of 50 mg of hydroxyapatite; a major portion of the activity was excreted through the kidneys. With the exception of excretory organs, gastrointestinal tract organs, including the liver, intestine, and colon, showed significant uptake; however, the bone uptake was low (<1%) at 30 min after
the injection. The data were also confirmed by sequential imaging at 30-90 min following the intravenous injection.
Conclusion: The high solubility and anionic properties of the complex led to major renal excretion and low hydroxyapatite uptake; therefore, the complex failed to demonstrate bone imaging behaviors.


Main Subjects

1. Sudbrock F, Fischer T, Zimmermann B, Guliyev M, Dietlein M, Drezezga A, et al. Characterization of SnO2-based (68)Ge/ (68)Ga generators and (68) Ga-DOTATATE preparations: radionuclide purity, radiochemical yield and long-term constancy. EJNMMI Res. 2014;4(1):36.
2. Velikyan I. Prospective of 68Ga-radiopharmaceutical development. Theranostics. 2013;4(1):47–80.
3. Fazaeli Y, Jalilian AR, Amini MM, Ardaneh K, Rahiminejad A, Bolourinovin F, et al. Development of (68)Ga-fluorinated porphyrin complex as a possible PET imaging agent. Nucl Med Mol Imaging. 2012;46(1):20–6.
4. Bayouth JE, Macey DJ, Kasi LP, Fossella FV. Dosimetry and toxicity of samarium-153-EDTMP administered for bone pain due to skeletal metastases. J Nucl Med. 1994;35(1):63–9.
5. Mitterhauser M, Toegel S, Wadsak W, Lanzenberger RR, Mien LK, Kuntner C, et al. Pre vivo, ex vivo and in vivo evaluations of [68Ga]-EDTMP. Nucl Med Biol. 2007;34(4):391–7.
6. Mirzaei A, Jalilian AR, Badbarin A, Mazidi M, Mirshojaei F, Geramifar P, et al. Optimized production and quality control of (68)Ga-EDTMP for small clinical trials. Ann Nucl Med. 2015;29(6):506–11.
7. Fellner M, Biesalski B, Bausbacher N, Kubicek V, Hermann P, Rösch F, et al. (68)Ga-BPAMD: PET-imaging of bone metastases with generator based positron emitter. Nucl Med Biol. 2012;39(7):993–9.
8. Chadha N, Sinha D, Anjani K, Tiwari AK, Chuttani K. Mishra AK. synthesis, biological evaluation and molecular docking studies of high-affinity bone targeting N,N’-Bis (alendronate) diethylenetriamene‐N, N’-triacetic acid: a bifunctional bone scintigraphy. agent. Chem Biol Drug Des. 2013;82(4):468–76.
9. Fakhari A, Jalilian AR, Yousefnia H, Shafiee- Ardestani M, Johari-Daha F, Mazidi M, et al. Development of radiolanthanide-labeled-Bis- alendronate complexes for bone pain palliation therapy. Austin J Nucl Med Radiother. 2015;2(1):1012-9.
10. Fakhari A, Jalilian AR, Ardestani MS, Deha FJ, Mirzaie M, Moradkhan S, et al. Radiosynthesis and Animal Studies of 111In-DTPA-bis-alendronate Complex. Front Biomed Technol. 2015;2(3):163-71.
11. Nikzad M, Jalilian AR, Shirvani-Arani S, Bahrami- Samani A, Golchoubian H. Production, quality control and pharmacokinetic studies of 177Lu-zoledronate for bone pain palliation therapy. J Radioanal Nucl Chem. 2013;298(2):1273–81.
12. Breeman WA, de Jong M, de Blois E, Bernard BF, Konijnenberg M, Krenning EP. Radiolabelling DOTA-peptides with 68Ga. Eur J Nucl Med Mol Imaging. 2005;32(4):478–85.