Journal of Nuclear Science, Engineering and Technology (JONSAT)
In cooperation with the Iranian Nuclear Society

Synthesis and evaluation of zoledronate acid derivative labeled by 68Ga for PET diagnosis of bone diseases

Document Type : Research Paper

Authors

Y. Noshadi 1
E. Sattarzadeh Khameneh 2
S.M. Aghamiri 3
S. Kakaei 2
H. Yousefnia 2

1 Radiation Application Department, Shahid Beheshti University, P.O. Box: 1983963113, Tehran -Iran

2 Radiation Application Research School, Nuclear Science and Technology Research Institute, P. O. Box 11365-3486, Tehran - Iran

3 Radiation Application Department, Shahid Beheshti University, P.O. Box: 1983963113, Tehran - Iran

https://doi.org/10.24200/nst.2022.1468
Abstract
Bone metastases are one of the main consequences of some cancers, such as breast, lung and prostate cancers, which are accompanied by severe pain in the bone area. Gallium-68 radioisotope with a half-life of 68 minutes is one of the most suitable options in Positron emission tomography (PET) is used in nuclear medicine. In this study, one of the zoledronic acid derivatives was synthesized as a bone-seeking agent and then attached to the DOTA chelator. The DOTA-ZOL compound was finally used for 68Ga labeling. All synthesized products were identified by FT-IR, NMR and MASS spectroscopies. The radionuclide purity of gallium-68 was calibrated by HPGe detector and determined with a multi-channel analyzer (99.9%). The radiochemical purity of the generator wash solution was investigated by thin layer chromatography using two different solutions (100%). Labeling of the prepared complex with 68Ga was performed by DOTA chelator and the radiochemical purity of the final complex at the optimized conditions (pH=4, temperature 98ºC, reaction time: 30 min) was examined by thin layer chromatography technique and determined about 97%. The results of this study showed that 68Ga-DOTA-ZOL is a suitable diagnostic radiopharmaceutical for imaging bone metastases by PET method.

Highlights

  1. A. Kuźnik, et al., Bisphosphonates—much more than only drugs for bone diseases, Eur. J. Pharmacol., 866, 172773 (2020).

 

  1. M. YangandX. Yu, Management of bone metastasis with intravenous bisphosphonates in breast cancer: a systematic review and meta-analysis of dosing frequency, Support. Care. Cancer., 28, 2533 (2020).

 

  1. K.B. Farrell, et al., Bisphosphonate conjugation for bone specific drug targeting, Bone. Rep., 9, 47 (2018).

 

  1. R.G.G. Russell, Bisphosphonates: from bench to bedside, Ann. N. Y. Acad. Sci., 1068, 367 (2006).

 

  1. A.J. Roelofs, et al., Bisphosphonates: molecular mechanisms of action and effects on bone cells, monocytes and macrophages, Curr. Pharm. Des., 16, 2950 (2010).

 

  1. B.J. Edwards, et al., Pharmacovigilance and reporting oversight in US FDA fast-track process: bisphosphonates and osteonecrosis of the jaw, Lancet. Oncol., 9, 1166 (2008).

 

  1. D. Heymann, et al., Bisphosphonates: new therapeutic agents for the treatment of bone tumors, Trends. Mol. Med., 10, 337 (2004).

 

  1. N. Ponte Fernández, R. Estefanía Fresco, J.M. Aguirre Urízar, Bisphosphonates and oral pathology I: general and preventive aspects, Med Oral Patol Oral Cir Bucal., 1, E396 (2006).

 

  1. Z. Mbese, B.A. Aderibigbe, Bisphosphonate-Based Conjugates and Derivatives as Potential Therapeutic Agents in Osteoporosis, Bone Cancer and Metastatic Bone Cancer, Int. J. Mol. Sci., 22, 6869 (2021).

 

  1. D. Isla, et al., Zoledronic acid in lung cancer with bone metastases: a review, Expert. Rev. Anticancer. Ther., 13, 421 (2013).

 

  1. R. Coleman, et al., Zoledronic acid use in cancer patients: more than just supportive care?, Cancer., 117, 11 (2011).

 

  1. N. Pfannkuchen, et al., In vivo evaluation of [225Ac]Ac-DOTAZOL for α-therapy of bone metastases, Curr. Radiopharm., 11, 223 (2018).

 

  1. M. Farhanghi, et al., Samarium-153-EDTMP: pharmacokinetic, toxicity and pain response using an escalating dose schedule in treatment of metastatic bone cancer, J. Nucl. Med., 33, 1451 (1992).

 

  1. M.P. Yadav, et al., [177 Lu] Lu-DOTA-ZOL bone pain palliation in patients with skeletal metastases from various cancers: efficacy and safety results, EJNMMI Res., 10, 1 (2020).

 

  1. I. Velikyan, Prospective of 68Ga-radio-pharmaceutical development, Theranostics., 4, 47 (2014).

 

  1. G. Bandoli, et al., Mononuclear six-coordinated Ga (III) complexes: A comprehensive survey, Coord. Chem. Rev., 253, 56 (2009).

 

  1. S. Kakaei, E.S. Khameneh, An efficient and simple ultrasound-assisted approach to synthesis of Baclofen, Main. Group. Chem., 17, 161 (2018).

 

  1. E.S. Khameneh, et al., Preparation of dual-modality yttrium-90 radiolabeled nanoparticles for therapeutic investigation, Radiochim. Acta., 106, 897 (2018).

 

  1. E. Sattarzadeh, et al., 68Ga-radiolabeled magnetic nanoparticles for PET–MRI imaging, J. Radioanal. Nucl. Chem., 317, 1333 (2018).

 

  1. H. Tayeri, et al., Optimized production, quality control and biological assessment of 68Ga-bleomycin as a possible PET imaging agent, Int. J. Radiat. Res., 18, 235 (2020).

 

  1. Z. Pourmanouchehri, et al., Magnetic Nanocarrier Containing 68Ga–DTPA Complex for Targeted Delivery of Doxorubicin, J. Inorg. Organomet. Polym. Mater., 28, 1980 (2018).

 

  1. S. Kakaei, et al., Targeted Drug Delivery of Teniposide by Magnetic Nanocarrier, Curr. Nanosci., 16, 608 (2020).

 

  1. M.M. Mohareri, et al., Preparation and application of Fe3O4@Acetamidoxanthate as a unique nanosorbent in heavy metal removing, Main. Group. Chem. Preprint, 1-11 (2021), doi: 10.3233/MGC-210073.

 

  1. S. Kakaei, E. Sattarzadeh Khameneh, A. Monji Boveiri, Effect of ionic radius on Ti (IV), Zr (IV), and Hf (IV) adsorption by RB biomass, Rad. Phy. Eng., 2, 21 (2021).

 

  1. T. Ehteshamzadeh, et al., Doxorubicin Embedded Polyvinylpyrrolidone-Coated Fe3O4 Nanoparticles for Targeted Drug Delivery System, J. Supercond. Nov. Magn., 34, 3345 (2021).

 

  1. W.D. Hage, et al., Incidence, location, and diagnostic evaluation of metastatic bone disease, Orthop. Clin. North Am., 31, 515 (2000).

 

  1. S. Zolghadri, et al., Production, biodistribution assessment and dosimetric evaluation of 177Lu-TTHMP as an agent for bone pain palliation, Asia Ocean J. Nucl. Med. Biol., 3, 35 (2015).

 

  1. M. Blau, et al., Fluorine-18: a new isotope for bone scanning, J. Nucl. Med., 3, 332 (1962).

 

  1. G.M. Blake, et al., Quantitative studies of bone with the use of 18F-Fluoride and 99mTc-methylene diphosphanate, Semin. Nucl. Med., 1, 28 (2001).

 

  1. A. Mine, et al., 18F–NaF PET/CT in metastatic bone disease, J. Bone. Oncol., 4, 92 (2015).

 

  1. S. Shanehsazzadeh, et al., Estimated human absorbed dose for 68Ga-ECC based on mice data: comparison with 67Ga-ECC, Ann. Nucl. Med., 29, 475 (2015).

 

  1. HD. Zacho, et al., 68Ga-PSMA PET/CT for the detection of bone metastases in prostate cancer: a systematic review of the published literature, Clin Physiol Funct Imaging., 38, 911 (2018).

 

  1. M. Fellner, et al., 68Ga-BPAMD: PET-imaging of bone metastases with a generator based positron emitter, Nuclear Medicine and Biology, 39, 993 (2012).

 

  1. M. Meisenheimer, et al, DOTA-ZOL: A Promising Tool in Diagnosis and Palliative Therapy of Bone Metastasis Challenges and Critical Points in Implementation into Clinical Routine, Molecules., 25, 2988 (2020).

Keywords

68Ga
Labeled composition
PET
Zoledronic acid derivatives
Bone Metastases
  1. A. Kuźnik, et al., Bisphosphonates—much more than only drugs for bone diseases, Eur. J. Pharmacol., 866, 172773 (2020).

 

  1. M. YangandX. Yu, Management of bone metastasis with intravenous bisphosphonates in breast cancer: a systematic review and meta-analysis of dosing frequency, Support. Care. Cancer., 28, 2533 (2020).

 

  1. K.B. Farrell, et al., Bisphosphonate conjugation for bone specific drug targeting, Bone. Rep., 9, 47 (2018).

 

  1. R.G.G. Russell, Bisphosphonates: from bench to bedside, Ann. N. Y. Acad. Sci., 1068, 367 (2006).

 

  1. A.J. Roelofs, et al., Bisphosphonates: molecular mechanisms of action and effects on bone cells, monocytes and macrophages, Curr. Pharm. Des., 16, 2950 (2010).

 

  1. B.J. Edwards, et al., Pharmacovigilance and reporting oversight in US FDA fast-track process: bisphosphonates and osteonecrosis of the jaw, Lancet. Oncol., 9, 1166 (2008).

 

  1. D. Heymann, et al., Bisphosphonates: new therapeutic agents for the treatment of bone tumors, Trends. Mol. Med., 10, 337 (2004).

 

  1. N. Ponte Fernández, R. Estefanía Fresco, J.M. Aguirre Urízar, Bisphosphonates and oral pathology I: general and preventive aspects, Med Oral Patol Oral Cir Bucal., 1, E396 (2006).

 

  1. Z. Mbese, B.A. Aderibigbe, Bisphosphonate-Based Conjugates and Derivatives as Potential Therapeutic Agents in Osteoporosis, Bone Cancer and Metastatic Bone Cancer, Int. J. Mol. Sci., 22, 6869 (2021).

 

  1. D. Isla, et al., Zoledronic acid in lung cancer with bone metastases: a review, Expert. Rev. Anticancer. Ther., 13, 421 (2013).

 

  1. R. Coleman, et al., Zoledronic acid use in cancer patients: more than just supportive care?, Cancer., 117, 11 (2011).

 

  1. N. Pfannkuchen, et al., In vivo evaluation of [225Ac]Ac-DOTAZOL for α-therapy of bone metastases, Curr. Radiopharm., 11, 223 (2018).

 

  1. M. Farhanghi, et al., Samarium-153-EDTMP: pharmacokinetic, toxicity and pain response using an escalating dose schedule in treatment of metastatic bone cancer, J. Nucl. Med., 33, 1451 (1992).

 

  1. M.P. Yadav, et al., [177 Lu] Lu-DOTA-ZOL bone pain palliation in patients with skeletal metastases from various cancers: efficacy and safety results, EJNMMI Res., 10, 1 (2020).

 

  1. I. Velikyan, Prospective of 68Ga-radio-pharmaceutical development, Theranostics., 4, 47 (2014).

 

  1. G. Bandoli, et al., Mononuclear six-coordinated Ga (III) complexes: A comprehensive survey, Coord. Chem. Rev., 253, 56 (2009).

 

  1. S. Kakaei, E.S. Khameneh, An efficient and simple ultrasound-assisted approach to synthesis of Baclofen, Main. Group. Chem., 17, 161 (2018).

 

  1. E.S. Khameneh, et al., Preparation of dual-modality yttrium-90 radiolabeled nanoparticles for therapeutic investigation, Radiochim. Acta., 106, 897 (2018).

 

  1. E. Sattarzadeh, et al., 68Ga-radiolabeled magnetic nanoparticles for PET–MRI imaging, J. Radioanal. Nucl. Chem., 317, 1333 (2018).

 

  1. H. Tayeri, et al., Optimized production, quality control and biological assessment of 68Ga-bleomycin as a possible PET imaging agent, Int. J. Radiat. Res., 18, 235 (2020).

 

  1. Z. Pourmanouchehri, et al., Magnetic Nanocarrier Containing 68Ga–DTPA Complex for Targeted Delivery of Doxorubicin, J. Inorg. Organomet. Polym. Mater., 28, 1980 (2018).

 

  1. S. Kakaei, et al., Targeted Drug Delivery of Teniposide by Magnetic Nanocarrier, Curr. Nanosci., 16, 608 (2020).

 

  1. M.M. Mohareri, et al., Preparation and application of Fe3O4@Acetamidoxanthate as a unique nanosorbent in heavy metal removing, Main. Group. Chem. Preprint, 1-11 (2021), doi: 10.3233/MGC-210073.

 

  1. S. Kakaei, E. Sattarzadeh Khameneh, A. Monji Boveiri, Effect of ionic radius on Ti (IV), Zr (IV), and Hf (IV) adsorption by RB biomass, Rad. Phy. Eng., 2, 21 (2021).

 

  1. T. Ehteshamzadeh, et al., Doxorubicin Embedded Polyvinylpyrrolidone-Coated Fe3O4 Nanoparticles for Targeted Drug Delivery System, J. Supercond. Nov. Magn., 34, 3345 (2021).

 

  1. W.D. Hage, et al., Incidence, location, and diagnostic evaluation of metastatic bone disease, Orthop. Clin. North Am., 31, 515 (2000).

 

  1. S. Zolghadri, et al., Production, biodistribution assessment and dosimetric evaluation of 177Lu-TTHMP as an agent for bone pain palliation, Asia Ocean J. Nucl. Med. Biol., 3, 35 (2015).

 

  1. M. Blau, et al., Fluorine-18: a new isotope for bone scanning, J. Nucl. Med., 3, 332 (1962).

 

  1. G.M. Blake, et al., Quantitative studies of bone with the use of 18F-Fluoride and 99mTc-methylene diphosphanate, Semin. Nucl. Med., 1, 28 (2001).

 

  1. A. Mine, et al., 18F–NaF PET/CT in metastatic bone disease, J. Bone. Oncol., 4, 92 (2015).

 

  1. S. Shanehsazzadeh, et al., Estimated human absorbed dose for 68Ga-ECC based on mice data: comparison with 67Ga-ECC, Ann. Nucl. Med., 29, 475 (2015).

 

  1. HD. Zacho, et al., 68Ga-PSMA PET/CT for the detection of bone metastases in prostate cancer: a systematic review of the published literature, Clin Physiol Funct Imaging., 38, 911 (2018).

 

  1. M. Fellner, et al., 68Ga-BPAMD: PET-imaging of bone metastases with a generator based positron emitter, Nuclear Medicine and Biology, 39, 993 (2012).

 

  1. M. Meisenheimer, et al, DOTA-ZOL: A Promising Tool in Diagnosis and Palliative Therapy of Bone Metastasis Challenges and Critical Points in Implementation into Clinical Routine, Molecules., 25, 2988 (2020).

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