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ORIGINAL ARTICLE
Year : 2015  |  Volume : 14  |  Issue : 2  |  Page : 95-100

Studies on the labeling of Ethylenediaminetetramethylene phosphonic acid, Methylene Diphosphonate, Sodium pyrophosphate and Hydroxyapatite with Lutetium-177 for use in nuclear medicine


Directorate of Technology, Pakistan Institute of Nuclear Science and Technology, Nilore Islamabad, Pakistan

Date of Web Publication15-May-2015

Correspondence Address:
Imtiaz Ahmed Abbasi
LEU Quality Control Group, Pakistan Institute of Nuclear Science and Technology, Nilore, Islamabad
Pakistan
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DOI: 10.4103/1450-1147.155752

PMID: 26097419

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   Abstract 

For the treatment of skeletal metastasis, a therapeutic radionuclide tagged with a bone seeking ligand is required, while for radiation synovectomy (RS), a therapeutic radionuclide irreversibly attached to pre-formed particles of appropriate size is required. Radio lanthanides are mostly therapeutic, and ligands containing phosphate groups are predominantly bone seekers. Exploiting these facts, number of new therapeutic radiopharmaceuticals could be developed. Labeling of four phosphate containing materials was pursued in the present study. It was hypothesized that various 177 Lu-labeled bone-seeking complexes such as 177 Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP), 177 Lu-methylene diphosphonate (MDP) and 177 Lu-pyrophosphate (PYP) could be developed as agents for palliative radiotherapy of bone pain due to skeletal metastases, and 177 Lu-Hydroxyapatite (HA) could be developed as an agent for radiosynovectomy of small joints. Lyophilized kit vials of EDTMP, MDP and sodium pyrophosphate (Na-PYP) were formulated. HA particles were synthesized locally and purity was checked by high-performance liquid chromatography (HPLC). 177 Lu was labeled with EDTMP, MDP, PYP, and HA and the behavior of all was studied by radio-thin layer chromatography (TLC) radio-HPLC and radio-electrophoresis. Radio-TLC confirmed the labeling. HPLC analysis too verified the labeling. Radio-electrophoresis results depicted peaks for 177 Lu-MDP, 177 Lu-EDTMP and 177 Lu-PYP at 3.37 ΁ 0.06 cm, 5.53 ΁ 0.15 cm and 7.03 ΁ 0.06 cm respectively confirming negative charge on each specie as all migrated toward positive anode. All 3 methods verified the labeling. The study demonstrated that EDTMP, MDP and PYP form stable complexes with 177 Lu in injectable solution form. HA particulates could too be labeled with 177 Lu with high radiochemical yields (>98%) in suspension form. Former three could be utilized as bone-pain palliation agents for the treatment of bone metastases, and the later could be applied for the treatment of Rheumatoid arthritis of small joints. The study has also indicated the possibility of developing other numerous radiolanthanide analogs with the potentials of possible use in radiation therapy.

Keywords: 177 Lu-labeled methylene diphosphonate, bone-pain palliation, radiation synovectomy, radio-labeling


How to cite this article:
Abbasi IA. Studies on the labeling of Ethylenediaminetetramethylene phosphonic acid, Methylene Diphosphonate, Sodium pyrophosphate and Hydroxyapatite with Lutetium-177 for use in nuclear medicine. World J Nucl Med 2015;14:95-100

How to cite this URL:
Abbasi IA. Studies on the labeling of Ethylenediaminetetramethylene phosphonic acid, Methylene Diphosphonate, Sodium pyrophosphate and Hydroxyapatite with Lutetium-177 for use in nuclear medicine. World J Nucl Med [serial online] 2015 [cited 2019 Nov 20];14:95-100. Available from: http://www.wjnm.org/text.asp?2015/14/2/95/155752


   Introduction Top


Phosphate containing ligands like Ethylenediaminetetramethylene phosphonic acid (EDTMP), methylene diphosphonate (MDP) sodium pyrophosphate (Na-PYP) all labeled with a radionuclide act as bone-seeking radiopharmaceuticals . Structures of EDTMP, MDP and Na-PYP are shown in [Figure 1].

Bone scanning using the 99m Tc-phosphate analogs is an established diagnostic modality for a variety of pathologies. [1] Complex of MDP with 99m Tc has been widely used as radiopharmaceutical for bone scintigraphy in cases of metastatic bone disease, Paget's disease, fractures in osteoporosis, and henceforth for the last quarter of a century. [2],[3],[4],[5] Bone scanning with 99m Tc pyrophosphate is very useful for the detection of soft-tissue lesions that produce extra skeletal ossification. [6] EDTMP labeled with 153 Sm give rise to 153 Sm-EDTMP ( 153 Sm labeled EDTMP) a bone-seeking tetraphosphonate, which have been approved by the Food and Drug Administration for the treatment of painful osseous metastases. [7] Synovectomy by an intra-articular application of a β-emitting radioisotope in colloidal form or radiation synovectomy (RS) was introduced in 1952 for treatment of inflamed synovial membrane. [8] An ideal agent for RS would be one in which the radionuclide is irreversibly attached to pre-formed particles of appropriate size . The 177 Lu-Hydroxyapatite (HA) [Ca 10 (PO 4 6 )(OH) 2 ] is one of the preferred particulates as it is constituent of bone matrix and natural substance known to be biodegradable. [9]
Figure 1: Structure of (a) 177Lu-Methylene diphosphonate, (b) Sodium pyrophosphate and (c) 177Lu-ethylenediaminetetramethylene phosphonic acid

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177
Lu (t½ =6.71 d) is an adequate radionuclide for therapy, which has both beta particle emissions with Emax = 497 keV (78.6%), 384 keV (9.1%) and 176 keV (12.2%) for therapeutic effect and gamma emissions 113 keV (6.4%) and 208 keV (11%) for imaging. 177 Lu decays to stable 177 Hf and its long half-life provides logistic advantage for facilitating the supply to places far away from the reactor. [9],[10],[11] The major advantage of 177 Lu lies in the feasibility of its large-scale production with excellent radionuclide purity and adequate specific activity owing to the high thermal neutron capture cross-section of 176 Lu (2100 b) using moderate flux reactors. [12]

For the treatment of skeletal metastasis, a therapeutic radionuclide tagged with a bone seeking ligand is required while, for RS, a therapeutic radionuclide irreversibly attached to pre-formed particles of appropriate size is required. Radio lanthanides are mostly therapeutic, and ligands containing phosphate groups are predominantly bone seekers. Fortunately, lanthanides have a strong affinity towards ligands containing phosphate groups. Exploiting these facts, number of new therapeutic radiopharmaceuticals could be developed. Complex formation of four phosphate containing materials was pursued in the present study. It was hypothesized that various 177 Lu-labeled bone-seeking complexes such as 177 Lu-EDTMP, 177 Lu-MDP and 177 Lu-PYP could be developed as agents for palliative radiotherapy of bone pain due to skeletal metastases, and 177 Lu-HA could be developed as an agent for radiosynovectomy.


   Materials and Methods Top


Methylene Diphosphonic acid (99.0%), Tetra Na-PYP (95.0% F. Wt. =265.9) and EDTMP all of Aldrich Chemistry were used in the study.

Natural Lu 2 O 3 (99.9% chemically pure, 2.6% 176 Lu) powder from A Johnson Mathey Company (UK) was used as a target for the production of 177 Lu. 177 LuCl 3 solution was prepared by dissolving irradiated natural Lu 2 O 3 powder in 0.1 MHCl with a little heating. Normally, vials containing 10 mg/ml MDP, 28 mg/ml Na-PYP and 35 mg/ml EDTMP (except reported) were used for labeling studies. 177 LuCl 3 solution was used for labeling of kit vials. HA [Ca 10 (PO 4 ) 6 (OH) 2 ], was synthesized locally. Kits of EDTMP, MDP and Na-PYP were formulated by dissolving appropriate amounts of the ligands in double distilled water with adjustment of relevant pH. These solutions were dispensed in vials. Vials were placed in a freeze dryer. Freeze drying was performed for 24 h with a shelf temperature of −80°C and 0.630 mbar pressure. Vials were caped under vacuum and stored at room temperature. Composition of each freeze dried kit is mentioned in [Table 1].
Table 1: Composition of freeze dried kits


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Natural Lu 2 O 3 ( 10 mg) target was irradiated at a thermal flux ~8.0 × 10 13 n/cm 2 /s for 12 h for the production of 177 Lu. The irradiated target was dissolved in 1 MHCl with gentle heating and filtered inside a home-made lead-shielded plant. Specific activity of the product was ~25.3 mCi/mg at EOB. Analysis of the gamma ray spectrum of the irradiated target revealed major γ-peaks at 72, 113, 208, 250 and 321 keV, which correspond to the photopeaks of 177 Lu as per literature [13] and the radionuclide purity of 177 Lu more than 99%. Analysis of the gamma ray spectrum was carried out by using a p-type coaxial HPGe detector (Eurisys Mesures, France) coupled through a 570 ORTEC made spectroscopy amplifier toTrump PCI, 8 k ADC/MCA card with Gamma Vision-32 ver. 6 software (ORTEC, USA).

Desired volume of 177 LuCl 3 solution (containing required activity) was taken in the vials containing MDP 10 mg/ml Na-PYP 28 mg/ml and EDTMP 35 mg/ml Resulting solutions were incubated for ½ h at room temperature. 1 ml NaHCO 3 (0.5M) and 1 ml normal saline were added to 100 mg of HA in a vial. A volume of 1 ml NaOH was added to make the pH > 7. 1 77 LuCl 3 (solution in HCl) was injected to the vial and shaken for 30 min. The shaken mixture was centrifuged at 3500 rpm for 10 min. Supernatant was removed carefully and again saline was added for washing. Centrifugation was carried out for another 5 min. Supernatant was removed again to have 177 Lu-labeled hydroxyapatite ( 177 Lu-HA), which was used for further studies.

The centrifuged shaken mixture of 177 LuCl 3 and HA in 1 ml saline in the form of suspension was used for radiochemical purity check by thin layer chromatography (TLC) system using EDTA as mobile phase. Aliquots from the vial were spotted on Whatman 3 MM paper strips and eluted to develop actigrams.

The kit vials (MDP, PYP and EDTMP) containing 177 LuCl 3 solution (0.5-1.0 mCi/vial) were shaken and kept at room temperature, and the radiochemical purity check was carried out by TLC system using ammonium hydroxide: Methanol: Water (1:20:20) as mobile phase. Aliquots from the vials were spotted on Whatman 3 MM paper strips of 2 × 14 cm and eluted up to 12 cm. The chromatograms were dried and after drying the strip was subjected to 2π-scanner Berthold coupled with NaI detector to get actigrams depicting the labeling yield.

All the 4 Lu labeled complexes were incubated for >24 h at room temperature. To observe the stability of the complexes, aliquots from the vials containing 177 Lu-PYP, 177 Lu-MDP, 177 Lu-EDTMP and 177 Lu-HA complex at different time intervals (1 h-24 h) were also spotted on paper strips, eluted and processed likewise by virtue of which in vitro stability of the labeled preparations were ascertained.

To determine the effect of temperature on labeling yield, 177 Lu-MDP, 177 Lu-PYP and 177 Lu-EDTMP solutions were heated in three vials with temperature monitoring and aliquots from the vials at various temperatures 20, 40, 60, and 80°C (each vial was heated at the specified temperatures other than 20°C for 1 min) were spotted on paper strips and eluted and subjected to 2π-scanner Berthold coupled with NaI detector to get actigrams depicting the labeling yield and hence the effect of temperature on the labeling yield was determined. Vial containing 177 Lu-HA particulates in 1ml saline was also subjected to high temperatures likewise and aliquots from the vials at various temperatures were spotted on paper strips and eluted with EDTA and actigrams were developed. The centrifuged shaken mixture of 177 LuCl 3 and HA in 1 ml saline in the form of suspension was used for radiochemical purity check by TLC system using EDTA as mobile phase. Aliquots from the vial were spotted on Whatman 3 MM paper strips and eluted to develop actigrams.

To verify the complex formation and to determine the retention time of 177 Lu-PYP, 177 Lu-MDP and 177 Lu-EDTMP complexes, the reaction mixtures were analyzed by high performance liquid chromatography (HPLC). First 20 μl of 177 LuCl 3 (10 mCi) solution was injected (thrice) into the column, and the elution was monitored by observing the radioactivity profile. Similarly, 20 μl of the test solution of each type was injected (thrice) into the column and the elution was monitored. Chromatograms were obtained on Hitachi L6200 HPLC system with NaI crystal detector using C-18 reversed phase (25 × 0.5 cm) column utilizing (1:1) mixture of water and methanol as the mobile phase. Both results of TLCTLC and HPLC were compared for the said reaction mixture.

To determine the charge on the 177 Lu-PYP, 177 Lu-MDP and 177 Lu-EDTMP complex, radio-electrophoresis was conducted. 10.0 μl of each solution ( 177 Lu-PYP, 177 Lu-MDP and 177 Lu-EDTMP and 177 LuCl 3 ) was spotted in the center of 30 cm strip of Whattman 3 MM chromatography strips (30 × 2 cm) at 15 cm from each electrode. Paper electrophoresis was carried out for 1 h under a voltage of 300 V using 0.025M phosphate buffers pH 6.9 and 45 mA current. Wet paper strips were removed and placed on a tissue paper to dry for an hour. Radio electrophoretograms were accomplished by placing the filter paper strip on the 2π-scanner. Paper electrophoresis was carried out with the Delux electrophoresis chamber coupled with the power supply (Gelman Instrument Company USA).


   Results Top


After elution, the dried Whatman 3 MM paper strips were subjected to 2π-scanner. The scanner generated radiochromatograms [Figure 2]a-2c which depicted the labeling of 177 Lu-PYP, 177 Lu-MDP and 177 Lu-EDTMP to be 99.689%, 99.379% and 99.698%, respectively. All the complexes moved towards solvent front while free 177 LuCl 3 remained at the origin. Radiochemical purity and labeling efficiency was found to be >99%. While the radiochromatogram [Figure 2]d showed peak at RT = 1.14 (98.021%) indicating 177 Lu-HA and shoulders at RT = 5.52 indicating 177 Lu-EDTA.
Figure 2: Peaks of actigrams (a-c) representing 177Lu-pyrophosphate complex, 177Lu-Methylene diphosphonate complex and 177Lu-ethylenediaminetetramethylene phosphonic acid complex respectively and actigram (d) representing 1777Lu-Hydroxyapatite (% radiochemical purity is depicted as shown by the Printout of 2ð-scanner)

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Labeling yield at different time intervals 1 h, 6 h, 18 h and 24 h after the initiation of reaction came out to be 99.99 ± 0.01, 99.34 ± 0.89 98.74 ± 0.74, and 98.14 ± 0.67 for 177 Lu-PYP complex while 99.14 ± 0.25, 99.31 ± 0.20, 99.19 ± 0.10, 99.35 for 177 Lu-MDP, and 99.11 ± 0.21, 99.04 ± 0.29 98.44 ± 0.14, and 98.05 ± 0.37 for 177 Lu-EDTMP and 99.88 ± 0.52, 99.74 ± 0.49, 99.44 ± 0.34 and 98.55 ± 0.47 for 177 Lu-HA. The complexes retained >98% labeling efficiency even after 24 h hence all the 4 complexes could be considered quite stable. Graphic representation of this result is depicted in [Figure 3].
Figure 3: Labeling yield at various time intervals

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The labeling yield for 177 Lu-PYP at various temperatures 20, 40, 60 and 80°C was determined to be 98.09 ± 0.13, 99.13 ± 0.10, 99.76 ± 0.14 and 100.00 ± 0.00 respectively. The labeling yield for 177 Lu-MDP was 65.43 ± 5.05, 81.03 ± 1.29, 90.42 ± 0.61, 99.11 ± 0.21 and was 60.53 ± 4.25, 89.05 ± 1.18, 90.12 ± 0.43, 99.41 ± 0.31 for 177 Lu-EDTMP and 99.79 ± 0.15, 99.63 ± 0.19, 99.26 ± 0.24, 99.06 ± 0.04 for 177 Lu-HA. The results as depicted in [Figure 4] showed that the stability of the complexes remained intact at temperatures higher than room temperature.
Figure 4: Labeling yield at various temperatures

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The HPLC chromatogram of the test solutions clearly showed distinct peaks at different retention times thereby confirming the labeling of 177 Lu with PYP, MDP and EDTMP. The HPLC chromatograms are shown in [Figure 5]. It was observed that the retention time of 177 Lu-PYP complex was 1.42 ± 0.01 min, 177 Lu-MDP 1.35 ± 0.05 min and 177 Lu-EDTMP 1.54 ± 0.01 min while that of the free 177 LuCl 3 was found to be 2.23 ± 0.02 min. On injecting all the three labeled species simultaneously, 4 distinct peaks appeared as shown in [Figure 6]. Results shown by HPLC were in close agreement with those shown by TLC.
Figure 5: Radio-electrophoratograms (A) free 177LuCl3 (B) 177Lu-pyrophosphate complex (C) 177Lu-methylene diphosphonate complex (D) 177Lu-ethylenediaminetetramethylene phosphonic acid complex

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In paper radio-electrophoresis (0.025 M phosphate buffers pH 6.9), 177 LuCl 3 did not show any movement from point of spotting. Peaks for 177 LuCl 3 appeared at 15 cm (point of spotting). Activity peaks of 177 Lu-PYP complex appeared far from point of spotting [Table 2]. 177 Lu-PYP complex showed migration toward anode to the extent of 7.03 ± 0.06 cm, indicating the formation of negatively charged complex. Point of spotting for each experiment was 15.0 cm. Data pertaining to all three radiopharmaceuticals is tabulated in [Table 3].

Peaks for 177 Lu-MDP and 177 Lu-EDTMP appeared at 3.37 ± 0.06 cm and 5.53 ± 0.15 cm respectively. Radio electrophoretograms accomplished by placing the filter paper strip on the 2π-scanner are shown in [Figure 5].
Table 2: Labeling yields of 177Lu-PYP 177Lu-MDP and 177Lu-EDTMP complexes for various quantities of Lutetium as a function of fixed quantity of ligands


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Table 3: Electrophoresis data of Lu-phosphate complexes


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Radio-electrophoresis not only confirmed the labeling of 177 Lu with PYP, MDP and EDTMP but also confirmed that all thee complexes 177 Lu-MDP, 177 Lu-PYP and 177 Lu-EDTMP are negatively charged as they migrated toward positive anode.


   Discussion Top


Large-scale production of 177 Lu with excellent radionuclide purity and adequate specific activity due to high thermal neutron capture cross-section of 176 Lu using moderate flux reactors makes it a suitable candidate for therapeutic applications. As much interest is being shown currently in the use of 177 Lu for various applications, so pursuing, the evaluation of any of its complexes would be quite reasonable [14],[15]

From the present study, it is clearly evident that 177 Lu could be labeled with MDP, PYP and EDTMP with radiochemical purity higher than 99% at 30 min after the start of the reaction. Also, the preparation of complexes 177 Lu-MDP, 177 Lu-PYP and 177 Lu-EDTMP is very simple, and the complexes are quite stable. Lu + 3 ions are oxygen seekers and phosphonic acid groups (containing oxygen) of MDP, PYP and EDTMP are available for co-ordination with 177 Lu + 3 . HA particulates too, could be labeled with 177 Lu with high radiochemical yields (>98%). The lanthanides chemically are very similar, and any ligand that makes complex with one could make complexes with all of them.

This study has indicated that numerous radiolanthanide complexes like 169 Er-MDP, 161 Tb-MDP, 143 Pr-MDP, 159 Gd-MDP, 153 Sm-MDP, 149 Pm-MDP, 165 Dy-MDP, 166 Ho-MDP, 142 Pr-MDP, could be developed as well as their analogs with HA, PYP and EDTMP. All these complexes have potentials to be utilized as palliative agents for bone metastasis. Based on the results obtained, hypothetical Structures of the polyphosphate complexes namely 177 Lu-PYP, 177 Lu-MDP and 177 Lu-EDTMP could be designed as mentioned in [Figure 7].
Figure 6: High performance liquid chromatography pattern of (a) Free 177LuCl3 (b) 177Lu-pyrophosphate complex (c) 177Lu-Methylene diphosphonate complex (d) 177Lu-ethylenediaminetetramethylene phosphonic acid complex

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Figure 7: Hypothetical structure of (a) 177Lu-pyrophosphate (b) 177Lu-Methylene diphosphonate and (c) 177Lu-ethylenediaminetetramethylene phosphonic acid complex

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   Conclusion Top


The study demonstrated that MDP, EDTMP and Na-PYP form stable complexes with 177 Lu in injectable solution form. HA, particulates too could be labeled with 177 Lu with high radiochemical yields (>98%) in suspension form. Former three could be utilized as bone-pain palliation agents for the treatment of bone metastases, and the later could be applied for the treatment of Rheumatoid arthritis of small joints. The study has also indicated the possibility of developing other numerous radiolanthanide analogs with the potentials of possible use in radiation therapy.

 
   References Top

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Subramanian G, McAfee JG, Blair RJ, Kallfelz FA, Thomas FD. Technetium-99m-methylene diphosphonate - A superior agent for skeletal imaging: Comparison with other technetium complexes. J Nucl Med 1975;16:744-55.  Back to cited text no. 2
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Domstad PA, Coupal JJ, Kim EE, Blake JS, DeLand FH. 99mTc-hydroxymethane diphosphonate: A new bone imaging agent with a low tin content. Radiology 1980;136:209-11.  Back to cited text no. 3
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Kampen WU, Brenner W, Czech N, Henze E. Intraarticular application of unsealed beta-emitting radionuclides in the treatment course of inflammatory joint diseases. Curr Med Chem Anti Inflamm Anti Allergy Agents 2002;1:77-87.  Back to cited text no. 8
    
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Chakraborty S, Das T, Banerjee S, Sarma HD, Venkatesh M. Preparation and preliminary biological evaluation of 177Lu-labelled hydroxyapatite as a promising agent for radiation synovectomy of small joints. Nucl Med Commun 2006;27:661-8.  Back to cited text no. 9
    
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Chang Y, Jeong J, Lee YS, Kim Y, Lee D, Chung JK, et al. Comparison of potential bone pain palliation agents Lu-177-EDTMP and Lu-177-DOTMP. J Nucl Med 2008;49:93P.  Back to cited text no. 10
    
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Pillai MR, Chakraborty S, Das T, Venkatesh M, Ramamoorthy N. Production logistics of 177Lu for radionuclide therapy. Appl Radiat Isot 2003;59:109-18.  Back to cited text no. 11
    
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Chakraborty S, Das T, Sarma HD, Venkatesh M, Banerjee S. Preparation and preliminary studies on 177Lu-labeled hydroxyapatite particles for possible use in the therapy of liver cancer. Nucl Med Biol 2008;35:589-97.  Back to cited text no. 12
    
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Firestone R. In: Shirly VS, editor. Table of Isotopes. 8 th ed. New York: John Wiley; 1996. p. 2112-4.  Back to cited text no. 13
    
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Abbasi IA. Studies on 177 Lu -labeled methylene diphosphonate as potential bone-seeking radiopharmaceutical for bone pain palliation Nucl Med Biol 2011;38:417-25.  Back to cited text no. 14
    
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Abbasi IA. Preliminary studies on 177 Lu-labeled sodium pyrophosphate ( 177 Lu-PYP) as a potential bone-seeking radiopharmaceutical for bone pain palliation Nucl Med Biol 2012;39:763-9.  Back to cited text no. 15
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]


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