Ethylene Diamine Tetramethylene Phosphonic Acid Labeled with Various β − -Emitting Radiometals: Labeling Optimization and Animal Biodistribution

Abstract

Skeletal uptake of β⁻-emitting radionuclides may be used for bone pain palliation or myeloablation. The physical characteristics of the β⁻ particles required for the two conditions are, however, different, that is, higher energies are favorable for destruction of bone marrow. In this study, the labeling conditions of ethylene diamine tetramethylene phosphonic acid (EDTMP) with three rare earth metals (⁹⁰Y, ¹⁶⁶Ho, and ¹⁷⁷Lu) having β⁻ particles of diverse physical characteristics were optimized, and their animal biodistributions were studied and compared with ¹⁵³Sm-EDTMP. All the four radiometals (X = ⁹⁰Y, ¹⁶⁶Ho, ¹⁷⁷Lu, and ¹⁵³Sm) were produced from n,γ reactions of their respective precursors (⁸⁹Y, ¹⁶⁵Ho, ¹⁷⁶Lu, and ¹⁵²Sm). They were labeled with EDTMP at varying degrees of pH and molar ratios, and labeling yields were determined by paper chromatography at each data point. The complexes with optimal labeling yields and their chloride forms (XCl₃) were then studied for biodistributions in 66 Sprague–Dawley male rats at 30 minutes, 2 hours, and 24 hours after injection. All the radiopharmaceuticals gave ∼98% complex yields at pH 8. At optimum pH level, good labeling was achieved at X:EDTMP molar ratios of 1:5, 1:8, and 1:20 for ⁹⁰Y, ¹⁶⁶Ho, and ¹⁷⁷Lu complexes, respectively. ¹⁷⁷Lu-EDTMP showed the best biodistribution results among all the complexes, with a total skeletal uptake of 70.2% ± 2.4% at 24 hours (¹⁵³Sm-EDTMP = 59.1% ± 2.6%). ⁹⁰Y-EDTMP had skeletal accumulation significantly higher than ¹⁶⁶Ho-EDTMP (45.5% ± 2.9% and 27.4% ± 3.6%, respectively). Blood activity of all the agents disappeared promptly through the kidneys. This study demonstrates higher localization of ¹⁷⁷Lu-EDTMP in skeleton than ¹⁵³Sm-EDTMP and shows that the localization of ⁹⁰Y-EDTMP is better among the high-energy radiometals studied.

Introduction

Therapeutic bone-seeking radiopharmaceuticals emitting β⁻ particles are either used for bone pain palliation therapy in metastatic skeletal disease or proposed for bone marrow ablation in hematological malignancies, such as multiple myeloma. β⁻ particles of low energies are recommended for bone pain, whereas those with higher energies are used for bone marrow ablation.¹ Ethylene diamine tetramethylene phosphonic acid (EDTMP) is an active bone seeker that is taken up by the bone matrix. Labeled with a lanthanoid, that is, ¹⁵³Sm, it is frequently used as a bone seeker, primarily for bone pain palliation therapy, and is also evaluated for bone marrow ablation.^2
–4153Sm has beta energy of a medium range (E _β(max) = 808 keV, maximum soft-tissue range: 3.1 mm, T½ = 47 hours). Because of this it has an untoward effect of myelosuppression, a major dose-limiting factor.^5,6 On the other hand, when used alone its beta energy falls short in efficiency for bone marrow ablation.⁷

Several other lanthanoids have β⁻ particle energies that may be more suitable for the aforementioned clinical situations. ¹⁶⁶Ho (E _β(max) = 1855 keV, maximum soft-tissue range: 8.7 mm, T½ = 27 hours), ¹⁷⁷Lu (E _β(max) = 498 keV, maximum soft-tissue range: 2.0 mm, T½ = 161 hours), and ⁹⁰Y (E _β(max) = 2280 keV, maximum soft-tissue range: 11.9 mm, T½ = 64 hours) are few of them that are under evaluation.^8
–10 The present study's authors have recently produced these isotopes at Isotope Production Division, PINSTECH, Islamabad. This study was done to label them with EDTMP while optimizing various labeling parameters and to perform and compare their animal biodistributions with ionic forms of the respective radiometals and ¹⁵³Sm-EDTMP. The experiments on animals were conducted with prior approval of the ethics committee of the Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad, and according to appropriate guidelines to conduct experiments on laboratory animals.

Materials and Methods

Preparation of labeled EDTMP

Radioisotopes (X = ⁹⁰Y, ¹⁶⁶Ho, ¹⁷⁷Lu, and ¹⁵³Sm) were produced locally by n,γ reactions from stable oxides of their precursors (⁸⁹Y₂O₃, ¹⁶⁵Ho₂O₃, ¹⁷⁶Lu₂O₃, and ¹⁵²Sm₂O₃) obtained from International Hospital Supply Corp., New York, using previously published procedures.¹¹ Known quantities of the targets were sealed in quartz ampoules and cold-welded into aluminum cans. The irradiations were carried out inside the core of the 10 MW swimming pool type nuclear reactor Pakistan Research Reactor-I for up to 12 hours at a neutron flux of ∼1.0 × 10¹⁴ cm² s⁻¹. The irradiated material was dissolved in 5 M hydrochloric acid and evaporated to dryness and the residue was dissolved in distilled water to obtain radionuclide solutions in their chloride forms (XCl₃). Radionuclide purity was assured by HPGe gamma spectrometry.

EDTMP was dissolved in distilled water and labeling was done separately for different radiometals by adding their respective chloride solutions to it. Labeling conditions of metal-to-ligand molar ratio (X:EDTMP) and pH of the reaction mixture were optimized to achieve maximum complexation yield. Reaction mixture volumes were ∼2 mL and all the studies were performed at room temperature (22°C ± 2°C). The pH levels of the resulting solutions were adjusted with 1 M HCl or 1 M NaOH and were incubated for 30 minutes before examining the labeling yields.

Paper chromatography

The radiolabeling yields of complexes were determined by ascending paper chromatography. Five microliters of the test solution was spotted at 2 cm from bottom end of Whatman 3 MM chromatography paper strips (14 × 2 cm). The strips were developed in pyridine/ethanol/water (1:2:4) and then dried. Activity was measured using either 1 cm cut-sections of the strip separately in a well counter or, alternatively, the whole strip by a 2π scanner (Berthold). Labeled complex moved with the solvent front (R _f = 9–10), while ionic form remained at the point of spotting (R _f = 0). The labeling yields of solutions were determined for various pH levels and molar ratios. The solutions to be used in animals were first adjusted to pH 7 and were made sterile by using a Millipore filter prior to injection.

Labeling yields of all the complexes under study were evaluated at various pH levels (n = 3 at each level), keeping high X:EDTMP molar ratios (1:12 for ⁹⁰Y and ¹⁶⁶Ho; and 1:30 for ¹⁷⁷Lu). Labeling percentage was also analyzed after changing X:EDTMP molar ratio from 1:1 to 1:12 for ⁹⁰Y and ¹⁶⁶Ho and from 1:5 to 1:30 for ¹⁷⁷Lu (n = 3 at each point), keeping pH at optimal level. Labeling yields of the complexes prepared at optimal parameters were also studied after 1 week to evaluate the stability.

Biodistribution study

The biodistribution study of ionic radionuclides and labeled complex was performed in Sprague–Dawley male rats having weight ranging from 175 to 200 g. Rats were anesthetized in a covered jar containing cotton swab dipped in ether followed by injection of 200 μL of the complex into the tail veins and housed separately for a certain period. They were then killed with an overdose of anesthesia. Three dissections were done at 30 minutes, 2 hours, and 24 hours for each radiopharmaceutical and its free ionic radionuclide (only 2 and 24 hours in case of ¹⁵³Sm). One (1) milliliter of blood was drawn from the heart and weighed immediately after sacrificing the animal. Rat was then weighed and subsequently dissected taking special care to separate the blood and urine on the kill papers. The tissue washing and the urine from the cages was also collected separately. The required organs were taken out for the calculations of percentage of activity per organ (%ID/g). The larger organs such as liver and intestines were weighed and then a small weighed portion was taken for the purpose of counting and adjusted for whole organ. Femur was taken as representative bone for skeletal uptake and total skeletal uptake was estimated 25 times the %ID of femur.¹² Counting was done in Ludlum™ Model 261 spectrometer using γ photons of energies with respective to radionuclide or, alternatively, using bremsstrahlung for ⁹⁰Y.

A total of 66 animals were sacrificed, 3 each for EDTMP labeled with ⁹⁰Y, ¹⁶⁶Ho, and ¹⁷⁷Lu and their ionic forms at each time point of 30 minutes, 2 hours, and 24 hours and for the study of the biodistribution of ¹⁵³Sm-EDTMP and free ionic ¹⁵³Sm for comparison at 2 and 24 hours.

Scintigraphic studies

Scintigraphic studies at Department of Medical Sciences (PIEAS) were also done on Sprague–Dawley male rats to visually evaluate the distribution of EDTMP labeled with ¹⁶⁶Ho and ¹⁷⁷Lu for comparison with ¹⁵³Sm. The animal was anesthetized by intramuscular injection of 100 mg diazepam as the initial dose. The additional amounts were given later to retain the effect of anesthesia. Approximately 25 MBq of radiopharmaceutical was injected into the tail vein and imaging was done under Siemens Integrated ORBITER Camera System interfaced with high-resolution parallel-hole collimator. Twenty-percent energy windows were set at 103 and 81 keV for ¹⁵³Sm and ¹⁶⁶Ho, respectively. For ¹⁷⁷Lu, the setting of dual energy windows at 113 and 208 keV was used to attain adequate count rate. Ten (10)-minute static image of whole body was acquired on 64 × 64 matrix at 2 hours after the injection. All the radiopharmaceuticals were studied in separate animals.

Results

Production and labeling

Twelve (12) hours of irradiation of Sm₂O₃, Y₂O₃, Ho₂O₃, and Lu₂O₃ produced ∼3700, 160, 5920, and 925 MBq/mg activities of ¹⁵³Sm, ⁹⁰Y, ¹⁶⁶Ho, and ¹⁷⁷Lu, respectively. No other gamma-emitting radionuclide was detected by gamma spectrometry in all productions.

Nearly 98% of labeling yields could be achieved with all radioisotopes at pH 8 (Fig. 1), with only a minimal change at higher pH levels. However, at pH levels below 7, the yield was significantly low (Fig. 2A).

FIG. 1.

Paper chromatography scans of ⁹⁰Y-EDTMP (A), ¹⁶⁶Ho-EDTMP (B), ¹⁷⁷Lu-EDTMP (C), and ¹⁵³Sm-EDTMP (D) labeled at their respective optimum pH values and X:EDTMP molar ratios. Small peaks represent unlabeled ionic radionuclides, which was <2% in all scans. EDTMP, ethylene diamine tetramethylene phosphonic acid.

FIG. 2.

Variation in labeling yields of different complexes with change in pH (A) and X:EDTMP molar ratio (B). n = 3 at each data point.

Keeping optimum pH level, that is, pH 8, good labeling yield (97.7% ± 1.3%) was possible at a molar ratio of 1:5 in case of ⁹⁰Y-EDTMP. Above this ratio the labeling remained >98% (Fig. 2B). The labeling efficiency of ¹⁶⁶Ho-EDTMP reached 98.8% ± 0.3% with a molar ratio of 1:8 or above. However, ¹⁷⁷Lu could be labeled efficiently at 1:20 onward (98.1% ± 0.4% at 1:20). All the complexes remained adequately stable after 7 days (>95%).

For ¹⁵³Sm-EDTMP, a labeling efficiency of >99% could be achieved after 30 minutes of incubation at room temperature. The complex remained stable even after 7 days (98%).

Biodistribution studies

Complexes prepared at optimum labeling parameters and giving labeling yields of ∼98% as mentioned in the above section were used for biodistribution studies. There was a significant difference in the distributions of labeled EDTMP and their respective free ionic forms (Table 1). The ionic forms mainly accumulated in the liver with low skeletal and renal uptake. Free ¹⁵³Sm ions showed the highest hepatic uptake, whereas free lutetium was the lowest among all the free ions (8.29% ± 0.72% and 0.47% ± 0.34%, respectively, at 24 hours after injection). Uptake in the lung at 24 hours postinjection was also highest for ¹⁵³Sm ions (6.83% ± 0.62%), and ¹⁶⁶Ho ions showed the highest renal accumulation. No significant uptake of the free ions was seen in the femur, with ¹⁵³Sm being the highest (0.36% ± 0.03% at 24 hours).

Table 1.

Biodistributions of Radiopharmaceuticals and Their Free Ions in Sprague–Dawley Male Rats

	0.5 hour		2 hours		24 hours
Organ/tissue	Y-EDTMP	Free ionic Y	Y-EDTMP	Free ionic Y	Y-EDTMP	Free ionic Y
Blood	0.03 ± 0.01	0.03 ± 0.01	0.05 ± 0.01	0.01 ± 0.01	0.01 ± 0.00	0.04 ± 0.02
Lungs	0.26 ± 0.20	0.07 ± 0.01	0.12 ± 0.01	0.02 ± 0.01	0.07 ± 0.01	0.02 ± 0.02
Liver	0.03 ± 0.01	0.83 ± 0.23	0.04 ± 0.03	1.82 ± 0.17	0.07 ± 0.01	2.33 ± 0.51
Kidneys	0.64 ± 0.21	0.07 ± 0.06	0.17 ± 0.01	0.15 ± 0.03	0.07 ± 0.01	0.09 ± 0.04
Femur	2.71 ± 0.16	0.07 ± 0.05	3.22 ± 0.32	0.11 ± 0.01	2.94 ± 0.16	0.04 ± 0.01

	Ho-EDTMP	Free ionic Ho	Ho-EDTMP	Free ionic Ho	Ho-EDTMP	Free ionic Ho
Blood	0.02 ± 0.01	0.05 ± 0.01	0.01 ± 0.01	0.01 ± 0.01	0.00	0.00
Lungs	0.50 ± 0.12	0.19 ± 0.03	0.12 ± 0.01	0.12 ± 0.01	0.10 ± 0.04	0.03 ± 0.01
Liver	0.21 ± 0.03	1.21 ± 0.41	0.01 ± 0.01	4.83 ± 0.37	0.00	3.75 ± 0.71
Kidneys	1.51 ± 0.18	2.11 ± 0.13	2.21 ± 0.51	3.25 ± 0.53	1.70 ± 0.13	1.22 ± 0.30
Femur	0.52 ± 0.04	0.10 ± 0.05	1.20 ± 0.06	0.11 ± 0.01	0.94 ± 0.45	0.07 ± 0.05

	Lu-EDTMP	Free ionic Lu	Lu-EDTMP	Free ionic Lu	Lu-EDTMP	Free ionic Lu
Blood	0.00	1.26 ± 0.21	0.00	0.92 ± 0.60	0.00	0.02 ± 0.03
Lungs	0.03 ± 0.01	0.78 ± 0.12	0.07 ± 0.01	1.54 ± 0.29	0.05 ± 0.01	0.21 ± 0.07
Liver	0.07 ± 0.01	0.54 ± 0.30	0.14 ± 0.02	0.89 ± 0.71	0.11 ± 0.01	0.47 ± 0.34
Kidneys	0.32 ± 0.02	0.04 ± 0.12	0.40 ± 0.23	0.48 ± 0.01	0.29 ± 0.03	0.56 ± 0.01
Femur	2.71 ± 0.32	0.07 ± 0.05	5.10 ± 0.32	0.17 ± 0.01	6.76 ± 0.63	0.16 ± 0.02

	Sm-EDTMP	Free ionic Sm	Sm-EDTMP	Free ionic Sm	Sm-EDTMP	Free ionic Sm
Blood	—	—	0.01 ± 0.01	0.10 ± 0.01	0.00	0.02 ± 0.01
Lungs	—	—	0.20 ± 0.02	5.57 ± 0.41	0.01 ± 0.01	6.83 ± 0.62
Liver	—	—	0.03 ± 0.01	7.84 ± 0.57	0.04 ± 0.02	8.29 ± 0.72
Kidneys	—	—	0.25 ± 0.14	0.47 ± 0.12	0.23 ± 0.13	0.34 ± 0.01
Femur	—	—	3.80 ± 0.31	0.61 ± 0.37	3.72 ± 0.52	0.36 ± 0.03

n = 3 for each radiopharmaceutical and its free ionic form.

EDTMP, ethylene diamine tetramethylene phosphonic acid.

¹⁷⁷Lu-EDTMP showed the high percentage of uptake in the femur among all the labeled radiopharmaceuticals, increasing from 2.71% ± 0.32% at 30 minutes to 6.76% ± 0.63% at 24 hours in femur. It was twice as high as ¹⁵³Sm-EDTMP at 24 hours. ⁹⁰Y-EDTMP demonstrated femur accumulation similar to ¹⁷⁷Lu-EDTMP at 30 minutes (2.71% ± 0.16%), but remained almost steady in 2- and 24-hour samples. ¹⁶⁶Ho-EDTMP gave the minimum femur uptake in all complexes (a maximum of 1.20% ± 0.06% at 2 hours).

Total skeletal uptake was estimated from percentage of femur uptake (Fig. 3). ¹⁷⁷Lu-EDTMP had highest bone uptake reaching 70.2% ± 2.4% at 24 hours. ¹⁶⁶Ho-EDTMP uptake in the skeleton was the lowest of all, that is, 15.6% ± 1.7% at 30 minutes to a maximum of 36.1% ± 2.1% at 2 hours after injection. Peak activity for ⁹⁰Y-EDTMP was also found at 2 hours (56.9% ± 2.8%).

FIG. 3.

Comparison of total skeletal uptake of EDTMP complexes with ⁹⁰Y, ¹⁶⁶Ho, ¹⁷⁷Lu, and ¹⁵³Sm in Sprague–Dawley male rats sacrificed at different times. n = 3 at each time point.

A significant pool of renal activity was seen in all the labeled compounds, with ¹⁶⁶Ho-EDTMP being the highest. In 24 hours the activities in all the other organs were minimal for all the radiopharmaceuticals.

Scintigraphic studies

Sprague–Dawley rats were also imaged under a gamma camera at 2 hours after tail injections of ¹⁵³Sm-, ¹⁶⁶Ho-, or ¹⁷⁷Lu-labeled EDTMP. The images (Fig. 4) demonstrated selective uptake in the skeleton and accumulation in the urinary system, findings which were in accordance with the biodistribution results.

FIG. 4.

Scintigraphic images of Sprague–Dawley male rats at 2 hours after intravenous injections of ¹⁵³Sm-EDTMP (A), ¹⁶⁶Ho-EDTMP (B), and ¹⁷⁷Lu-EDTMP (C). Masking of urinary bladder was done in images A and B using computer software, whereas the rat voided just before acquiring the image C.

Discussion

EDTMP labeled with a lanthanoid ¹⁵³Sm is used clinically for metastatic bone pain and is anticipated for use in bone marrow ablation, but its β⁻ energy and range of the particles are not ideal for both indications.^1,5
–7 There are several other β⁻-emitting lanthanoids that are being evaluated for this purpose. They include ¹⁶⁶Ho and ¹⁷⁷Lu and the chemically similar ⁹⁰Y.^8
–10 In the present study, parameters for labeling of EDTMP with these radiometals were optimized and their animal biodistributions were determined, comparing with ¹⁵³Sm-EDTMP. The latter was prepared in the authors' department and was of standards similar to that in the study by Goeckeler et al.¹² (%ID/g in femur 3.80 ± 0.31 and 3.720 ± 0.259, respectively).

¹⁶⁶Ho, which has a long range of β⁻ particles (E _β(max) = 1855 keV, maximum soft-tissue range: 8.7 mm), was considered for bone marrow ablation before marrow transplantation. It was labeled with EDTMP efficiently at pH 7 and 8 (≥98% at both pH levels) but dropped slightly at higher pH (Fig. 2A). A research group in South Africa also achieved >97% labeling efficiency at similar pH levels.⁸ In contrast, Appelbaum et al.¹³ showed 99.7% labeling efficiency at a higher pH level (pH 10.2). They applied ion exchange technique to assess the yield, whereas the South African and the present studies used paper chromatography. In the present study, ¹⁶⁶Ho was efficiently labeled with EDTMP at a molar concentration of 1:8, whereas only 80% labeling was reported at 1:250 by Ernestová et al.¹⁴

¹⁶⁶Ho-EDTMP gave the lowest bone uptake among all the radiopharmaceuticals studied (maximum at 2 hours, i.e., 1.20% ± 0.06%ID/g of femur and 36.1% ± 2.1%ID in whole skeleton). This could be explained by excessive removal of the complex from blood via kidneys (nine times higher than ¹⁵³Sm-EDTMP at 2 hours). Excretion of ¹⁶⁶HoCl₃ was also significantly high when compared with other ions. Variation of in vivo distribution of ¹⁶⁶Ho-EDTMP from ¹⁵³Sm-EDTMP has also been observed in previous studies, with its uptake in bone being inferior to the latter as seen in canine and baboon models.^8,13,15

In the present study, ¹⁷⁷Lu was efficiently labeled with EDTMP at a pH suitable for intravenous use (98.3% ± 0.4% at pH 7), which is consistent with a preliminary work of Chakraborty et al.⁹ In the present study, efficient labeling of ¹⁷⁷Lu could only be possible with higher ligand concentrations compared with other metals studied (98.5% ± 0.4% at a metal:ligand ratio of 1:20 or above). Chakraborty et al.¹⁶ in another study, however, produced 98.1% ± 0.5% ¹⁷⁷Lu-EDTMP at 1:5 ratio possibly because of slight variation in the method of labeling.

¹⁷⁷Lu-EDTMP prepared in this study showed highest bone uptake compared with other three metals when tagged to EDTMP. At 24 hours after injection, its total skeletal uptake was 70.2% ± 2.4%ID, whereas that of ⁹⁰Y-, ¹⁶⁶Ho-, and ¹⁵³Sm-labeled EDTMP was 45.5% ± 2.9%ID, 27.4% ± 3.6%ID, and 59.1% ± 2.6%ID, respectively. Significantly lower uptake in rats (46.25% ± 3.48%ID) has been reported by Chakraborty et al.¹⁶ Garnuszek et al.¹⁷ found femur uptake similar to the present study (5.32% ± 0.55%ID/g and 5.10% ± 0.32%ID/g, respectively).

The appearance of distribution of ¹⁷⁷Lu-EDTMP on the scintigraphic images of rats was consistent with direct measurements of biolocalization after animal sacrifice (Fig. 4C). There was, however, a higher level of noise seen in¹⁷⁷Lu-EDTMP compared with ¹⁵³Sm-EDTMP because of registration of scattered photons of higher energies. Similarly, the scattered events of 1379 keV photons of ¹⁶⁶Ho-EDTMP distorted its image, which was recorded at 81 keV.

Yttrium is a nonlanthanoid rare earth metal that possesses chemical properties similar to lanthanoids. In this study, ⁹⁰Y-EDTMP was prepared with a high labeling yield (98.4% ± 0.3%) at pH 8, which remained almost steady at higher pH levels (Fig. 2A). At higher acidic contents (pH 7 and less), the efficiency of labeling sharply declined.

As expected, while analyzing the biodistribution results it was found that ⁹⁰YCl₃ primarily accumulated in the liver, findings which were also observed with all other free ions. In contrast, however, the free ionic ⁹⁰Y activity in lungs was significantly low when compared with other chlorides. Its uptake in bone was minimal (a maximum of 0.11% ± 0.01%ID/g at 2 hours), but when tagged with EDTMP the accumulation in femur was 74 times higher at 24 hours. Total uptake of ⁹⁰Y-EDTMP in the skeleton was 56.9% ± 2.8%ID at 2 hours, which was parallel to ¹⁵³Sm-EDTMP (59.1% ± 4.6%ID) (Fig. 3). de Witt et al.¹⁸ using computer simulations predicted the localization of ⁹⁰Y-EDTMP in bone similar to ¹⁵³Sm-EDTMP, which was demonstrated by the present study's experiments in rats.

Bone uptake of a beta-emitting radiopharmaceutical gives a radiation dose to the malignant lesions of the skeleton and also at the same time to the bone marrow. Later, an untoward effect is caused, which may be reduced by using β⁻ particles of lower E _max and hence lesser penetration.¹ In the present study, ¹⁷⁷Lu-EDTMP has shown biolocalization similar to ¹⁵³Sm-EDTMP. However, it earns a better place than the latter because of the shorter soft-tissue range of its β⁻ particles when bone marrow toxicity is considered. Further, because of its half-life nearly four times than that of the latter agent, reinjections may be required after longer durations, reducing the overall cost. Further studies in human volunteers and patients are underway in the authors' institute.

On the other hand, limited success has been reported using ¹⁵³Sm-EDTMP for bone marrow ablation without support of a chemotherapeutic agent.^19,2090Y and ¹⁶⁶Ho have been proposed in literature for this purpose,^8,10 and as they have higher particle penetration they could be better choices. In the present study, however, ⁹⁰Y-EDTMP showed favorable skeletal localization compared with ¹⁶⁶Ho-EDTMP. Later, it was found inadequate for producing bone marrow ablation in dog models.¹³

Conclusions

This study demonstrates a convenient and efficient labeling of EDTMP with ⁹⁰Y, ¹⁶⁶Ho, and ¹⁷⁷Lu similar to ¹⁵³Sm-EDTMP, with slight dissimilarities in optimum labeling conditions. There is considerable variation in the skeletal accumulation of the four agents, which is in the following sequence: ¹⁷⁷Lu-EDTMP > ¹⁵³Sm-EDTMP > ⁹⁰Y-EDTMP > ¹⁶⁶Ho-EDTMP. It is recommended that ¹⁷⁷Lu-EDTMP is a better choice for bone pain palliation therapy, and ⁹⁰Y-EDTMP should be further evaluated for bone marrow ablation.

Footnotes

Acknowledgments

The authors thank Mohammad Yousuf Kakakhel, Shabana Saeed, and Tariq Majeed of the Department of Medical Sciences of PIEAS for their valuable technical assistance to accomplish this project. The authors also appreciate the technical staff of IPD, PINSTECH and DMS, PIEAS, for their selfless help in performing the animal studies. Support from Khurshid Ahmed and Nadeem Khalid is also appreciated. Tremendous help also came from Sallahud-Din, Khalid, Samina Roohi, and Ibrar Haider of Isotope Production Division of PINSTECH. This study was financially supported by PINSTECH and PIEAS.

Disclosure Statement

No competing financial interests exist regarding this publication.

References

Bouchet

, Bolch

, Goddu

et al. Considerations in the selection of radiopharmaceuticals for palliation of bone pain from metastatic osseous lesions. J Nucl Med, 2000; 41:682.

Serafini

, Houston

, Resche

et al. Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: A double-blind placebo-controlled clinical trial. J Clin Oncol, 1998; 16:1574.

Turner

, Claringbold

, Berger

et al. ¹⁵³Sm-EDTMP and melphalan chemoradiotherapy regimen for bone marrow ablation prior to marrow transplantation: An experimental model in the rat. Nucl Med Commun, 1992; 13:321.

Bartlett

, Webb

, Durrant

et al. Dosimetry and toxicity of quadramet for bone marrow ablation in multiple myeloma and other haematological malignancies. Eur J Nucl Med Mol Imaging, 2002; 29:1470.

Anderson

, Wiseman

, Dispenzieri

et al. High-dose samarium-153 ethylene diamine tetramethylene phosphonate: Low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases. J Clin Oncol, 2002; 20:189.

Maini

, Bergomi

, Romano

et al. ¹⁵³Sm-EDTMP for bone pain palliation in skeletal metastases. Eur J Nucl Med Mol Imaging, 2004; 31:S171.

Turner

, Claringbold

, Manning

et al. Radiopharmaceutical therapy of 5T33 murine myeloma by sequential treatment with samarium-153 ethylenediaminetetramethylene phosphonate, melphalan, and bone marrow transplantation. J Natl Cancer Inst, 1993; 85:1508.

Louw

, Dormehl

, van Rensburg

et al. Evaluation of samarium-153 and holmium-166-EDTMP in the normal baboon model. Nucl Med Biol, 1996; 23:935.

Chakraborty

, Das

, Unni

et al. ¹⁷⁷Lu labelled polyaminophosphonates as potential agents for bone pain palliation. Nucl Med Commun, 2002; 23:67.

10.

Rösch

, Herzog

, Plag

et al. Radiation doses of yttrium-90 citrate and yttrium-90 EDTMP as determined via analogous yttrium-86 complexes and positron emission tomography. Eur J Nucl Med, 1996; 23:958.

11.

Ishfaq

, Mushtaq

, Jawaid

. Experience on the neutron activation of natural/enriched Re, Sm, and Ho nuclides in a reactor for the production of radiotherapeutic radionuclides. Biol Trace Elem Res, 1999; 71–72:519.

12.

Goeckeler

, Edwards

, Volkert

et al. Skeletal localization of samarium-153 chelates: Potential therapeutic bone agents. J Nucl Med, 1987; 28:495.

13.

Appelbaum

, Brown

, Sandmaier

et al. Specific marrow ablation before marrow transplantation using an aminophosphonic acid conjugate ¹⁶⁶Ho-EDTMP. Blood, 1992; 80:1608.

14.

Ernestová

, Jedináková-Křížová

, Vaňura

. Potentiometric study of holmium complexes with EDTMP. Croat Chem Acta, 2004; 77:633.

15.

Jarvis

, Wagener

, Jackson

. Metal-ion speciation in blood plasma as a tool for elucidating the in vivo behaviour of radiopharmaceuticals containing ¹⁵³Sm and ¹⁶⁶Ho. J Chem Soc Dalton Trans, 1995; 9:1411.

16.

Chakraborty

, Das

, Sarma

et al. Comparative studies of ¹⁷⁷Lu–EDTMP and ¹⁷⁷Lu–DOTMP as potential agents for palliative radiotherapy of bone metastasis. Appl Radiat Isot, 2008; 66:1196.

17.

Garnuszek

, Pawlak

, Licińska

et al. Evaluation of a freeze-dried kit for EDTMP-based bone-seeking radiopharmaceuticals. Appl Radiat Isot, 2003; 58:481.

18.

de Witt

, May

, Webb

et al. Potentiometric and computer studies of yttrium-EDTMP. Inorg Chim Acta, 1998; 275–276:37.

19.

Turner

, Claringbold

, Berger

et al. ¹⁵³Sm-EDTMP and melphalan chemoradiotherapy regimen for bone marrow ablation prior to marrow transplantation: An experimental model in the rat. Nucl Med Commun, 1992; 13:321.

20.

Macfarlane

, Durrant

, Bartlett

et al. ¹⁵³Sm EDTMP for bone marrow ablation prior to stem cell transplantation for haematological malignancies. Nucl Med Commun, 2002; 23:1099.