High Skeletal Uptake Research Articles

Biodistribution of 68Ga-DTPMP as a potential bone-seeking imaging agent in normal rats and rats with experimental model of bone callus

Bone metastases are common in advanced stages of various cancers. Positron emission tomography (PET) with radiotracers based on phosphonates and gallium-68 is a promising method of bone metastases detection. In this work a new complex based on diethylene triamine pentamethylene phosphonate (DTPMP) labeled with 68Ga was developed and its biodistribution in normal Wistar rats and rats with experimental model of bone callus was studied. The biodistribution studies in normal rats revealed high skeletal uptake of 68Ga-DTPMP (up to 1.45 %ID/g in femur) with rapid blood clearance and minimal uptake in any other major organs, except kidneys. In rats with experimental model of bone callus the accumulation of activity in bones and soft organs and tissues was slightly lower as compared with normal rats. The amount of 68Ga-DTPMP in femur with bone callus was higher than in non-lesion bones and reached 1.90 %ID/g at 2 h p.i. Therefore, 68Ga-DTPMP could be a promising radiotracer for bone tumors imaging and could be a valuable alternative to 18F-FDG and 18F-NaF for PET centers without an onsite cyclotron.

Preliminary studies on 177Lu-labeled sodium pyrophosphate (177Lu-PYP) as a potential bone-seeking radiopharmaceutical for bone pain palliation

(99m)Tc-Sn-PYP (Technetium-99(m) labeled tin pyrophosphate) has been widely used as a radiopharmaceutical for bone scanning as well as in nuclear cardiology. It is also found in the body in trace amounts. (177)Lu is presently considered as an excellent radionuclide for developing bone pain palliation agents. PYP is an analogue of MDP and MDP has been labeled with (177)Lu. No study on preparing a complex of (177)Lu with PYP has been reported yet. Based on these facts, it was hypothesized that a bone-seeking (177)Lu-PYP (Lutetium-177 labeled Pyrophosphate) radiopharmaceutical could be developed as an agent for palliative radiotherapy of bone pain due to skeletal metastases. (177)Lu was produced by irradiating lutetium foil (11mg) natural target at a flux ∼1.0×10(14)n/cm(2)/s for 12h in the swimming pool type reactor. (177)Lu in the form of (177)LuCl(3) was labeled with PYP. The radiochemical purity and labeling efficiencies were determined by paper chromatography. Labeling of (177)Lu with PYP was optimized and a labeled sample was subjected to HPLC analysis. To determine the charge on the (177)Lu-PYP complex, radio-electrophoresis was conducted for 1 h under a voltage of 300V and 45mA current using 0.025M phosphate buffer (pH 6.9). Bioevaluation studies with rabbit under γ-camera were also performed to verify the skeletal uptake. The quality control using paper radio-chromatography has shown >99% radiochemical purity of (177)Lu-PYP complex. Radio-chromatography also showed maximum labeling at ligand/metal ratio=60:1. HPLC analysis showed 1.42±0.01min retention time of (177)Lu-PYP complex. No decrease in labeling was observed at higher temperatures. Gamma-camera images of (177)Lu-PYP in normal rabbit at 24h post injection also showed high skeletal uptake. The study demonstrated that sodium pyrophosphate could be labeled with (177)Lu with high radiochemical yields (>99%). Negatively charged (177)Lu-PYP complex retained stability for a day and at high temperatures too. Gamma-camera images of (177)Lu-PYP in normal rabbit at 24h post injection showed high skeletal uptake, suggesting that it may be useful as a bone-pain palliation agent for the treatment of bone metastases.

Studies on 177Lu-labeled methylene diphosphonate as potential bone-seeking radiopharmaceutical for bone pain palliation

(99m)Tc-MDP (technetium-99(m)-labeled methylene diphosphonate) has been widely used as a radiopharmaceutical for bone scintigraphy in cases of metastatic bone disease. (177)Lu is presently considered as an excellent radionuclide for developing bone pain palliation agents. No study on preparing a complex of (177)Lu with MDP has been reported yet. Based on these facts, it was hypothesized that a bone-seeking (177)Lu-MDP (lutetium-177-labeled MDP) radiopharmaceutical could be developed as an agent for palliative radiotherapy of bone pain due to skeletal metastases. Biodistribution studies after intravenous injection of (177)Lu-MDP complex in rats may yield important information to assess its potential for clinical use as a bone pain palliation agent for the treatment of bone metastases. (177)Lu was produced by irradiating natural Lu(2)O(3) (10 mg) target at a thermal flux ∼ 8.0 × 10(13) n/cm(2) per second for 12 h in the swimming pool-type reactor.(177)Lu was labeled with MDP by adding nearly 37 MBq (1.0 mCi) of (177)LuCl(3) to a vial containing 10 mg MDP. The radiochemical purity and labeling efficiencies were determined by thin layer chromatography. Labeling of (177)Lu with MDP was optimized, and one sample was subjected to high-performance liquid chromatography (HPLC) analysis. Twelve Sprague-Dawley rats were injected with 18.5 MBq (0.5 mCi). (177)Lu-MDP in a volume of 0.1 ml was injected intravenously and then sacrificed at 2 min, 1 h, 2 h and 22 h (three rats at each time point) after injection. Samples of various organs were separated, weighed and measured for radioactivity and expressed as percent uptake of injected dose per gram. Bioevaluation studies with rats under gamma-camera were also performed to verify the results. The quality control using thin layer chromatography has shown >99% radiochemical purity of (177)Lu-MDP complex. Chromatography with Whatman 3MM paper showed maximum labeling at pH = 6, incubation time = 30 min, and ligand/metal ratio = 60:1. HPLC analysis showed 1.35 ± 0.05 min retention time of (177)Lu-MDP complex. No decrease in labeling was observed at higher temperatures, and the stability of the complex was found adequate. Biodistribution studies of (177)Lu-MDP revealed high skeletal uptake, i.e., 31.29 ± 1.27% of the injected dose at 22 h post injection. Gamma-camera images of (177)Lu-MDP in Sprague-Dawley rats also showed high skeletal uptake and verified the results. The study demonstrated that MDP could be labeled with (177)Lu with high radiochemical yields (>99%). The in vitro stability of the complex was found adequate. Biodistribution studies in Sprague-Dawley rats indicated selective bone accumulation, relatively low uptake in soft tissue (except liver) and higher skeletal uptake, suggesting that it may be useful as a bone pain palliation agent for the treatment of bone metastases.

Labeling, characterization, and in vivo localization of a new 90Y-based phosphonate chelate 2,3-dicarboxypropane-1,1-diphosphonic acid for the treatment of bone metastases: Comparison with 99mTc–DPD complex

The goal of this investigation was to examine the possibilities for yttrium-90-labeling of the 2,3-dicarboxypropane-1,1-diphosphonic acid (DPD), which is currently labeled with technetium-99m and as a 99mTc–DPD clinically used as bone imaging agent. Analysis of the complex enclosed the radiochemical quality control methods, biodistribution studies, as well as the determination of pharmacokinetic parameters. The biological behavior of complexes 90Y–DPD, 99mTc–DPD and 90Y-labeled DPD-kit formulation [ 90Y–(Sn)–DPD] in animal model was compared. The labeling conditions were standardized to give the maximum yield, which ranged between 93% and 98%. The examined 90Y complex could be easily prepared, with an outstanding yield and was also found to be very stable for at least 10 h after 90Y-labeling. Protein binding value was 4.6 ± 0.7% for 90Y–DPD complex and the complex possess a hydrophilic character. The satisfactory results of 90Y–DPD biodistribution in healthy test animals were obtained; the uptake in the bone was 11–13% ID/g after 24 h depending on the pH value during the preparation. With high skeletal uptake, a minimum uptake in soft tissues and rapid blood clearance the 90Y–DPD complex proved to be an excellent candidate for targeting tumor therapy.

Reduction of skeletal accumulation of radioactivity by co-injection of DTPA in [ 90Y-DOTA 0,Tyr 3]octreotide solutions containing free 90Y 3+

Peptide receptor-targeted radionuclide therapy is nowadays being performed with radiolabeled DOTA-conjugated peptides, such as [ 90Y-DOTA 0,Tyr 3]octreotide (also known as OctreoTher® or 90Y-DOTATOC). The incorporation of 90Y 3+ is typically ≥99%, however, since a total patient dose can be as high as 26 GBq or 700 mCi the amount of free 90Y 3+ (=non-DOTA-incorporated) can be substantial. Free 90Y 3+ accumulates in bone with undesired radiation of bone marrow as a consequence. 90Y-DTPA is excreted rapidly via the kidneys. Incorporation of free 90Y 3+ into 90Y-DTPA might prevent this fraction from being accumulated into bone, therefore we have investigated: the biodistribution in rats of 90YCl 3, [ 90Y-DOTA 0,Tyr 3]octreotide, and 90Y-DTPA; possibilities to complex 10% of free 90Y 3+ in a [ 90Y-DOTA 0,Tyr 3]octreotide containing solution into 90Y-DTPA prior to intravenous injection; and effects of 10% free 90Y 3+ in [ 90Y-DOTA 0,Tyr 3]octreotide solution, in the presence and in the absence of excess DTPA, on the biodistribution of in rats. The following results are presented: 90YCl 3 showed high skeletal uptake (i.e., 1% ID (injected dose) per gram femur, with main localization in the epiphyseal plates) and a 24 h total body retention of 74% ID; 90Y-DTPA had rapid renal clearance, and 24 h total body retention of <5% ID; added free 90Y 3+ in [ 90Y-DOTA 0,Tyr 3]octreotide solution could rapidly be incorporated into 90Y-DTPA at room temperature; and accumulation of 90Y 3+ in femur, blood, and liver was related to the amount of free 90Y 3+, whereas these accumulations could be prevented by the addition of DTPA. In conclusion, the addition of excess DTPA to [ 90Y-DOTA 0,Tyr 3]octreotide with incomplete 90Y-incorporation is recommended.

Pretherapy Gallium-67 Scanning in Paediatric Patients with Hodgkin’s Disease

Objective: To investigate the correlation between gallium-67 (⁶⁷Ga) uptake and histological subtypes of Hodgkin’s disease (HD) in paediatric patients. Subjects and Methods: Fifty-eight patients (45 males and 13 females aged 9.2 ± 4 years, range 1.5–17 years) with histologically diagnosed HD underwent pretherapy ⁶⁷Ga scanning on days 2, 5, 12 or 14 days after intravenous administration of 25–50 MBq (0.7–1.4 mCi) of ⁶⁷Ga citrate. The scans were evaluated both visually and quantitatively using the activity of ⁶⁷Ga in the liver as a reference. Clinical outcome of 11 patients with high diffuse ⁶⁷Ga skeletal uptake was compared with that of 17 patients showing normal distribution of ⁶⁷Ga in the skeleton. Results: Of the 58 patients, the ⁶⁷Ga scans were positive in 47 patients with 117 lesions. Visual analysis did not differentiate between the histological variants of HD. However, quantitative analysis of lesion-to-liver ratios showed significantly higher values of ⁶⁷Ga uptake in the mixed cellularity type than in the nodular sclerosis type (t = –3.7, p < 0.001). Patients with high skeletal uptake had a higher relapse rate (6/11) than those with normal skeletal uptake (3/17). Conclusion: The findings show that quantitative analysis of ⁶⁷Ga uptake can differentiate between the two main subtypes of HD (mixed cellularity and nodular sclerosis). Further diffuse skeletal uptake of ⁶⁷Ga indicates a higher relapse rate.

188Rhenium-EDTMP: A potential therapeutic bone agent

Bone seeking radiopharmaceuticals such as ethylenediaminetetramethylene phosphonate (EDTMP) complexes of 153Sm and 166Ho are receiving considerable attention for therapeutic treatment of bone metastases. Rhenium-188 has both beta-particle emissions for a therapeutic effect and gamma-emissions for imaging and it is available from an in-house generator system similar to the current 99mTc generator, which makes it convenient for clinical use. The preparation of 188Re-EDTMP is described using 188Re, which was obtained from the alumina-based 188W/188Re generator. Dependence of the radiolabeling yield of 188Re-EDTMP on reducing agent concentration, EDTMP concentration, incubation time, pH and addition of carrier was examined. In the case of optimum conditions, the radiolabeling yields of 188Re-EDTMP were ~98% for carrier-free as well as carrier-added 188Re. The addition of ascorbic acid plays an important role in the stability of carrier-free as well as carrier-added 188Re-EDTMP preparations. The biodistribution of carrier-free and carrier-added 188Re-EDTMP compounds in rats was also studied. The results show that 188Re (carrier-added)-EDTMP is a potential bone pain palliation radiopharmaceutical due to its high skeletal uptake, rapid blood clearance and relatively low soft tissue absorption.

Preparation of ( [formula omitted]) Re-AEDP and its biodistribution studies

The synthesis of the Re (V) complex and preparation of 188 Re -AEDP are described using 188 Re which was obtained from the alumina-based 188 W/ 188 Re generator. Dependence of the radiolabeling yields of 188 Re -AEDP on reducing agent concentration, AEDP concentration, pH and addition of carrier was examined. In the case of optimum conditions, the radiolabeling yields of 188 Re -AEDP were 92–93% for carrier-free 188 Re and 95–98% for carrier-added 188 Re . The stability of 188 Re -AEDP at pH≈6 was studied and it is found that the carrier has a significant effect on the stability of 188 Re -AEDP. The biodistribution of carrier-free and carrier-added 188 Re -labelled compounds in rats was also measured. The results show that 188 Re (carrier-added)-AEDP is a potential bone palliation radiopharmaceutical due to its high skeletal uptake, rapid blood clearance and relatively low soft tissue absorption.

Poor Renal Uptake of Tc-99m DMSA and Tc-99m MDP in a Patient With Fanconi Syndrome and Near Normal Glomerular Filtration Rate

The authors present a patient with Fanconi syndrome who demonstrated poor renal uptake of Tc-99m DMSA and high urinary concentration of the tracer. Tc-99m DTPA imaging was normal and the creatinine clearance was only minimally decreased. These findings suggest that Tc-99m DMSA may be accumulated in the kidney by glomerular filtration and subsequent tubular reabsorption. A Tc-99m MDP bone scan showed faint renal uptake, as well as diffuse high skeletal uptake, particularly in the spine, demonstrating that the metabolic bone disease associated with Fanconi syndrome can be one of the causes of poor renal visualization on a bone scan.