Bor-Tsung Hsieh

Rhenium-188 hydroxyethylidene diphosphonate: a new generator-produced radiotherapeutic drug of potential value for the treatment of bone metastases

The search for an ideal radioisotope for systemic radiotherapy continues. As a generator-produced radioisotope emitting both beta and gamma rays and having a short physical half-life of 16.9 h, rhenium-188 is a very good potential candidate for systemic radiotherapy. In this study, we labeled hydroxyethylidene diphosphonate (HEDP) with188Re and analyzed the biodistribution and bone uptake following intravenous injection in rats to assess its potential for clinical use. The rats were injected with approximately 14.8 MBq (0.4 mCi)188Re-HEDP in a volume of 0.1 ml intravenously and then sacrificed at 1 h, 24 h, or 48 h (four rats at each time). Samples (about 0.1 g) of lung, liver, kidney, spleen, testis, muscle, stool, and bone (thoracic vertebra) were taken and weighed carefully. In addition, a 1-ml sample of blood was drawn from the heart and 1 ml of urine was taken from the urinary bladder immediately after killing. Tissue concentrations were calculated and expressed as percent injected dose per gram or per milliliter (% ID/g or ml). Bone lesions were created in the right tibial bone in three rabbits to calculate the lesion to normal uptake ratio (UN ratio). The biodistribution data showed that the radioactivity in the bone tissue was as high as 1.877% ID/g at 1 h and that it climbed to 2.017% ID/g at 4 h. The activity level in the kidney was highest at 1 h but declined rapidly throughout the study. The radioactivities in the lung, liver, muscle, spleen, testis, blood, and stool were all lower than 0.3% ID/g at I h and also declined rapidly. The biological half-life in bone was the longest (60.86 h). In contrast, the biological half-lives in muscle and blood were short (2.99 h and 6.21 h respectively). The concentrations of radioactivity in muscle, spleen, testis, and stool were quite low throughout the study. Most of the radiotracer was excreted by the urinary system. The L/N ratio was 4.23±0.21 in rabbits injected with188Re-HEDP and 4.25±0.23 in those injected with technetium-99m methylene diphosphonate. In conclusion, we would suggest that188Re-HEDP is a very good potential candidate for the treatment of bone metastases because of the following characteristics: (1) it is generator produced; (2) it has a short half-life; (3) it emits gamma rays suitable for imaging; (4) there is highly selective uptake in the skeletal system and bone lesions; and (5) it has a low non-target uptake and rapid clearance in nonosseous tissue.

Biodistribution of rhenium-188 Lipiodol infused via the hepatic artery of rats with hepatic tumours

The purpose of this study was to analyse the biodistribution of rhenium-188 Lipiodol in rats with hepatic tumours following intrahepatic arterial injection to assess the potential of188Re-Lipiodol as a radiopharmaceutical for the treatment of hepatic tumours in humans. Twelve male rats with hepatic tumours were killed at 1 h, 24 h and 48 h after injection of approximately 7.4 MBq of188Re-Lipiodol via the hepatic artery. Samples of various organs were obtained and counted to calculate the tissue concentration. Radioactivity in the hepatic tumours was very high throughout this study, with a biological half-life of 122.9 h. Radioactivity in the normal liver tissue was also high, but was significantly lower than in the tumour. The biological half-life in the normal liver tissue was 31.7 h. The ratio of tumour concentration to the normal liver tissue concentration was 5.15 at 1 h and rose to 7.7 at 24 h and 10.84 at 48 h. The level of radioactivity in the lung was high at 1 h, and declined rapidly over time. The level of radioactivity in the kidney was moderate throughout the study. The radiation concentrations in muscle, spleen, testis, bone and whole blood were insignificant. We conclude that188Re-Lipiodol should be considered as a potential radiopharmaceutical for the intra-arterial treatment of hepatic tumours.

Rhenium-188 sulphur colloid as a radiation synovectomy agent

Radiation synovectomy has been shown to be an effective treatment for the rheumatoid arthritic knee. In this study, we evaluated the suitability of rhenium-188 as a radiation synovectomy agent. In addition, we were successful in labelling sulphur colloid with188Re. In vitro stability tests revealed that more than 95% of the188Re remained in colloid form over a 3-day period. Intra-articular injection of188Re sulphur colloid into arthritic rabbit joints was followed by gamma camera imaging to quantify the leakage. The mean retention percentages of188Re colloid in arthritic knees were 93.7% (±1.4%), 90.8% (±1.7%) and 87.2% (±0.6%) at 1 h, 1 day and 2 days, respectively. A biodistribution study of the arthritic rabbits revealed that the highest activity outside the knees was in the liver and the kidneys. Our preliminary results indicate that 188Re sulphur colloid may be an effective radiopharmaceutical for radiation synovectomy.

Effect of reaction conditions on preparations of rhenium-188 hydroxyethylidene diphosphonate complexes.

Rhenium-186 (Re-186) hydroxyethylidene diphosphonate (HEDP) has been shown to localize in metastatic foci within bone in a manner similar to Tc-99m bone-seeking agents. Usually, in the preparation of diagnostic Tc-99m radiopharmaceuticals, the concentration of Tc is at trace level (10(-8) M). However, large amounts of carrier are included in the preparation of Re-186 radiopharmaceuticals (10(-4) M), which may significantly affect the preparation of Re-HEDP. In this study, Re-188 was used as an Re tracer. The effects of pH and concentrations of Re carrier on the preparation of Re-HEDP were investigated. Re-188-Sn-HEDP was prepared by reconstitution of a kit of lyophilized HEDP mixture, and tin chloride with a radioactive solution of perrhenate in saline. The total concentration of Re present in this work ranged from 10(-8) to 10(-3) M. The results showed that high labeling efficiency was obtained for each preparation. Although the chemical behaviors of the Re-188 HEDP complexes, with and without carrier, were similar, the biodistribution patterns of carrier free Re-188 HEDP in rats were found to differ from the biodistribution patterns of carrier-added Re-188 HEDP.

Comparison of various rhenium-188-labeled diphosphonates for the treatment of bone metastases

In the past, many diphosphonates were introduced as bone scan radiopharmaceuticals. In addition, diphosphonates have been labeled with beta-emitted isotopes and developed into useful therapeutic drugs for bone metastases. However, it is not clear which diphosphonate is the best choice when labeling with Re-188. In this study, we labeled methylene diphosphonate (MDP), hydroxyethylidene diphosphonate (HEDP), and hydroxymethane diphosphonate (HDP) with Re-188. Each radiopharmaceutical was further evaluated in two conditions (with and without carrier). Twenty-four rabbits were used (four in each group) for the analysis of the biodistributions and bone uptakes of these radiopharmaceuticals to assess their potential for clinical applicability. Four hours after intravenous injection of approximately 37 MBq (1 mCi) Re-188-labeled diphosphonate preparations, whole body scans were performed using a large-field gamma camera equipped with a high resolution collimator. Bone-to-soft tissue ratios (B/S ratio) were calculated using a computer program. Our data showed that Re-188 HEDP with carrier (10(-4) M carrier) could accumulate in the skeletal system whereas very little absorption by bone was observed in the rabbits that were injected with carrier-free Re-188 HEDP. In addition, no significant bone uptake was demonstrated for Re-188 MDP or Re-188 HDP, with or without carrier. The B/S ratio was 25.06 in the Re-188 HEDP with carrier group but less than 3 in the other groups. In conclusion, HEDP is the best choice among these three bone-seeking drugs when labeled with Re-188. But, it is necessary to add carrier when preparing Re-188 HEDP for the treatment of bone metastases.

Histologic study of effects of radiation synovectomy with Rhenium-188 microsphere

Rhenium-188 microsphere is a relatively new radiation synovectomy agent developed for the treatment of rheumatoid arthritis. It has been shown that the levels of unwanted extra-articular radiation are negligible with this agent. A histologic study was conducted to assess the effect of radiation synovectomy on synovium and articular cartilage after intra-articular injection of various doses of Re-188 microspheres into the knee joints of rabbits. Intra-articular injection of Re-188 microspheres into rabbit knee joints resulted in mild reactive inflammation and thrombotic occlusion of vessels which subsided rapidly. Sclerosis of subsynovium could be seen 12 weeks after injection. No evidence of damage to articular cartilage was noted. There was no significant difference in the articular pattern after injection of 0.3 or 0.6 mCi Re-188 microspheres. This study suggests that a treatment dose of Re-188 microspheres causes transient inflammation of synovium without any detectable damage to the articular cartilage of knee joint.

Preparation of carrier-free yttrium-90 for medical applications by solvent extraction chromatography

Abstract The separation of carrier-free 90Y from fission product 90Sr by solid supported solvent extraction chromatography was investigated using Teflon grain as solid support and a di-(2-ethylhexyl) phosphoric acid (D2EHPA) extraction agent as liquid phase. The optimum separation conditions are: (1) solid support using Dupont TF800 Teflon grains, (2) using 5% D2EHPA extraction agent as liquid phase, (3) setting the flow rate at 1 cm3/min, and (4) using a column diameter of 0.5 cm which was packed with 1 g treated Teflon. After loading 90Sr/90Y equilibrium solution, the loaded column was washed with 0.3 N hydrochloric acid to remove 90Sr species; subsequently, 8 N hydrochloric acid was used as an eluent to obtain a 90Y solution. Chemical yield was about 90%; radionuclide impurity of 90Sr in the final product was

Rhenium-188-labeled DTPA: a new radiopharmaceutical for intravascular radiation therapy

Balloon angioplasty is a standard treatment for artherosclerotic coronary artery disease. However, its clinical value is reduced by a high restenosis rate. A new concept in preventing restenosis is the use of a liquid-filled balloon containing a beta-emitting radioisotope. In this study, we performed biodistribution studies of Re-188 perrhenate and Re-188 diethylenetriaminopentaacetate (DTPA) to assess the resulting organ dose values in the event of balloon rupture if these agents are used for the clinical inhibition of restenosis after percutaneous transluminal coronary angioplasty (PTCA). After injecting Re-188 preparations intravenously, rats were killed at 10 min, 30 min, 60 min, 2 h, and 6 h (n = 5 per group). Tissue concentrations were calculated and expressed as percent injected dose per gram or per milliliter (%ID/g or %ID/mL). In addition, urine excretion and thyroid gland uptake were evaluated in rats (n = 5 per group) with a gamma camera after administration of 37 MBq (1 mCi) of each agent. Our data showed that both agents were excreted primarily via urine. However, the excretion of Re-188 DTPA was much faster than that of Re-188 perrhenate via the urinary system. The biodistribution data revealed that radioactivity levels in the stomach and the thyroid gland were high in the perrhenate group but low in the Re-188 DTPA group. The concentration levels in other tissues including lung, liver, testis, muscle, and blood were low throughout this study for both agents. The thyroid radiation value in the Re-188 perrhenate group was 0.163 mGy/MBq, which was much higher than that of the Re-188 DTPA group (0.0167 mGy/MBq). The stomach radiation value was as high as 0.127 mGy/MBq for Re-188 perrhenate, compared with 0.013 mGy/MBq for Re-188 DTPA. In conclusion, in the event of balloon rupture, the release of Re-188 DTPA results in lower radiation doses than Re-188 perrhenate, especially to the thyroid gland and the stomach. Our data suggest that Re-188 DTPA is a useful radiopharmaceutical for endovascular irradiation.

Radiolabelling of lipiodol with generator-produced 188Re for hepatic tumor therapy

In this study we prepared and analyzed the biodistribution of 188Re-labelled Lipiodol ([188Re]-Lipiodol) in rats after intrahepatic arterial injection. EDTB was synthesized by condensation of 1,2-benzenediamine and ethylenediaminetetraacetic acid (EDTA). The labelling efficiency of [188Re] Lipiodol was determined to be greater than 97% by ITLC developed with n-hexane. Following incubation of the [188Re] Lipiodol with an equal volume of serum at 37 degrees C for 48 h, ITLC indicated good in vitro stability. Approximately 7.4 MBq [188Re] Lipiodol was injected in each rat via the hepatic artery and samples of liver, spleen, muscle, lung, kidney, bone, whole blood and testis were obtained. [188Re] Lipiodol tissue concentrations showed that after 1 h intrahepatic injection most of the radiotracer was retained in the liver, and was eliminated slowly with a biological half-life of 33.5 h. Radioactvity levels in the lung, kidney and blood were moderate at 1 h, and declined rapidly over time. In the spleen, muscle, testis and bone, radiation levels were insignificant. These initial results indicate that -188Re- Lipiodol may be a potential radiopharmaceutical agent for the treatment of liver tumors.

Determination of impurities in the eluate of rhenium generator using hydrated magnesium oxide as the preconcentration agent

In recent years chances of using rhenium-186 and rhenium-188 as radioactive isotopes in diagnostic and therapeutic applications are increased very much due to the characteristic radiochemical and chemical properties of these two radioisotopes. In particular, chemical similarities between99Tc and99mTc pair and186Re and188Re pair make it easier to correlate the two groups of compounds. Rhenium-188 is generated from the beta-decay of tungsten-188 which was produced by double neutron capture on enriched tungsten-186 oxide. It is of great interest to examine the impurities in the eluate by radiochemical neutron activation. For this purpose, the preconcentration of the impurities in samples were necessary, and it was achieved by adsorption on hydrated magnesium oxide.