D. Djokić

Alteration of the organ uptake of the 99mTc-radiopharmaceuticals, 99mTc-DPD, 99mTc-DMSA, 99mTc-tin colloid and 99mTc-MAA, induced by the applied cytotoxic drugs methotrexate sodium and cyclophosphamide

AimTo investigate the influence of certain cytotoxic drugs on the organ uptake of the following 99mTc-radiopharmaceuticals: 99mTc-2,3-dicarboxypropane-1,1-diphosphonic acid (99mTc-DPD), 99mTc-meso-2,3-dimercaptosuccinic acid (99mTc-DMSA), 99mTc-tin colloid and 99mTc-macroaggregated albumin (99mTc-MAA). Methotrexate sodium and cyclophosphamide were used as models to evaluate these effects. MethodsTwo groups of healthy male Wistar rats were treated separately by oral application of the drugs for 7 days. On the eighth day, each of the 99mTc-radiopharmaceuticals was applied in a separate group of treated animals. They were sacrificed at different time intervals and the radioactivity in the organs of interest was measured. The organ uptake of the 99mTc-radiopharmaceuticals in an additional control group of animals was also studied. ResultsThe results obtained showed an alteration in the organ uptake of 99mTc-radiopharmaceuticals in animals treated with cytotoxic drugs. In rats treated with methotrexate sodium, there was a higher uptake of 99mTc-DMSA in the bones, stomach and intestine, a higher uptake of 99mTc-DPD in the bones, intestine, blood and muscle, a lower uptake of 99mTc-tin colloid in the liver and a lower accumulation of 99mTc-MAA in the lungs. Cyclophosphamide-treated animals showed enhanced uptake of 99mTc-DMSA in the kidneys, a twofold enhanced uptake of 99mTc-DPD in all organs except the stomach, a decreased uptake of 99mTc-tin colloid in the lungs, spleen and kidneys and a significantly decreased uptake of 99mTc-MAA in the lungs. ConclusionThese results confirm that both methotrexate sodium and cyclophosphamide may alter the organ uptake of 99mTc-radiopharmaceuticals in experimental animals.

Particle size analysis: 90Y and 99mTc-labelled colloids

Colloidal particle size is an important characteristic to consider when choosing a radiopharmaceutical for diagnosis and therapeutic purposes in nuclear medicine. Photon correlation spectroscopy (PCS) and transmission electron microscopy (TEM) were used to determine the particle‐size distribution of 90Y‐ and 99mTc‐labelled antimony trisulfide (Sb2S3) and tin colloids (Sn‐colloid). 90Y‐Sb2S3 and 99mTc‐Sb2S3 were found to have a diameter of 28.92 ± 0.14 and 35.61 ± 0.11 nm, respectively, by PCS. By TEM, 90Y‐Sb2S3 particles were measured to be 14.33 ± 0.09 nm. 90Y‐labelled Sn colloid were found to exist with a dv(max1) of 805 nm and a dv(max2) of 2590 nm, by PCS, whereas 99mTc‐Sn colloid was shown to have more than 80% of radioactive particles of approximately 910 nm by PCS. For 90Y‐labelled Sb2S3 and Sn colloid, a comparison of TEM and PCS indicates that these techniques found significantly different mean diameters. TEM has an excellent resolution necessary for radiocolloid particle‐sizing analysis, and it is a desirable size‐measuring technique because it is more reliable than PCS.

90Y-Labeled Tin Fluoride Colloid as a Promising Therapeutic Agent: Preparation, Characterization, and Biological Study in Rats

In this study, tin fluoride colloid (SnF-c) was prepared, labeled with yttrium-90 ((90)Y), and characterized with respect to its physicochemical properties and biological behavior in an animal model. Particle size of SnF-c, at constant concentration of SnF(2), was dependent on pH, concentration of sodium fluoride (NaF), temperature, and time. The particle size of SnF-c decreased with an increase in NaF concentration and a decrease in reaction mixture pH. Radiolabeling yield of (90)Y-SnF-c at higher temperature increased and it was greater than 98% for the preparation at 95 °C. The (90)Y-SnF-c demonstrated high in vitro stability both in human serum and human synovial fluid at 37 °C up to 7 days. In vivo distribution studies in healthy male Wistar rats of (90)Y-SnF-c (particles <1 μm), following intravenous administration, revealed that the localization takes place preferably in the liver. The (90)Y-SnF-c (particles >1 μm) was well retained in the synovial space for 96 h after intra-articular injection, whereas leakage of (90)Y from the joint was 1.96% over this period. Because of high labeling yield and stability, (90)Y-SnF-c might be a promising agent for radiosynovectomy or therapy of liver malignancies.

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 (99m)Tc-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 (90)Y-DPD, (99m)Tc-DPD and (90)Y-labeled DPD-kit formulation [(90)Y-(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 (90)Y complex could be easily prepared, with an outstanding yield and was also found to be very stable for at least 10h after (90)Y-labeling. Protein binding value was 4.6+/-0.7% for (90)Y-DPD complex and the complex possess a hydrophilic character. The satisfactory results of (90)Y-DPD biodistribution in healthy test animals were obtained; the uptake in the bone was 11-13%ID/g after 24h depending on the pH value during the preparation. With high skeletal uptake, a minimum uptake in soft tissues and rapid blood clearance the (90)Y-DPD complex proved to be an excellent candidate for targeting tumor therapy.

Comparison of some physicochemical and pharmacokinetical parameters of 99mTc-PAH, 99mTc-MAG3 and 131I-OIH

The purpose of this study was to compare some physicochemical characteristics as well as pharmacokinetic behavior of 99mTc-PAH, as a novel renal agent, with 99mTc-MAG3 and 131I-OIH. 99mTc-PAH was prepared from lyophilized kit by adding 99mTcO4–. Labeled complex was stabile and high radiochemical purity radiopharmaceutical, with a low percentage of protein bound to human albumin and hydrophilic character. In spite of its smaller renal uptake, 99mTc-PAH gave satisfactory renal images. 99mTc-PAH showed faster urinary elimination than 99mTc-MAG3 and similar to those one for 131I-OIH. The comparison of pharmacokinetic parameters of 99mTc-PAH, 99mTc-MAG3 and 131I-OIH indicated the favorable characteristics of 99mTc-PAH.

Technetium-99m labeling of hippuric and p-amino-hippuric acid in the presence of DTPA: Biological and pharmacokinetic evaluation and comparison with99mTc-DTPA

Abstract99mTc-Hipp as a modified99mTc-DTPA, and99mTc-PAH as a new renal agent are developed. Each veal of lyophilised kit contain hippuric (Hipp) or p-aminohippuric acid (PAH), diethyltriaminepentaacetic acid as calciumtrisodium salt (CaNa3DTPA) and stannouschloride (SnCl2·xH2O), in molar ratio Hipp/PAH:DTPA=4∶1. They are high radiochemical purity radiopharmaceuticals, with hydrophilic character and low percentage of protein binding. The ITL chromatography and HPLC analyses of these labeled compounds have shown almost identical results as99mTc-DTPA, but their biological behavior in rats confirm certain differences.99mTc-Hipp is a renal agent clearing by the glomerular system, with better pharmacokinetical parameters than99mTc-DTPA:t1/2(α)=4.1 min,t1/2(β)=198.6 min,Kcl=1.2·10−2min−1 and a twofold value for blood clearance (Cl=2.07 ml/min).99mTc-PAH is a quite different renal agent, rapidly secreted by kidney as a tubular secretion agent. Its pharmacokinetical parameters:t1/2(α)=2.5 min,t1/2(β)=41.7 min andKcl=5.1·10−4 min−1 are almost equal to those of99mTc-MAG3, but the blood clearance of Cl=5.22 ml/min is even higher than that of IOH clearance.

Modified pyrophosphate-99mTc kit for application in nuclear cardiology

A modified99mTc(Sn)-pyrophosphate (PyP) kit for the application in nuclear cardiology (radioventriculography, angiocardiography, scintigraphy of blood pool) was developed. Each vial contains 12 mg PyP (Na4P2O7), 4 mg SnCl2·2H2O, 2.5 mg gentisic acid and 10 mg NaCl. The reconstitution is performed by dissolving the lyophilized kit in 3 ml 0.9% NaCl. In comparison with the standard pyrophosphate kit for bone scanning and detection of miocardial infarction, it contains an increased amount of Sn(II) so that the molar ratio ligand/reductant is lowered from 25 to 2.5. The radiochemical analyses showed that the radiochemical purity of the labeled kit is high (>90%) during three hours after addition of99mTc-activity. The shelf-life of the inactive freeze-dried preparation is up to four months providing that it is kept in vacuum and at appropriate temperature (2–8°C). The biodistribution studies revealed increased accumulation in blood and low uptake by liver and kidneys. It was concluded that the modified kit performs stable and reproducible properties.

Preparation and In Vivo Evaluation of 90Y-Meso-Dimercaptosuccinic Acid (90Y-DMSA) for Possible Therapeutic Use: Comparison with 99mTc-DMSA

INTRODUCTION The aim of this study was to find out if (90)Y could form a stabile complex with meso-2,3-dimercaptosuccinic acid (DMSA) and if (90)Y-DMSA may have potential for tumor therapy in the palliative treatment of bone metastases. METHODS The preparing of (90)Y-DMSA was carried out by varying experimental parameters, such as ligand concentration, pH, time, and temperature of the reaction, in order to maximize the labeling yield. Analysis of the complexes enclosed the radiochemical quality control (instant thin-layer chromatography, paper chromatography, and high-performance liquid chromatography), determination of pharmacokinetical parameters as well as biodistribution study in healthy male Wistar rats. In vitro stability of the complexes was tested too. RESULTS (90)Y-DMSA could be prepared in high yields (>95%) under optimized conditions of reaction. Stability studies in saline and human serum in vitro showed no significant release of activity from the ligand over 24 hours and 10 days, respectively. The preliminary biodistribution results in rat at 2 hours indicated that (90)Y-DMSA, at both pH levels, was significantly retained into bone. The uptake in the kidneys was lower for (90)Y-DMSA at pH 8.0 then at pH 3.0. The retention in other organs was negligible. CONCLUSIONS (90)Y complexes could be made with ease with DMSA. (90)Y-DMSA was obtained in good yield and was found to be very stable. A promising biodistribution result of this complex pointed at potential in the palliative treatment of bone metastases.

99Tcm-p-aminohippuric acid as a new renal agent.

99Tcm-p-aminohippuric acid (99Tcm-PAH) is a new renal radiopharmaceutical prepared from a lyophilized kit by the addition of sodium pertechnetate (Na99TcmO4). Each vial contains PAH, the calcium trisodium salt of diethylenetriamine pentaacetic acid (CaNa3DTPA) and stannous chloride (SnCl2.2H2O) in an inert atmosphere. It is a stable radiopharmaceutical with high radiochemical purity (> 95%). Its protein binding is very similar to that of 131I-OIH, but it is hydrophilic in character. Animal studies using 99Tcm-PAH have indicated that it provides renal images of satisfactory quality with no external background. Despite its almost identical radiochemical purity and HPLC analysis results to 99Tcm-DTPA, 99Tcm-PAH is rapidly secreted by the kidneys in a manner consistent with tubular secretion, as confirmed by rat probenecid studies, whereas 99Tcm-DTPA is excreted by glomerular filtration. The pharmacokinetic parameters of 99Tcm-PAH (t1/2(alpha)) = 2.5 min, t1/2(beta) = 41.7 min, Cl = 5.22 ml.min-1, Kel = 5.1 x 10(-4) min-1) differ from those of 99Tcm-DTPA. Evaluation of 99Tcm-PAH in two human volunteers confirmed its good renal characteristics: rapid disappearance from the vascular system, high uptake in kidneys followed by its very fast elimination, and low residual activity 20 min after its intravenous administration.

Statistical Evaluation of the Quality Control Results of 99mTc(Sn)-DPD

The results of the quality control of 99mTc-DPD produced during five consequtive years are statistically evaluated. Radiochemical purity of the kit determined in 75 batches was 98.3±1.3%. TLC on silica gel with the mixture of acetone and methanole (1:1, v/v) was used to determine the content of free pertechnetate. The labeled complex and 99mTc-hydrolyzate was separated by using ascending paper (Schleicher & Schull) chromatography and lN NaCl as the mobile phase. Reliable results were obtained showing that the content of the impurities 99mTc-pertechnetate and 99mTc-hydrolyzate is 1.7±1.3% and 3.4±2.1%, respectively. The biodistribution depends on the quantity of DPD. For the animal experiments its content should be 70–80 μg/kg b.w. The experiments revealed that the mean value of bone distribution was 8.8±1.9%/g and in muscles 0.043± 0.42%/g. The uptake in liver and kidneys was below 3%, i.e., 0.65±0.29 and 1.71±0.68%/organ, respectively. The bone/muscle ratio should be at least 160. The analysis shows that the obtained values are arranged around their, statistically allowed, mean values.