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 g/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.     

Rapid and sensitive determination of pertechnetate in99Mo/99mTc generator eluates by reversed-phase high-performance liquid chromatography

Reversed-phase high-performance liquid chromatography with u.v. detection was applied for rapid and sensitive determination of pertechnetate in⁹⁹Mo/^99mTc generator eluates, using a mixture solvent of acetonitrile and 0.04M aqueous acetate buffer (1/1) containing a few volume percentage of 0.5 M tetra-n-butylammonium hydroxide as the mobile phase. Employing a -bondapak C₁₃ column, the TcO ₄ ^– species was separated, monitored with absorbance at 254 nm, and observed at the retention time of 3.5 min. The detection limit was found to be 5.2·10^–10 g of Tc for each injection. Total Tc contents in the^99mTc eluates from clinically-used⁹⁹Mo/^99mTc generator were analyzed by this technique. The^99mTc (⁹⁹Tc) species was separated from the contaminant⁹⁹Mo. This method was found to be useful for the purification of^99mTc (⁹⁹Tc) as well as the determination of total Tc content.     

Statistical analysis of biodistribution of99mTc-colloid preparations

The results of radiochemical purity measurements for^99mTc–S colloid, 90.7±1.4, and^99mTc–Sn colloid, 98.9±1.2 obtained by ITLC (SG) with 80% methanol are given. The range of biodistribution normal values for^99mTc colloid preparations for animal organs is determined. The results of^99mTc–S and^99mTc–Sn colloid distribution in liver are 95.4±6.1% and 100,0±5.4%, respectively.     

Effect of aluminium on the radiochemical purity and99mTc-MDP biodistribution

Results on aluminium and^99mTc-MDP interaction under in vivo and in vitro conditions are presented. Aluminium, as chemical impurity, which in^99mTc-eluate some times appears above the allowed concentration (more than 20 g/ml) in the course of preparate labeling procedure may interact under in vitro conditions. Such a form of interaction was discovered by radiochromatographic methods. The highest Al³⁺-ion concentration studied (200 g/ml) increases the^99mTc-hydrolysate content by about ten times compared to the control. However, the same Al³⁺-ion concentration decreases by about four times the content of^99mTc-MDP complex, which is responsible for deposition in bones. According to biodistribution results obtained on wistar rats, significant increase of radioactivity in liver is observed, and at the same time the decrease in bones, in dependence on the aluminium ion dose. With a maximum dose of 200 g Al³⁺/kg b.w. the uptake of^99mTc-MDP in liver was higher for about 35% and lower in bones for 3.6%/g. With compensan (antacide drug) with which the animals were primarily treated per os, only considerably small changes were observed in^99mTc-MDP uptake, if compared to the control group. These findings are very important for clinical application of this preparate.     

Application of macroautoradiography and instantimage in radiopharmaceutical research

The evaluation of the pharmacokinetics of pure, beta radiopharmaceuticals is not possible with scintigraphy. Both whole-body autoradiography (WBAR) and Packard Instantimager, a device for rapid imaging, were used to study the whole body distribution of γ- and β-emitting radionuclides (^99mTc-MDP,^99mTc-sulfur colloid, or¹⁸⁸Re-HEDP), and results obtained from both methods were compared. The biodistribution of^99mTc-MDP and¹⁸⁸Re-HEDP were seen mainly in bones including skull, spine, and vertebrae of spine and cardiac and skeletal muscles. The^99mTc-sulfur colloid localized in liver, bone marrow, and spleen. The resolution of WBAR is superior than that of Packard Instantimager. However, the advantage of Packard Instantimager is that rapid imaging within few minutes is possible with it, while WBAR imaging requires several hours to days.     

Technetium-99m generator based on 12-molybdocerate —99Mo precipitate as column matrix

The preparation of insoluble 12-molybdocerate(IV) from⁹⁹Mo of low specific activity, produced by thermal neutron irradiation of MoO₃, is described. Samples of the material are dried at 50, 100 and 200°C and used as column matrices from which the generated^99mTc activity is periodically eluted with saline solution or saline solution containing 5·10^–5M K₂CrO₄ as an oxidant. The elution yields of^99mTc are high and reproducible (95–81%) with radionuclidic purity 99.98%. Both chemical and radiochemical purity (as TcO ₄ ^– ) of the eluates decrease with increasing drying temperature of the column matrix. Using chromated saline solution as eluent improves the radiochemical purity of the^99mTc eluate.     

A99Mo-99mTc generator based on the use of zirconium molybdophosphate-99Mo gel

A modified⁹⁹Mo–^99mTc gel generator is described. The present generator uses an insoluble zirconium molybdophosphate (ZrMP) gel tagged with⁹⁹Mo. Molybdenum-99 is chemically combined in the gel structure and cannot be eluted from the matrix. The presence of phosphate increases the chemical stability of the gel and decreases the molybdenum breakthrough. The prepared gel is sufficiently porous to permit ready diffusion of^99mTcO ₄ ^– which can be cluted with saline in yields of up to 90%. The gel was found to contain 25.1% Mo, 21.9% Zr, and 0.7% P in a molar ratio of 1.09:1.0:0.09, respectively. The high molybdenum content of the gel allows the use of cheap, non-polluting (n, )⁹⁹Mo. The eluted^99mTc was of high purity and can be used for medical and pharmaceutical applications.     

Comparative evaluation of four different99mTc-sulfur colloid kits used for liver scanning

The distribution of four different commercially available A, B, C, D kits (^99mTc-sulfur colloid) for hepatoimaging was compared in mice by organ radioassay and in rabbits for blood clearance. The distribution of kits A and C (single step kits) was assessed in the human by blood clearance, external liver, spleen measurement, and scintillation camera imaging. Kit A reaches a high concentration in liver within 15–20 minutes with relatively high surrounding tissue background, and superior spleen scintiphotos. However, when kit C was used, a high activity concentration in the liver was reached within 10–15 minutes with low tissue background and faint visualization of the radiotracer in the spleen. Blood clearance of the four^99mTc-sulfur colloids was determined in rabbits. The data obtained indicated that the four hepatoagents exhibit rapid blood clearance but the initial decrease of blood activity curve of kit D was relatively faster than the other three hepatic agents. The biodistribution is similar for the four^99mTc-S-colloids but the blood retained higher activity residue using kit A compared with others. The formation of^99mTc-sulfur colloid using kits B, D (multistep kits) involves many steps after the addition of^99mTcO ₄ ^– to the reagent. These procedures are time consuming, required facilities at the medical institutions and give rise to the radiation exposure. While single step kits A and C have the same diagnostic value, the use of kit C allows a reduction of absorbed radiation, which may be useful in the liver exploration in children.     

Synthesis,radiochromatography and biodistribution of99mTc-dimethylphosphinoethane (DMPE) complexes

The title complexes were prepared from no-carrier-added^99mTc–TcO ₄ ^– and the air-sensitive reducing ligand DMPE under argon in ethanol-water. At acidic pH [Tc(III)Cl₂ dmpe₂]⁺ was formed, while alkaline pH led to the formation of [Tc(I)dmpe₃]⁺. About 150°C and at least 10^–3M DMPE was needed to achieve over 95% yield in less than 1 hour, otherwise the [Tc(V)O₂dmpe₂]⁺ intermediate was present. Electrophoresis demonstrated the unit positive charge and reversed-phase ion-pair HPLC provided separation and identification of^99mTc-products by direct comparison with known⁹⁹Tc-complexes. In rats the^99mTc-complexes were excreted by kidneys and liver and reached high heart/blood but only low heart/lung and heart/liver ratios. In dogs satisfactory myocardial scintigrams were obtained in spite of high liver activity.     

A novel technique for the separation of99mTc from99Mo

A new technique for the separation of^99mTc from low specific activity⁹⁹Mo is reported. A separation based on the principle of precipitation of⁹⁹Mo as calcium molybdate has been investigated. On precipitating⁹⁹MoO ₄ ^2– from alkaline solution as calcium molybdate under controlled conditions, the^99mTcO ₄ ^– is found to remain quantitatively in the supernatant solution with little carry-over of⁹⁹Mo. This calcium molybdate (⁹⁹Mo) could be redissolved and reprecipitated at regular intervals, yielding^99mTc quantitatively in aqueous neutral solutions. Calcium molybdate precipitates containing up to 1.5 GBq of⁹⁹Mo and 130–180 mg of molybdenum were prepared and evaluated. The performance in terms of repeated^99mTc separation gave yields of 75–93% with acceptable readionuclidic and radiochemical purity.     

99mTc complexes of 1,3-propanedithiol derivatives

The labelling of 1,3-n alkylpropanedithiols and of 15-/1,3-dimercapto 2-propyl/ pentadecanoic acid by^99mTc has been performed by an exchange reaction with the hexachlorotechnetate ion^99mTcCl ₆ ^2– and by reduction of^99mTcO ₄ ^– with Sn/II/ in the presence of the ligand. The biological distribution of the exotechnetium complexes obtained by the latter method in mouse does not reveal a high tropism of these labelling compounds in relation to a particular tissue.     

Thermochemistry of Amines: Experimental Standard Molar Enthalpies of Formation of N-Alkylated Piperidines

The standard molar enthalpies of formation _f H _m ^° (l) at the temperature T = 298.15 K were determined using combustion calorimetry for N-methylpiperidine (A), N-ethylpiperidine (B), N-propylpiperidine (C), N-butylpiperidine (D), N-cyclopentylpiperidine (E), N-cyclohexylpiperidine (F), and N-phenylpiperidine (G). The standard molar enthalpies of vaporization _l ^g H ^{m °} of these compounds were obtained from the temperature variation of the vapor pressure measured in a flow system. From these data the following standard molar enthalpies of formation in gaseous phase _f H _m ^° (g) were derived for: A –(61.39 ± 0.88); B –(88.1 ± 1.3); C –(105.81 ± 0.66); D –(126.2 ± 1.3); E ( –88.21 ± 0.75); F –(135.21 ± 0.94); G (70.3 ± 1.4) kJ · mol^–1. They are used to determine the strain enthalpies of the cyclic amines A–G. The N-alkylated piperidine rings have been found to be about strainless.     

Biodistribution of A14C-and99mTc-labeled N-substituted nitrosourea (CCNU) in an animal tumor model

One formulation of¹⁴C labeled and another of^99mTc labeled 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) were administered i.v. to tumor (glioma) bearing rats. The radiopharmacokinetics of¹⁴C-CCNU were followed up to 24 hours post injection. On a per organ basis the blood, liver, small bowel, kidney cortex and muscle contained most of the activity. Optimum tumor to organ ratios occurred at 4–12 hours. The^99mTc-CCNU biodistribution was determined at 4 hours and compared to^99mTc-NaTcO₄. Tumor capsule to brain (29.5) and to muscle (10.59) ratios suggest^99mTc-CCNU to be a potential tumor seeking agent. Funded in part by USPHS Grant RR-05486-12.     

Using Tc-Re chemical analogy to synthesize and identify new99mTc complexes

The strong chemical resemblance between Tc and Re is applied to design and evaluate experiments with^99mTc complexes. A combination of spectrophotometric and electrophoretic techniques allows to propose the formula [TcO₂/amine/₂]⁺ for compounds prepared by reduction of^99mTcO ₄ ^– with Zn /solid phase/ in presence of several /bidentate/ amines.     

Quality control and statistical analysis of biodistribution of commercial99mTc-IDA derivatives

The results obtained for radiochemical purity of ITLC (SA) and (SG) using different solvent systems and low voltage electrophoresis are presented in the paper. Radiochemical purities obtained for^99mTc-dimethyl IDA (^99mTc-HIDA) and^99mTc-diethyl IDA (^99mTc-EHIDA) are 98.1±0.6% and 98.7±0.5%, respectively. Variable^99mTc hydrolyzate contents, depending on the ionic strength of the eluents and on the time interval between labelling and analysis, have been obtained by Sephadex chromatography. The eluent containing Sn-EHIDA inhibits dissociation of^99mTc-EHIDA due to dilution of the preparation during elution of the column and yielding only a small percent of Sephadex bound fraction, as compared to other investigated eluents. The range of normal^99mTc-IDA biodistribution values in the organs of experimental animals and statistical significance of the difference between these two preparations have also been determined. The results obtained for^99mTc-HIDA and^99mTc-EHIDA in the liver are 33.9±5% and 25.7±4.7%, respectively p<0.01.     

Kinetics and mechanisms of the oxidation of the octacyanoniobate(III)ion by oxyanions in alkaline aqueous media

Summary The kinetics and mechanisms of the oxidation of Nb(CN) _inf8 ^sup5– by the oxyanions S₂O _inf8 ^sup2– , BrO _inf3 ^sup– , and IO _inf4 ^sup– have been investigated in alkaline aqueous media (pH 12). The second-order rate constant for the electron transfer reaction between Nb(CN) _inf8 ^sup5– and S₂O _inf8 ^sup2– at 25.0 °C, I = 0.36m (K⁺), is 11.1± 0.3 m ^–1 s ^–1 with H = 30 ± 2kJmol^–1 and S = - 125 + 7JK^–1 mol^–1. The rate constant for the oxidation of Nb(CN) _inf8 ^sup5– by BrO _inf3 ^sup– at 25.0 °C, I = 0.20m (Na⁺), is 2.39 ± 0.08m ^–1 s ^–1 with H = 28 ± 2kJmol^–1 and S = -139 ± 7JK^–1mol^–1. The oxidation of Nb(CN) _inf8 ^sup5– by IO _inf4 ^sup– proceeds by two parallel pathways involving the monomeric IO _inf4 ^sup– ion and the hydrated dimer H₂I₂O _inf10 ^sup4– . The second-order rate constant for the oxidation of Nb(CN) _inf8 ^sup5– by monomeric IO _inf4 ^sup– at 5.0 °C, I = 0.050m (Na⁺), is (3.3 ± 0.6) × 10³ m ^–1 s ^–1 with H = 75 ± 6 kJ mol^–1 and S = 94 ± 15 J K^–1 mol^–1, while the rate constant for the oxidation by H₂I₂O _inf10 ^sup4– is (1.8 ± 0.1) × 10³ m ^–1 s ^–1 with H = 97 ± 5 kJ mol^–1 and S = 166 ± 16 J K^–1 mol^–1 under the same reaction conditions. The rate constants for each of the oxidants employed display specific cation catalysis with the order of increasing rate constants: Li⁺ < Na+ < NH _inf4 ^sup+ < K⁺ < Rb⁺ < Cs⁺, in the same direction as the electronic polarizability of the cations. The results are discussed in terms of the outer-sphere electron-transfer processes and compared with the corresponding data and mechanisms reported for other metal-cyano reductants.     

Exchange labeling of proteins:99mTc labeled transferrin

^99mTc-labeled transferrin was prepared by reduction of^99mTcO ₄ ⁻ ; with stannous DTPA or stannous citrate followed by equilibration of the technetium chelate with human transferrin. The rate of transfer of^99mTc to transferrin in the presence of 0.015M citrate buffer was dependent on pH in the order pH 2.1> pH 7.2> pH 4.1> pH 5.9. The incorporation rate was inversely proportional to the concentration of DTPA and citrate buffer. The replacement of citrate buffer by acetate buffer or oxalate buffer reduced drastically the formation of^99mTc-labeled transferrin at pH 4.1. The formation of^99mTc-labeled transferrin prepared from the reduction of^99mTcO ₄ ⁻ with stannous citrate was faster than that from the reduction with stannous DTPA in the presence of 0.015M citrate buffer and pH 2.5. Equilibration of transferrin with^99mTc-labeled pyrophosphate did not produce^99mTc-labeled transferrin at pH 4.5. The ligand exchange labeling of^99mTc to transferrin in 0.015M citrate did not cause appreciable denaturation of the protein at all pH values. This method also enabled labeling of the protein in a low concentration (2.6·10⁻⁴ M) via tin reduction. Sequential external imaging of the^99mTc-labeled transferrin in Sprague-Dawley rats bearing Walker-256 carcinosarcoma showed optimal tumor localization occurred at 3 hr after injection. In spite of this,^99mTc-labeled transferrin does not appear to be a suitable imaging agent because of the low tumor to blood ratio of^99mTc (0.50±0.17) at 3 hr post injection. This is similar to that of^{6 7}Ga-citrate (0.43±0.15%).     

Beta-branching fraction of117Cd isomers and it branching of117mIn

Using radiochemical and gamma spectrometric technique the branching fractions in the beta decay of¹¹⁷Cd isomers and the internal transition branching of^117mIn have been established. The beta branching fraction of^117gCd^117gIn was obtained as 0.86±0.06 and the value of^117mCd^117gIn was found to be less than 1%. The internal transitin branching and the isomer cross-section ratio were obtained as 0.31±0.02 and 0.197±0.002, respectively. From the measured isomer cross-section ratio the spin cut-off parameter was evaluated, which agreed with the value reported in the literature.     

Technetium-99m generators based on neutron irradiated 12-molybdocerate as column matrix

Neutron irradiated 12-molybdocerate(IV) is evaluated as a column matrix for use in preparation of small chromatographic column type^99mTc generators. Greater than 87% of the generated^99mTc activity is immediately and reproducibly eluted with passing 10 cm³ of saline or chromated saline solutions through 3.0 g of molybdocerate column bed at flow rates of about 1.0 cm³/min. The elution performance of^99mTc does not drastically change with increasing the drying temperature and/or the particles sixe of the column matrix in the range investigated. Saline eluent containing 5·10^–5M CrO ₄ ^2– increases the radiochemical purity of the eluate to >98% TcO ₄ ^– . Radionuclidic and chemical purities of the eluates satisfy the specifications for use in nuclear medicine.     

Preparation of113mIn radiocolloid for liver scanning

Kits were developed for the preparation of a sterile^113mIn colloid as a radiopharmaceutical for liver scanning. 2.5 ml of^113mIn sterile generator eluate was added to 0.5 ml of ferric chloride dissolved in 0.04N HCl (40 g/ml). The pH was adjusted by addition of 2 ml of phosphate buffer. The optimal pH for the formation of^113mIn colloid was found to be equal to 7.5–8.5. Liver uptake in mice was determined to be 85–90%.