Evaluation by using radionuclide uptake of bone in Paget's disease of bone: special reference to treatment with calcitonin

Bone scintigraphy using 99mTc-MDP was performed on 2 patients with Paget's disease of bone before and after the treatment with a synthetic eel calcitonin analogue [Asu1,7)-eel calcitonin, ECT] at a dose of 40 U per day. All pagetic lesions showed markedly the increased accumulation of the radionuclide. The uptake ratio, defined as the count rate of 99mTc-MDP over each bone lesion to that over the control bone, was calculated. The response to the calcitonin therapy was evaluated with the uptake ratio of the radionuclide. The uptake ratio decreased markedly within the first 3 months of the treatment, in association with a palliation of bone pain, while the serum alkaline phosphatase activities which had been within the normal range or slightly high before the treatment did not show any significant change or did not reflect a clinical feature (e.g. bone pain) with the treatment. Thus, the uptake ratio on the bone scintigram seemed to offer the most sensitive and most reliable information for the evaluation of calcitonin treatment of Paget's disease of bone.     

A preliminary study of new imaging agents on inflammatory lesions

The purpose of the investigation was to evaluate the feasibility of imaging inflammatory lesions with five small molecular weight complexes of ^99mTc. The labeling yields of D-glucaric acid (D-Gca), citric acid (Cit), DL-malic acid (DL-Mal), L-malic acid (L-Mal) and tartaric acid (Tar) were all more than 90%. The percentage uptake/g tissue of them and ^99mTc-pertechnetate (P) in mice with turpentine-induced abscesses and abscess/muscle (A/M), blood (A/B), liver (A/L), kidney (A/K) concentration ratios were calculated. The maximum A/M ratios were 4.02±0.21 (Cit, 3h), 4.30±0.77 (D-Gca, 3h), 4.04±0.21 (DL-Mal, 6h), 3.50±0.23 (L-Mal, 1h), 3.20±0.17 (Tar, 1h) and 3.23±0.41 (P, 1h) respectively. The scintigram was obtained in a rabbit with turpentine-induced abscess after ^99mTc-D-Gca i.v. injection. Results demonstrated they all can accumulate in inflammatory lesions. Of them, ^99mTc-D-Gca is probably a potential imaging agent on inflammatory lesions.     

99mTc水杨醛Schiff碱配合物的制备与生物分布

One novel complex of ^99mTc-salicylidene-tyrosine Schiff base was designed and synthesized, and its biodistribution was investigated. The theoretical simulation revealed that the cis- and trans-isomers might co-exist in aqueous solution. A yield higher than 90% under the optimal condition of synthesis was obtained. Good water-solubility was demonstrated. Very little uptakes in muscle, brain, heart and S-180 sarcoma, as well as very rapid blood clearance were revealed in mice. Good accumulation in bone was shown. At 1h postinjection the bone uptake was 10.9% ID/g. At 3 and 5h postinjection, bone-to-muscle ratios were 19.0 and 9.3, and bone-to-blood ratios were 31.6 and 28. 9, respectively. The result indicates a bone imaging potency of the complex.     

Paper chromatographic and paper elettrophoretic study of the solution chemistry of Tc-99m-methylendiphosphonate and of Tc-99m-dimercaptosuccinate for improving the tumour-affinity of Tc-99m during scintigraphic imaging of cancer

In order to find the conditions under which Tc-99m-methylenediphosphonate (Tc-99m-MDP) and Tc-99m(V)-dimercaptosuccinate (Tc-99m(V)-DMSA) may become tumour-seeking agents, leaving healthy organs free from the radionuclide uptake, the solution chemistry of these radiopharmaceuticals was studied by paper chromatography and paper electrophoresis in distilled water, in physiological saline, in NAHCO3, and ascorbic acid solutions. Both radiopharmaceuticals are anionic in the radiopharmaceutical solution but get easily hydrolysed to form cationic Tc-99m species which concentrates in healthy bone and in some bone metastases. Tc-99m (V)-DMSA being more stable remains long in the blood pool giving undesirable presence of the radionuclide in lung, heart and kidneys, in addition to its reduced uptake in bone metastases and in some primaries. We are trying to eliminate these drawbacks of healthy organ uptake of Tc-99-m(V)-DMSA not only to get a clean scintigraphic image of the tumour with this radiopharmaceutical but to extend its formulation, thus obtained, to prepare radiopharmaceutical with Re-188, which is the higher homologue of Tc-99m, for systemic therapy of cancer. Essentially similar solution chemistry of both radiopharmaceuticals suggests that like Tc-99m-MDP, technetium-99m-dimercaptosuccinate is also a complex of tetravalent Tc-99m and not of pentavalent Tc-99m as so far supposed to be.     

Synthesis and biological evaluation of a novel <Superscript>99m</Superscript>Tc complex of HYNIC-conjugated aminomethylenediphosphonate as a potential bone imaging agent

A conjugate of 6-hydrazinopyridine-3-carboxylic acid (HYNIC) with aminomethylenediphosphonic acid (AMDP) was synthesized through a multiple-step reaction. HYNIC–AMDP could be labeled easily and efficiently with ^99mTc using N-(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)glycine (tricine) as coligand to form the ^99mTc–HYNIC–AMDP complex in high yield (> 95%). Its partition coefficient indicated that it was a good hydrophilic complex. The biodistribution studies of ^99mTc–HYNIC–AMDP in normal ICR mice showed that this complex had high bone uptake and low or negligible accumulation in non-target organs. As compared with ^99mTc–MDP, ^99mTc–HYNIC–AMDP had a higher bone uptake and the ratios of bone/blood and bone/muscle at early time after injection, suggesting that it could be potentially useful for bone imaging at an earlier time after injection according to further investigations of the biological behavior of this complex.     

Clinical significance of 99mTc-N-pyridoxyl-5-methyltryptophan (99mTc-PMT) in the diagnosis of intrahepatic masses

Hepatobiliary scintigraphy with 99mTc-N-pyridoxyl-5-methyltryptophan (99mTc-PMT) was carried out on 48 patients with intrahepatic masses, 44 with hepatocellular carcinoma and one each of hepatocellular adenoma, focal nodular hyperplasia, cholangiocellular carcinoma, and adenoid cystic carcinoma. Scans were performed twice, early scan (30 min post i.v.) and delayed scan (2.5 h post i.v.), and the delayed scan was used for assessing the accumulation of 99mTc-PMT in the intrahepatic masses. In the hepatocellular carcinoma group, based on individual patients, 17 out of 44 (38.6%) showed accumulation of 99mTc-PMT in various degrees; and based on individual masses, accumulation was noted in 21 out of 55 masses (38.2%). However, only the cases which had not received transarterial infusion of anti-cancer drugs (TAI) and/or blocking agents (TAE) were taken into consideration, 9 out of 18 patients (50%) and 12 out of 25 masses (48.0%) were found capable of picking up 99mTc-PMT. A case of hepatocellular adenoma showed a strong accumulation of 99mTc-PMT in the mass which was depicted as a defect on the 99mTc-colloid scan and did not show a significant accumulation of 67Ga. In a case of focal nodular hyperplasia, there were two space-occupying lesions (SOLs), one of which showed a clear-cut defect on the 99mTc-colloid scan and the other which showed only a distorted uptake pattern. However, both masses were strongly positive with 99mTc-PMT. 99mTc-PMT scintigraphy is useful in connection with 99mTc-colloid scan and sometimes with 67Ga-citrate in the diagnosis of intrahepatic masses originating from hepatocytes.     

Synthesis of novel nano-radiotracer for in-vivo bone imaging: 99mTc- citric acid based PEG dendrimer and its conjugation with alendronate

Bone scan is the test that guide physician to diagnose diseases in the bone at the early stage, to prevent metastases to other organs. In this study, citric acid dendrimer conjugation with alendronate was synthesized. Obtained product was confirmed by FT-IR and TEM. Cytotoxicity assay at different concentrations showed no toxicity on normal cell line compared to control group. Radiolabeling process was optimized by Box-Behnken software which is a computational method to determine optimum of important radiolabeling parameters. Optimized parameter for reducing agent, dendrimer-G₂-alendronate, and time for shaking was 1 mg, 12.3 mg, and 25 min respectively. For determination of in-vivo accumulation of ^99mTc-dendrimer-G₂-alendronate, SPECT imaging was done. Images showed high accumulation of radio-tracer in the skeletal compared to ^99mTc-MDP which is the frequent bone scan agent. All in all, obtained results confirmed our hypothesis that the dendrimer-G₂-alendronate can be noteworthy nano-radiopharmaceuticals to bone cancer imaging at early stage.     

The influence of stereoisomerism on the biological behavior of 99mTc labeled penicillamine

The aim of this study is to investigate stereoisomeric behavior of penicillamine and the effect of temperature on labeling. In addition, it was explored how stereoisomerism affected biological behavior of them. In the present work, D- and L-enantiomers of penicillamine(D-PA, L-PA) were labeled with ^99mTc using SnCl₂ as reducing agent and their radiopharmaceutical potentials were investigated. Quality control procedures were carried out using thin layer radiochromatography (TLRC), electrophoresis and high performance liquid radiochromatography (HPLRC). HPRLC chromatograms showed two peaks for ^99mTc-D-PA, while a single peak was observed for ^99mTc-L-PA at room temperature. However, the single peak was observed at 90 °C for both isomers. Labeling yields of each isomer were found to be over 98%. Biological activity of these complexes was determined on male Albino Wistar rats by biodistribution studies. While the biodistribution result of ^99mTc-D-PA showed high uptake in the liver, maximum uptake of ^99mTc-L-PA was observed in the kidneys. Both two complexes were cleared rapidly from the blood, mainly by the renal system. Since the activity concentration of ^99mTc-D-PA at the 30th minute in the kidneys and the liver reached a maximum value and at the 120th minute, it was removed by renal and hepatobiliary excretion. As a result, it can be concluded that stereoisomerism affect not only the chemical behavior, but also differs their biological behavior of these compounds.     

Accumulation velocity of 99mTc-HMDP in hip joint diseases

The accumulation rate and velocity of 99mTc-hydroxymethylene diphosphonate (99mTc-HMDP) in hip joints were determined within four minutes after a bolus of injection of 99mTc-HMDP in the patients with hip joint disorders. There exist a significant relationship between accumulation velocity of 99mTc-HMDP in the affected joint and serum osteocalcin in the patients with eight cases of degenerative osteoarthropathy and six cases of femoral necrosis. This result indicates that the accumulation velocity of 99mTc-HMDP in the affected joint is likely to become a marker of bone turnover in hip joint disorder.     

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.     

Statistical analysis of the results of99mTc-MDP quality control

The methods used for control of radiochemical purity of^99mTc-MDP are presented. TLC method on silica gel, developed with methanol and acetone (11 v/v), was convenient for determination of^99mTcO ₄ ^– with the content of 2.6±1.2%. The reliable results on detection of^99mTc hydrolyzate (2.2±1.3%) and for another^99mTc-MDP complex (13.2±2.8%) were obtained by application of ITLC (SA), developed with Sn-MDP. By Sephadex G-25 column chromatography (1.5 cm×5 cm) the separation of^99mTcO ₄ ^– was not achieved. The range of normal^99mTc-MDP biodistribution values in the organs of experimental animals have been determined. The mean value of bone distribution was 8.4±1.13%/g, in muscles 0.071±0.033%/g, while uptake in liver and kidneys was below 5%. Chi-square test and P show that the results on biodistribution of^99mTc-MDP in liver, bones and muscles are arranged around their mean values, which is statistically allowed.     

Phosphonate complexes of 99mTc - Potential bone scintigraphy agents

The synthesis of several combined aminophosphonate ligands containing an N-carboxymethyl group is described. The complexes of these ligands were prepared both with ^99mTc and ⁹⁹Tc, and the dependence of their formation on pH and the stoichiometry of reagents was studied. All of the complexes were pharmacologically evaluated. The distribution of radioactivity and bone uptake were determined, and discussed in comparison with clinically used phosphonate complexes. This revised version was published online in August 2006 with corrections to the Cover Date.     

Biodistribution of the bone imaging agents99mTc-DHPE and99mTc-MDP in rats

The self life of the freeze-dried formulation kits utilized for the preparation of the new bone imaging radiopharmaceutical^99mTc-1,2-dihydroxy-1,2-bis/dihydroxyphosphinyl/ethane /^99mTc-DHPE/ has been investigated as well as the toxicity of the DHPE. In a biodistribution investigation of^99mTc-DHPE in rats, in comparison to^99mTc-methylenediphosphanate /^99mTc-MDP/,^99mTc-DHPE exhibited a certain extent higher skeleton uptake, a higher blood clearance rate, a very low concentration in other organs, a satisfactory biological stability and excretion primarily through the kidneys. These properties demonstrate that^99mTc-DHPE is a new promising skeleton imaging radio-pharmaceutical.     

Synthesis, radiolabeling and biological evaluation of propylene amine oxime complexes containing nitrotriazoles as hypoxia markers

Two propylene amine oxime (PnAO) complexes, 1, containing a 3-nitro-1,2,4-triazole and 2, containing two 3-nitro-1,2,4-triazoles, were synthesized and radiolabeled with (99m)Tc in high labeling yields. Cellular uptakes of (99m)Tc-1 and (99m)Tc-2 were tested using a S180 cells line. Under anoxic conditions, the cellular uptakes of (99m)Tc-1 and (99m)Tc-2 were 33.7 ± 0.2% and 35.0 ± 0.7% at 4 h, whereas the normoxic uptakes of the two complexes were 6.0 ± 1.6% and 4.6 ± 0.9%, respectively. Both (99m)Tc-1 and (99m)Tc-2 displayed significant anoxic/normoxic differentials. The cellular uptakes were highly dependent on oxygen and temperature. Biodistribution studies revealed that both (99m)Tc-1 and (99m)Tc-2 showed a selective localization in tumor and slow clearance from it. At 4 h, the tumor-to-muscle ratios (T/M) were 3.79 for (99m)Tc-1 and 4.58 for (99m)Tc-2. These results suggested that (99m)Tc-labeled PnAO complexes (99m)Tc-1 and (99m)Tc-2 might serve as novel hypoxia markers. By introducing a second nitrotriazole redox center, the hypoxic accumulation of the marker was slightly enhanced.     

Scintigraphic evaluation of brain death with 99mTc-d,l-hexamethyl-propyleneamine oxime (HMPAO)

Lately, the criteria of brain death is being discussed. Cerebral scintigram, especially scintigraphic evaluation of brain death by dynamic study, has been previously reported. Cerebral imaging using radiolabeled amines such as 123I-IMP N-isopropyl-p-iodoamphetamin (IMP) or 99mTc d,l-hexamethyl-propyleneamine oxime (HMPAO) offers a significant information of brain death by the finding of "non visualized brain". However, the dynamic scintigram acquired during the bolus injection of 99mTc-HMPAO provides an additional information of brain death by classical "hot nose sign". 99mTc-HMPAO is able to be administered relatively in a large amount of dose. This cerebral perfusion tracer is lipophilic and remains in the central nervous system, which characterize its role as an reliable indicator of cerebral blood flow. As a result, this compound became suitable for the non-invasive study of brain circulation when the diagnosis of brain death is uncertain. We report a case of brain death in which diagnosis was made by the classical "hot nose sign" in dynamic scintigraphy performed when 99Tc-HMPAO was injected as well as the SPECT which showed a lack of cerebral visualization at the equilibrium state. As far as we are informed, this additional procedure used in the diagnosis of brain death has not reported before. The importance of performing a dynamic scintigram at the administration of 99mTc-HMPAO is also discussed in this report.     

灌喂氯化汞大鼠组织中汞结合金属硫蛋白的色谱/质谱联用表征研究

通过测定大鼠脏器组织中汞的总量、金属硫蛋白(MTs)含量及利用尺寸排阻色谱(SEC)与电感耦合等离子体质谱(ICP-MS)联用技术,分析了灌喂HgCl2大鼠脏器组织中汞与MTs的积累量及金属与MTs的结合形态。结果表明,灌喂HgCl2大鼠各脏器中汞的积累量显著高于其相应的对照组,特别是在肾、肝和睾丸中汞的含量较高,表明此3个脏器受汞的危害最大。MTs的含量水平说明当大鼠脏器受汞污染时,肌体中的MTs将被大量诱导产生以对重金属进行解毒。通过SEC-ICP-MS联用技术获得了组织中的金属与MTs的结合形态,其     

99mTc labeled ethylene-bis (valine) and ethylene-bis (α-alanine) and their preliminary biobistribution

The preparation of^99mTc-Sn-EBV and^99mTC-Sn-EBA is described. Different parameters affecting the labeling efficiency (ligand concentration, pH, molar ligand: reducing agent ratio) as well as the time-dependent stability of labeled compounds were investigated. Preliminary biodistribution studies in Wistar rats showed accumulation of the above mentioned compounds in kidneys.     

Synthesis, characterisation, and biodistribution of radioiodinated C-hydroxy-carboranes

The synthesis, radiolabelling and biodistribution of iodinated C-hydroxy-nido-carborane ligands is described. Microwave heating by using NaF in aqueous ethanol was used to prepare {sodium [7-hydroxy-7,8-dicarba-nido-undecaborate], nido-carboranol} and {sodium [7-hydroxy-7,8-dicarba-nido-undecaborate-8-carboxylic acid], nido-salborin} in 97 and 90?% yield, respectively. Radioiodination of these nido-carboranes was completed by using both (125) I and (123) I, and the products were obtained in high radiochemical purity (>99?%) and yield (72 to 87?%). The structures of the radiolabelled products were validated through comparison to authentic standards. Biodistribution studies in BALB/c mice showed low accumulation of the labelled compounds in the liver and intestines, which are sites where labelled carboranes typically localise. The labelled cluster bearing hydroxy and carboxylic acid groups on the two carbon vertices demonstrated preferential clearance through the kidneys and low thyroid uptake. This compound had substantially reduced non-specific binding than the deshydroxy analogue making it an attractive bifunctional ligand for preparing targeted molecular imaging and therapy agents.     

Synthesis and biological evaluation of novel 99mTc‐oxo and 99mTc‐tricarbonyl complexes with C3′‐functionalized thymidine dithiocarbamate for tumor imaging

A novel C3′‐functionalized thymidine dithiocarbamate derivative (3’DTC‐TdR) was successfully synthesized and labelled using [^99mTcO]³⁺ core and [^99mTc(CO)₃(H₂O)₃]⁺ core with high yields. The structures of the ^99mTc complexes were verified by preparation and characterization of the corresponding stable rhenium complexes. Both of the complexes were lipophilic and stable in vitro. Cell internalization experiments indicated that the uptakes of ^99mTcO‐3’DTC‐TdR were related to nucleoside transporters. Biodistribution of these complexes in mice bearing tumor showed that they had high tumor uptakes, good tumor/muscle ratios and tumor/blood ratios. Especially for ^99mTcO‐3’DTC‐TdR, it exhibited the highest tumor/muscle ratio and tumor/blood ratio at 4 h post‐injection. SPECT/CT imaging studies indicated clear accumulation in tumor, suggesting ^99mTcO‐3’DTC‐TdR would be a promising candidate for tumor imaging.     

99mTcN-MIBI在体外肿瘤细胞内的摄取及其与99mTc-MIBI的比较研究

研究了结肠癌细胞CL-187、肺腺癌细胞L-973以及乳腺癌细胞MCF-7分别对^99mTcN-MIBI和^99mTc-MIBI配合物的摄取情况.结果表明,^99mTcN-MIBI在3种肿瘤细胞内培养20～40min时的摄取达到极大值,并且摄取量明显高于^99mTc-MIBI,特别是在结肠癌细胞CL-187中.^99mTcN-MIBI在乳腺癌细胞MCF-7内的摄取量最高,培养40min时的单位细胞摄取百分率约为30%/105个细胞;在结肠癌细胞CL-187内的摄取量次之;在肺腺癌细胞L-973内的摄取量最低.细胞摄取条件实验结果表明:细胞浓度和培养温度的变化均会对细胞摄取产生影响.