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Complexing of reduced technetium and tin (II) by chelating phosphate compounds. I. Chemical state of technetium.

Complexing of reduced 99mTc, 99Tc and of 113Sn(II) by pyrophosphate was studied, using the in vivo distribution in the rat as an indicator for complex formation. 99mTc-pyrophosphate was only formed at very low technetium concentrations, otherwise colloid formation occurred. Reduced 99mTc in trace amounts and 113Sn(II) complexed equimolarly with pyrophosphate were concentrated in bone and excreted in urine in comparable amounts. The in vivo distribution of 32P-orthophosphate and -pyrophosphate was characterized by a considerable uptake in the liver and a poor urinary excretion. The distribution patterns of 32P-pyrophosphate, complexed equimolarly with tin(II), remained unchanged. Despite these findings it is concluded that real chelates are formed, since non-complexed reduced 99mTc was not concentrated in bone. Two variants of reduced technetium could be discerned: a 99mTc-kidney agent and a 99mTc protein-bound agent. Some evidence was found that reduced technetium may change its oxidation state, but it seems much more likely that both agents are technetium(IV) compounds. It is suggested that the kidney agent is hydrated technetium dioxide whereas the protein-bound agent is a charged technetium(IV) compound. Only hydrated technetium dioxide is obviously complexed by chelating phosphate compounds.

Animals

Skeletal uptake of pyrophosphate labeled with technetium-95m and technetium-96, as evaluated by autoradiography.

For animal experimentation, the 95m and 96 technetium isotopes offer many advantages over technetium-99m. Their long physical half-lives and the emission of extranuclear electrons of low penetrating power make it possible to obtain autoradiograms of a great precision. The uptake of technetium stannous pyrophosphate by the epiphyseal plate was studied using liquid-emulsion microautoradiography, 3 hr after i.v. injection into 10-week-old rabbits. Microautoradiograms showed a well-defined and rather specific pattern of localization with intense uptake beneath the epiphyseal disk on the extremities of the vascular buds and a lack of accumulation in the cartilage, whether calcified or uncalcified. In the metaphysis, the label was located where new bone was being laid down and also over the cytoplasm of osteoclasts. We deduce from these results that in normal bone the general distribution of this tracer reflects mainly the arrangement of the blood supply, but the specific sites of accumulation are the bone-forming surfaces and the active resorbing osteoclasts.

Animals

Liver and gall-bladder imaging with technetium-99m dihydorthioctic acid and technetium-99m pyridoxylidene glutamate-a study in the young pig.

Seventeen scans on ten young pigs were performed after injection of Technetium-99m labelled dihydrothioctic acid (99Tcm-DHT) and Technetium-99m labelled pyridoxylidene glutamate (99Tcm-PG) using a gamma-camera. Sequential images of the liver, gall-bladder and intestine were observed in all healthy animals. 99Tcm-DHT produced the clearer liver images, whereas 99Tcm-PG produced more rapid and intense gall-bladder images. Analysis of hepatic bile in three animals also suggested a more rapid and higher concentration of 99Tcm-PG than 99Tcm-DHT (36% vs. 4% of the injected dose over two hours). Bowel images were not seen in an animal that had undergone exicision of the extrahepatic biliary tract, but scans performed after hepaticojejunostomy demonstrated intestinal transit of isotope. This study shows that the hepatobiliary system can be easily imaged using Technetium-99m labelled compounds which are excreted into bile. These agents may be useful in the diagnosis of obstructive lesions of the extrahepatic biliary tract of adults and infants.

Animals

Can technetium-99m-mercaptoacetyltriglycine replace technetium-99m-dimercaptosuccinic acid in the exclusion of a focal renal defect?

The presence of focal renal damage dictates different management of a child with urinary tract infection (UTI) compared with children who have normal kidneys. Technetium-99m-dimercaptosuccinic (DMSA) has a high sensitivity in the detection of a focal defect, and allows estimation of differential function. The introduction of 99mTc-MAG3 with high renal extraction suggests that this may be useful in children with UTI but its role remains speculative. Fifty-nine children with previous UTI underwent both 99mTc-DMSA and MAG3 within 4 wk of each other. Differential function and assessment of the images were undertaken. There is close correlation (R2 = 0.97) between the differential function. Analysis of the 99mTc-DMSA and functional MAG3 images showed that the functional image had a specificity of 88% and a sensitivity of 88% in the detection of a focal parenchymal defect. Technetium-99m-MAG3 in the clinical setting of a child with UTl allows accurate assessment of differential function and a high probability of detecting a focal renal abnormality.

Adolescent

Technetium-99m-methylene diphosphonate--a superior agent for skeletal imaging: comparison with other technetium complexes.

Methylene diphosphonate (MDP) was formulated as a complex of 99mTc for skeletal imaging. This agent was compared with three other bone-seeking technetium agents: ethane-1-hydroxy-1, 1-diphosphonate (EHDP), pyrophosphate, and polyphosphate. In tissue radioassay experiments in rodents, the technetium complexes of MDP and EHDP were similar, but skeletal concentration with both of these agents was higher than that with pyrophosphate or polyphosphate. The total-body retention of MDP and EHDP complexed with 95mTc was studied in beagle dogs for 35 days by excretion measurements and total-body counting and compared with polyphosphate and pertechnetate. The long-term retention was greater for MDP. The 5-day cumulative fecal excretion of 95mTc was low when administered as EHDP or polyphosphate complexes and negligible when administered as MDP complex. In six human volunteers the blood clearance of 99mTc-mdp was similar to that of 18F and significantly faster than that of 99mTc-EHDP. Pyrophosphate cleared from the blood much faster than polyphosphate but slower than the diphosphonates. The urinary excretion of the MDP complex was greater than for EHDP within the first 2-3 hr after injection. The 24-hr urinary excretion of pyrophosphate and polyphosphate complexes was not as complete as for the diphosphonates. All four 99mTc complexes proved satisfactory for clinical imaging studies. The MDP complex produced images of superior quality as early as 2 hr after administration, attributable to its more rapid clearance from the blood and soft tissues. On the contrary, a longer interval of 3-4 hr after injection was usually needed for 99mTc-EHDP; pyrophosphate and polyphosphate complexes regularly required a waiting period of 4 hr. Comparitive radiation dose estimates were made based on the available biologic distribution data for these 99mTc skeletal-localizing agents.

Animals

Technetium-99m-MIBI uptake in benign and malignant bone lesions: a comparative study with technetium-99m-MDP.

The potential of hexakis (methoxyisobutylisonitrile) technetium (1) (MIBI) for the imaging of various bone pathologies and for assessment of effectiveness of therapy were investigated in a prospective study. MIBI was evaluated in comparison to MDP bone scans in 73 bone lesions (31 benign, 42 malignant). With MIBI, all but six malignant lesions were clearly visualized and the mean lesion/contralateral (L/C) ratio (2.21 +/- 1.17) was significantly higher than that of benign counterparts (1.26 +/- 0.40) (p less than 0.0005). No such significance was detected on corresponding MDP bone scans (4.86 +/- 3.48 versus 3.11 +/- 1.52). Ten cases with malignant tumor underwent both pre- and post-therapy MIBI evaluation and it was demonstrated that radiotherapy and/or chemotherapy significantly inhibited MIBI uptake. Moreover, post-therapeutic MIBI uptake was a good reflection of the effectiveness of therapy as confirmed by histopathological evaluation. Thus, with a strikingly higher uptake in malignant bone lesions MIBI might have good potential for the detection of malignant bone pathologies as well as for assessing tumor response to therapy.

Adolescent

Kit preparation of technetium-99m-mercaptoacetyltriglycine: analysis, biodistribution and comparison with technetium-99m-DTPA in patients with impaired renal function.

Technetium-99m-mercaptoacetyltriglycine (99mTc-MAG3) was prepared by a frozen solution method, enabling the preparation of kits yielding a product substantially free of lipophilic impurities (96% 99mTc-MAG3). However, biliary activity was not completely eliminated as HPLC-purified 99mTc-MAG3 was also excreted by that route. Sequential 99mTc-DTPA and 99mTc-MAG3 renal scans were performed in 15 patients with renal dysfunction, including renal transplant recipients. In all cases, the 99mTc-MAG3 kit preparation provided superior images to 99mTc-DTPA at all levels of renal function due to a higher target-to-background ratio and a plasma clearance twice as fast as 99mTc-DTPA. Interpretation of delayed 99mTc-MAG3 images, however, was complicated by biliary excretion which will limit quantitative estimates of renal clearance. A 99mTc-MAG3 kit is likely to be of value in renal transplant assessment and in cases of significant renal impairment but would not appear to offer major advantages over 99mTc-DTPA in routine renal imaging.

Chromatography, High Pressure Liquid

Comparison of technetium 99m polyclonal human immunoglobulin and technetium 99m monoclonal antibodies for imaging chronic osteomyelitis. First clinical results.

The accuracy of technetium-99m human immunoglobulin (HIG) for the detection of chronic osteomyelitis (OM) was compared with white blood cell scintigraphy using 99mTc-labelled monoclonal mouse antibodies (MAB). Seventeen patients suspected of having OM in 20 lesions went through three-phase skeletal scintigraphy, HIG scintigraphy and MAB scintigraphy. The final diagnosis was established by open surgery, histology and bacteriology. Chronic OM was proved in 14/20 lesions. Six of these 14 infections were located in peripheral areas without active bone marrow and 8/14 in central areas with active bone marrow. In peripheral OM, 5/6 with HIG and 6/6 with MAB were true positives. In the central skeleton all 8/8 infections appeared as cold lesions in the MAB study, which were defined as being false negative due to their non-specificity. Using HIG, 5/8 central infections were determined to be truly positive by showing photon-rich lesions. These 5 lesions were located in the hip region and in the pelvis, whereas 3 lesions of the spine were missed. There were no false-positive results in either studies. In conclusion, MAB was superior to HIG in peripheral OM concerning sensitivity, anatomical landmarks and differentiation of soft tissue versus bone infection. In central OM MAB detected all lesions accurately, but no differential diagnosis was possible due to the non-specificity of photon-low areas. In this respect HIG seems to be more specific due to the increased accumulation even in central infection sites.

Adult

Comparison between thallium-201, technetium-99m-sestamibi and technetium-99m-teboroxime planar myocardial perfusion imaging in detection of coronary artery disease.

Technetium-99m-sestamibi (MIBI) and 99mTc-teboroxime (TEBO) are two new myocardial perfusion imaging agents. The purpose of this prospective study was to compare MIBI and TEBO to 201TI planar imaging. Eighteen patients with significant coronary artery disease on coronary angiogram were submitted to three treadmill stress tests performed within 3 mo and were imaged with the three radiopharmaceuticals as follows. 1. TI: 2.2 mCi, immediate and delayed views (4 hr later, 8 min/view). 2. TEBO: 15-20 mCi at stress (1 min/view) and a second injection was repeated 4 hr later at rest (20-25 mCi). 3. MIBI: 15-18 mCi at stress (8 min/view) and 1-4 days later, 15-18 mCi at rest. Patients achieved similar levels of exercise. A blinded reading was performed by three observers. The left ventricle was divided into three segments/view and ischemic/normal wall ratios were also determined. Segmental comparison showed an agreement in 85% (138/162) of the segments between TI and TEBO, in 92% (149/162) between TI and MIBI and in 84% (136/162) between MIBI and TEBO. Abnormal TI, MIBI and TEBO studies were seen in 16 (89%), 16 (89%) and 15 (83%) patients, respectively, detecting 77, 75 and 65 abnormal segments. Ischemic-to-normal wall ratios were 0.75 +/- 0.06, 0.73 +/- 0.08 and 0.78 +/- 0.08 for TI, MIBI and TEBO, respectively. In conclusion, although the biologic characteristics of these agents are different, this study showed a good correlation between them in detection of significant coronary artery disease (high pretest likelihood population).

Aged

Rapid preparation and quality control method for technetium-99m-2-methoxy isobutyl isonitrile (technetium-99m-sestamibi).

Technetium-99m-2-methoxy isobutyl isonitrile (99mTc-sestamibi) is a radiopharmaceutical that can be useful in the evaluation of patients with acute myocardial infarction. The current method for preparation requires a lengthy boiling water bath procedure and the recommended quality control procedure is cumbersome and time-consuming. Using a microwave oven, the heating time necessary to provide a labeling efficiency (averaging 97% for sestamibi-labeled with maximum allowable 99mTc activity and volume has been reduced to 10 sec. A new mini-paper chromatography (MPC) system has been developed to analyze the radiochemical purity of 99mTc-sestamibi involving a 1:1 chloroform/tetrahydrofuran developing solvent. The recommended thin-layer chromatography (TLC) system involving the use of an AI2O3-coated plate requires an average time for drying and development of 34.8 +/- 1.6 min (n = 58) to complete, whereas the new MPC system has an average developing time of 2.3 +/- 0.1 min (n = 26). For radiochemical purity values ranging from 71-99% (n = 31), the MPC and TLC methods correlated closely (r = 0.99) with a regression line of MPC% = 1.05 TLC%--5.75. The combined use of the microwave oven heating method and our quick quality control system will facilitate the rapid, emergency use of 99mTc-sestamibi and eliminate the need for advance preparation of multiple kits each day.

Chromatography, Paper

Comparison of methods for calculating glomerular filtration rate: technetium-99m-DTPA scintigraphic analysis, protein-free and whole-plasma clearance of technetium-99m-DTPA and iodine-125-iothalamate clearance.

True glomerular filtration rate (GFR) was measured in normal volunteers and in patients with normal and impaired renal function by the iothalamate clearance (IC) method of Sigman. Within 24 hr, GFR was also determined by two other methods: technetium-99m- (99mTc) DTPA scintigraphic analysis (SA) utilizing a modification of the Gates computer program, and by measuring disappearance of 99mTc-DTPA from whole plasma (WPC) and from protein-free ultrafiltered plasma (PFPC). Determinations of GFR by IC and by PFPC methods were virtually identical (mean absolute error 5.36 ml/min, r = 0.99, p greater than 0.05). GFRs measured in protein-free, ultrafiltered plasma differed significantly from those obtained from whole plasma only in sicker patients and in those taking multiple medications (in whom alterations in protein-binding of DTPA may be seen). The SA method correlated less well with the iodine-125-(125I) IC method than did either the protein-free or whole-plasma clearance methods (mean absolute error 32.36 ml/min, r = 0.74, p less than 0.05). However, the SA method provided useful information with respect to differential (split) renal function.

Adult

Characterization of tin-technetium colloid in technetium-labeled albumin preparations.

The Tc-99m human serum albumin (HSA) system has been reinvestigated with gel filtration as the assay method. Other than Tc-99m HSA, two radioactive components have been isolated by this technique. Both components are tin-technetium colloids of differing particle sizes, and the relative quantity of each one is pH-dependent. The colloid has been further characterized by protein-induced x-ray emission analysis (PIXE) and by tissue distribution in rats. By this gel-filtration method, commercial Tc-99m HSA kits have been evaluated and have revealed varying amounts of colloids present.

Animals

Clinical comparison of cardiac blood pool visualization with technetium-99m red blood cells labeled in vivo and with technetium-99m human serum albumin.

Technetium-99m red blood cells (Tc-RBC) labeled by an in vivo technique were compared with two preparations of Tc-99m human serum albumin (HSA) for cardiac blood-pool imaging. Relative distribution of the tracers was analyzed on end-diastolic frames of gated blood-pool studies and on whole-body (head to mid-thigh) anterior pinhole images. The Tc-RBC demonstrated greater relative percentage localization in the cardiac blood pool, higher target-to-background ratios in the left ventricle, and less liver concentration. For cardiac blood-pool imaging, Tc-RBC labeled by the in vivo approach appears to be superior to the two Tc-HSA preparations studied.

Cardiac Volume

Images of liposarcoma using technetium-99m bleomycin and technetium (V)-99m DMSA.

The effectiveness of Tc-99m bleomycin (BLM) and Tc(V)-99m DMSA are compared with that of Ga-67 citrate, which is currently the most widely used agent. In four patients with lipomatous tumors, the clinical significance of tumor imaging with each of these three agents is discussed and compared. Results indicate that both Tc-99m BLM and Tc(V)-99m DMSA are superior in detecting the extension or localization of liposarcomas.

Adult

Radiation dosimetry for technetium-99m-MAG3, technetium-99m-DTPA, and iodine-131-OIH based on human biodistribution studies.

Radiation dose estimates were calculated for the renal agents 99mTc-DTPA, 99mTc-MAG3, and 131I-OIH from biodistribution data gathered in groups of healthy human volunteers. Biokinetics were evaluated by Anger camera imaging, blood sampling, and urine collection and counting. Collected data were fit to four- or five-compartmental models using the CONversational Simulation, Analysis, and Modeling (CONSAM) software. Radiation dose estimates were performed using standard MIRD techniques. Average residence times in urinary bladder, kidney, and remainder of the body were used to predict radiation dose equivalents and effective dose equivalents for the three agents. Doses for DTPA and MAG3 were very similar and much lower on a per unit injected activity than OIH. The effective dose equivalents were 3.3 mSv/370 MBq for 99Tc-DTPA, 3.7 mSv/370 MBq for 99mTc-MAG3, and 0.99 mSv/11.1 MBq for 131I-OIH for bladder voiding every 4.8 hr; effective dose equivalents were 2.0 mSv/370 MBq for 99mTc-DTPA, 1.5 mSv/370 MBq for 99mTc-MAG3, and 0.28 mSv/11.1 MBq for 131I-OIH for bladder voiding at 30 min and then every 4.0 hr. Patients should void at the conclusion of the study, as early voiding can reduce the gonadal radiation dose by a factor of 2 to 3.

Humans

Excretion of iodine-123-hippuran, technetium-99m-red blood cells, and technetium-99m-macroaggregated albumin into breast milk.

The amount of radioactivity excreted in breast milk following three different nuclear medicine procedures on twelve nursing mothers has been measured. Some of this information has already been incorporated into the latest guidelines on suspension of feeding after maternal radiopharmaceutical administration. The overall radiation dose that the patients' babies would have sustained had breast feeding not been interrupted has been estimated as an effective dose equivalent. A model has been developed to describe the relationship between clearance of activity from the milk, time between expressions, and the fraction of milk expressed. Some simple guidance is given on calculation of suitable interruption times for any individual mother from counts on her milk samples.

Erythrocytes

Comparison of technetium 99m-phytate and technetium 99m-sulphur colloid in primary bone tumours.

Eleven patients with proven primary bone tumour (five Ewing sarcomas, six osteosarcomas) and two cases of metastatic bone involvement (primary other than bone) were investigated with 99mTc-phytate and 99mTc-sulphur colloid to compare the behaviour of the two radiopharmaceuticals at the tumour site. After intravenous administration of the respective radiopharmaceutical, imaging of the tumour site and its contralateral part was carried out at 15 min and 1 h intervals. The data were stored in our computer. Bone scanning was also carried out in all patients. 99mTc-phytate uptake was observed at the tumour site in ten cases. The 99mTc-sulphur colloid study revealed sparse or no significant uptake in eight cases. In two patients, with osteosarcoma 99mTc-sulphur colloid investigation showed uptake at the primary tumour site. However, the distribution pattern is different from that of 99mTc-phytate. No significant uptake of either 99mTc-phytate or 99mTc-sulphur colloid was observed in the two patients with metastatic skeletal disease. It may be concluded that the unusual accumulation of 99mTc-phytate at the tumour site is not due to any generalized reticuloendothelial phenomenon and that the radiopharmaceutical itself is responsible for this.

Adolescent