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Transition metal chemistry of main group hydrazides, Part 14: Evaluation of new Tc-99m chelates of thiol functionalized phosphorus hydrazides.

Ligands containing a combination of amine or amide nitrogens and thiol functionalities have been found to form stable chelates with Tc-99m, presumably in oxidation state +5. Two new thio-phosphorus monohydrazides [(MeO)2P(S)NMeNHCH2C6H4SH], SL1 and [(MeO)2P(S)NMeNHC(O)C6H4SH], SL2 were synthesized and their complexation properties with Re(V) and Tc-99m have been studied. Neutral-lipophilic Tc-99m chelates with both SL1 and SL2 were formed in high yields (95-97%) as a single species ascertained by electrophoresis and reversed-phase HPLC. Biodistribution studies show good in vivo stability and primary clearance of both 99mTc chelates is via the hepatobiliary pathway. Re(V) complexes with SL1 and SL2 were also synthesized using the ReOCl3(PPh3)2 precursor to obtain the product ReOCl(L)(PPh3), where L = SL1 or SL2. H+ was lost from the N-atom and the thiol group in these Re chelates. Even though the Tc-99m chelates of SL1 and SL2 formed at tracer levels are not identical to the Re-chelates (different synthons were used), the Re data suggests complexation of Tc-99m by these hydrazido-thiol ligands will be similar to N,S ligand systems previously used. The good in vitro and in vivo stability and high yields of the Tc-99m complexes of SL1 and SL2 indicate the potential hydrazido-thiols hold for use as a basis in formulating new Tc-99m radiopharmaceuticals, particularly when thiol moieties are used in conjunction with multi-functional phosphorous hydrazide compounds.

Animals↗

Direct 99mTc-labeling of antibodies by sodium dithionite reduction, and role of ascorbate as a stabilizer in cysteine challenge.

A method for the direct 99mTc-labeling of antibodies by dithionite reduction was developed. Among three murine monoclonal IgG1 and one human polyclonal IgG (hIgG) antibodies tested, hIgG was the most quickly reduced by dithionite. These differences may reflect the reactivities of antibody disulfide bonds toward the oxidation products of dithionite. By optimizing reduction conditions to generate enough free sulfhydryl groups, it was possible to radiolabel human IgG and monoclonal antibody 170 with 99mTc with a 90% monomeric antibody efficiency. The process avoided colloid formation. In contrast, about 0.1 sulfhydryl groups per antibody molecule, less than 1% of the possible 36, were detected after treatment with ascorbate (up to 35,000:1 molar ratio) at room temperature for 1 h for the antibodies tested. Sulfhydryl groups generated in antibodies were estimated using a new method: 5-iodoacetamidofluorescein-labeled antibodies quantitated by size exclusion HPLC. Ascorbate was found to prevent antibody aggregate formation in cysteine-challenged samples.

Animals↗

The influence of radioisotope vehicle on breast sentinel node detection.

AIM: To assess the relationship between carrier molecule size and time elapsing between marker injection and sentinel node(s) biopsy in patients with breast cancer. MATERIAL: The study performed on 122 women, in whom the sentinel node(s) was identified according to the procedure described below. In Group I (n=72 patients), SN identification was done with radioisotope marker of 400-3000 nm molecule size (tin colloid). In Group II (n=50 patients) radioisotope marker of <100 nm molecule size (colloidal albumin) was used. METHODS: All the patients of both groups received the markers with a single-point, intradermal, periareolar injection. Four hours after the injection (Group I - surgery in the next day) or immediately before the surgery (in this same day) (Group II), stationary lymphoscintigraphy was performed. RESULTS: Mean numbers of sentinel nodes identified with the radioisotope method in Groups I and II were 1.22 and 1.48, respectively. The difference was statistically significant (p<0.01). CONCLUSIONS: There is a relationship between the radioisotope marker molecule size and the injection-to-intra-operative evaluation time. Administration of small molecule size radioisotope marker several hours prior to the planned surgery appears to be the optimum procedure in this method of SN identification in patients with breast cancer.

Breast Neoplasms↗

Acute gastrointestinal bleeding.

Radionuclide bleeding scintigraphy remains a simple yet powerful method of localizing sites of gastrointestinal hemorrhage and is most commonly performed today using the red blood cell technique. Radionuclide techniques for detecting bleeding remain safe, sensitive, and noninvasive. Based on several simple concepts, including the use of cine-mode imaging over the abdomen, it is possible to achieve excellent accuracy in localizing the site of bleeding. Studies often contain additional ancillary information, which is helpful for diagnosis and patient treatment.

Acute Disease↗

A multiscintigraphic approach to imaging of lymphedema and other causes of the congenitally enlarged extremity.

Nuclear imaging in the definition of the components of the congenitally enlarged extremity is important in the design of a successful therapeutic regimen. In our series of 32 patients evaluated for primary lymphedema, 85% were determined to have abnormalities that were not purely lymphatic in origin. The multiscintigraphic approach defines the components of the lymphatic and vascular systems with the use of technetium-99m [99mTc] antimony sulfide colloid (99mTc Sb2S3) for lymphatic, 99mTc diethylenetriamine pentacetic acid (DTPA) for capillary-interstitial, and 99mTc-tagged red blood cells for venous systems.

Antimony↗

[The stability of solid food labeled with different radiopharmaceuticals for studying gastric emptying].

OBJECTIVE: Sulfur colloid 99mTc-SC, the radiopharmaceutical of choice for solid gastric emptying studies, is not available in our country. It has led us to assess the solid binding stability of seven alternative radiopharmaceuticals that could present adequate fixation to it a priori. MATERIALS AND METHOD: The stability of labelled solid food with seven colloidal 99mTc-radiopharmaceuticals of different sizes and nature (MAA, tin colloid, rhenium sulphide macrocolloid, albumin microcolloid, sulfur nanocolloid, albumin nanocolloid and rhenium sulfur nanocolloid) has been studied by measuring their dissociated activity after two hours digestion in simulated gastric fluid (kept 120' in agitation, in HCl 0.1 M at 37). The survey also assesses radiopharmaceutical labelling stability after two hours digestion in identical conditions by measuring their radiochemical purity in ITLC. RESULTS: In these conditions, MAA, rhenium sulphide macrocolloid, albumin microcolloid and albumin microcolloid present the best behaviour, with an activity linked to food over 90 % of the previously fixed activity. CONCLUSIONS: According to the results, there is no relationship between the radiopharmaceutical size and nature and the stability of its binding to the solid food. Because rhenium sulphide macrocolloid is no longer manufactured and the other three radiopharmaceuticals which have a binding stability to the solid food over 90 % do not include digestive explorations amongst their indications, nowadays, there is a serious legal limitation to carry out this type of studies in our country.

Digestion↗

Synthesis and characterization of novel oxotechnetium (99Tc and 99mTc) and oxorhenium complexes from the 2,2'-bipyridine (NN)/thiol (S) mixed-ligand system.

The synthesis and characterization of oxotechnetium and oxorhenium mixed-ligand complexes of the general formula MO[NN][S](3) (M = (99)Tc and Re), where NN represents the bidentate ligand 2,2'-bipyridine and S represents a monodentate thiophenol, is reported. The complexes were prepared by ligand exchange reactions using (99)Tc-gluconate and ReOCl(3)(PPh(3))(2) as precursors for the oxotechnetium and oxorhenium complexes, respectively. Compound 1 (M = (99)Tc, S = 4-methylthiophenol) crystallizes in the monoclinic space group P2(1)/a, a = 23.12(1) A, b = 14.349(6) A, c = 8.801(4) A, beta = 94.81(2) degrees, V = 2918(2) A(3), Z = 4. Compound 3 (M = Re, S = 4-methylthiophenol) crystallizes in the monoclinic space group P2(1)/a, a = 23.018(9) A, b = 14.421(5) A, c = 8.775(3) A, beta = 94.78(1) degrees, V = 2903(2) A(3), Z = 4. Compound 4 (M = Re, S = 4-methoxythiophenol) crystallizes in the orthorhombic space group Pbca, a = 16.32(1) A, b = 24.55(2) A, c = 16.94(1) A, V = 6788(9) A(3), Z = 8. In all cases, the coordination geometry around the metal is distorted octahedral with the equatorial plane being defined by the three sulfur atoms of the thiophenols and one nitrogen atom of 2,2'-bipyridine, while the apical positions are occupied by the second nitrogen atom of 2,2'-bipyridine and the oxygen of the M=O core. The complexes are stable, neutral, and lipophilic. Complete (1)H and (13)C NMR assignments are reported for all complexes. The analogous oxotechnetium complexes have been also synthesized at tracer level ((99m)Tc) by mixing the 2,2'-bipyridine and the corresponding thiol with Na(99m)TcO(4) generator eluate using NaBH(4) as reducing agent. Their structure was established by chromatographic comparison with authentic oxotechnetium and oxorhenium complexes using high performance liquid chromatography techniques.

2,2'-Dipyridyl↗

Thiol- and thioether-based bifunctional chelates for the {M(CO)3}+ core (M = Tc, Re).

By analogy to the recently described single amino acid chelate (SAAC) technology for complexation of the {M(CO)3}+ core (M = Tc, Re), a series of tridentate ligands containing thiolate and thioether groups, as well as amino and pyridyl nitrogen donors, have been prepared: (NC5H4CH2)2NCH2CH2SEt (L1); (NC5H4CH2)2NCH2CH2SH (L2); NC5H4CH2N(CH2CH2SH)2 (L3); (NC5H4CH2)N(CH2CH2SH)(CH2CO2R) [R = H (L4); R = -C2H5 (L5). The {Re(CO)3}+ core complexes of L1-L5 were prepared by the reaction of [Re(CO)3(H2O)3]Br or [NEt4]2[Re(CO)3Br3] with the appropriate ligand in methanol and characterized by infrared spectroscopy, 1H and 13C NMR spectroscopy, mass spectrometry, and in the case of [Re(CO)3(L2)] (Re-2) and [Re(CO)3(L1)Re(CO)3Br2] (Re-1a) by X-ray crystallography. The structure of Re-2 consists of discrete neutral monomers with a fac-Re(CO)3 coordination unit and the remaining coordination sites occupied by the amine, pyridyl, and thiolate donors of L2, leaving a pendant pyridyl arm. In contrast, the structure of Re-1a consists of discrete binuclear units, constructed from a {Re(CO)3(L1)}+ subunit linked to a {Re(CO)3Br2}- group through the sulfur donor of the pendant thioether arm. The series of complexes establishes that thiolate donors are effective ligands for the {M(CO)3}+ core and that a qualitative ordering of the coordination preferences of the core may be proposed: pyridyl nitrogen approximately thiolate > carboxylate > thioether sulfur > thiophene sulfur. The ligands L1 and L2 react cleanly with [99mTc(CO)3(H2O)3]+ in H2O/DMSO to give [99mTc(CO)3(L1)]+ (99m)Tc-1) and [99mTc(CO)3(L2)] (99mTc-2), respectively, in ca. 90% yield after HPLC purification. The Tc analogues 99mTc-1 and 99mTc-2 were subjected to ligand challenges by incubating each in the presence of 1000-fold excesses of both cysteine and histidine. The radiochromatograms showed greater than 95% recovery of the complexes.

Amino Acids↗

[Skeletal scintigraphy for the observation of course and treatment of carcinoma of the prostate ].

Serial skeletal scintigraphy was carried out on 259 patients with carcinoma of the prostate; 5-10% developed bone metastases each year. Isotope uptake was measured in 79 patients receiving treatment; in 60.6% (48 patients) there was a reduction or disappearance of the areas of uptake, in 16.6% (13 patients) they were stationary and 22.8% (18 patients) the metastases progressed. Skeletal scintigraphy is therefore useful during the course of the disease in showing its extent and the effect of treatment.

Antineoplastic Agents↗

Lymphoscintigraphy for interpretation of changes of cervical lymph node function in patients with oral malignant tumors: comparison of Tc-99m-Re and Tc-99m-HSA-D.

OBJECTIVE: The purpose of this study is to compare the usefulness of technetium-99m-rhenium colloid (Tc-99m-Re) and technetium-99m-human serum albumin diethylene-triamine-pentaacetic acid (Tc-99m-HSA-D) as lymphoscintigraphic agents and to discuss the significance of lymphoscintigraphy in comparison with computed tomography (CT), magnetic resonance imaging (MRI), and ultrasonography (US). STUDY DESIGN: Dynamic and static lymphoscintigraphies were performed with Tc-99m-Re and Tc-99m-HSA-D. The usefulness of the 2 agents was evaluated statistically in comparison with pathologic findings and palpation. The significance of lymphoscintigraphy is discussed in comparison with CT, MRI, and US (by the literature of CT, MRI, and US). RESULTS: Lymphoscintigraphy was superior to palpation, and Tc-99m-Re was superior to Tc-99m-HSA-D in accuracy, specificity, and the incidence of true-positive and false-positive. Statistical significance was shown between the static lymphoscintigraphy with Tc-99m-Re and palpation. The reliability of lymphoscintigraphy seemed to be slightly inferior to CT and MRI in specificity and accuracy. However, lymphoscintigraphy had some advantages that CT and MRI lacked; for example, it showed very high sensitivity (100%) and no false-negative (0%). It also showed changes of lymph node function, showed all levels of neck nodes at one time, and showed a possibility of detecting small lymph node metastases. CONCLUSION: Lymphoscintigraphy was more useful than palpation in detecting lymph node metastases, and Tc-99m-Re was superior to Tc-99m-HSA-D as an agent. Lymphoscintigraphy is significant when it is performed as a preliminary examination before CT or MRI.

Adult↗

Sentinel node biopsy in melanoma using technetium-99m rhenium colloid: the London experience.

Nodal metastases in patients with melanoma identify a reduction of survival by 50%; however, elective lymph node dissection (ELND) has not been shown clearly to improve survival. Morton's technique of sentinel node biopsy, using preoperative lymphoscintigraphy and intraoperative blue dye, addresses elegantly the controversy regarding ELND. Sentinel node biopsy has been shown to stage the patient accurately because metastases from melanoma follow an orderly progression from the sentinel node to the remainder of the basin. Fifty-six consecutive patients with American Joint Committee on Cancer stage 1b or 2 melanoma seen at the London Health Sciences Center between July 1998 and January 2000 were enrolled prospectively to undergo sentinel node biopsy. Preoperative lymphoscintigraphy was conducted in the nuclear medicine department. A total of 10 to 15 MBq (0.27-0.41 mCi) of technetium 99m (99mTc) rhenium colloid or filtered sulfur colloid was injected intradermally around the biopsy scar. Images were obtained to localize all draining nodal basins. The location of the sentinel node was marked on the skin. The patient was taken to the operating room and anesthetized. Isosulfan blue dye was injected intradermally around the biopsy scar. A hand-held gamma probe was used intraoperatively as a guide to the first draining node. Blue-stained lymphatic channels aided in the dissection. Sentinel node localization was successful in 55 of 56 patients, for an overall success rate of 98%. Preoperative lymphoscintigraphy identified a sentinel node in an unpredictable location in 32% of patients. On average, 2.3 sentinel nodes per patient were identified on the initial scan, and 2.2 sentinel nodes per patient were recovered at surgery. Both 99mTc rhenium and filtered sulfur colloid showed no substantial differences in tracer uptake and retention in the sentinel node. Twelve patients had a positive sentinel node on routine histology, and 11 patients subsequently underwent completion lymphadenectomy. The mean thickness of the primary melanoma in the 12 patients with positive sentinel nodes was 3.7 mm compared with a mean tumor thickness of 1.8 mm in the remaining 41 patients with negative biopsies (p = 0.0003). Two patients experienced recurrence in a regional basin after negative pathological evaluation of the sentinel node. Reverse transcription-polymerase chain reaction analysis of both of these patients was positive. Two patients are alive with metastatic disease and 54 patients are alive without disease, with a mean follow-up of 1 year (range, 2-24 months). Complications occurred at a substantially higher rate (45%) after completion lymphadenectomy than after sentinel node biopsy alone (9%). Sentinel node biopsy is a feasible technique with a high success rate (98%), but it requires a multidisciplinary approach. This study validates the clinical usefulness of 99mTc rhenium colloid for lymphoscintigraphy.

Adult↗

Focal spinal abnormalities on bone scans in ankylosing spondylitis: a clue to the presence of fracture or pseudarthrosis.

Four cases of ankylosing spondylitis are presented in which radionuclide bone studies indicated focal abnormalities of the spine. In three patients, the area of abnormal nuclide uptake corresponded to a site of pseudarthrosis, and in the fourth an acute fracture was present. As such focal lesions on bone scans are unusual in cases of chronic ankylosing spondylitis in which a complication is not apparent, their presence can be a useful finding.

Aged↗

The effects of chemotherapy on bony metastases as measured by quantitative skeletal imaging.

The effect of chemotherapy on bony metastases from adenocarcinoma of the colon was investigated by quantitative skeletal imaging over a two-month interval. The quantitative skeletal imaging results correlated with conventional blood chemistry results over this time period. While chemical assay techniques furnish an average value of lesion response, the quantitative bone scan represents a method for individual lesion analysis. This methodology has the potential to provide a better understanding of metastatic bone disease therapy.

Adenocarcinoma↗

Splenic uptake of both technetium-99m diphosphonate and technetium-99m sulfur colloid in sickle cell beta (0) thalassemia.

A 19-year-old black woman with sickle cell beta(0) thalassemia had experienced more than 100 hospital admissions for sickle cell crisis and aseptic necrosis of both femoral heads. Her spleen was enlarged threefold and accumulated both radiocolloid and bone-seeking agent on two occasions, demonstrating an exception to the rule in sickle cell anemia that spleens that take up bone-seeking agents demonstrate functional asplenia. In the context of fever, left upper quadrant pain, and splenomegaly, the pattern of calcification in the patient's spleen as revealed in ultrasound and CT studies suggested possible abscess and led to unnecessary splenectomy. The nuclear medicine studies did not support this diagnosis. Nuclear medicine physicians should not be misled by splenic findings of sickle cell thalassemia (and possibly of other heterozygous sickle cell disorders) that differ from those of the more familiar homozygous sickle cell anemia.

Adult↗

An ectopic mediastinal parathyroid adenoma accurately located by a single-day imaging protocol of Tc-99m pertechnetate-MIBI subtraction scintigraphy and MIBI-SPECT-computed tomographic image fusion.

PURPOSE: Because ectopic parathyroid adenoma (PA) is a frequent cause of failed initial surgery, an imaging approach with accurate preoperative localization is recommended by some authors in patients with primary hyperparathyroidism (HPT). METHODS: The authors describe a 52-year-old woman in whom primary HPT was diagnosed incidentally during a screening program for osteoporosis. The peculiarity of this case is that the patient was examined before operation in a single-day multimodal imaging protocol based on the combination of high-resolution cervical ultrasound, planar Tc-99m pertechnetate-MIBI scans, and an MIBI-SPECT-computed tomographic (CT) image fusion study. An ectopic PA was accurately located in the upper middle mediastinum, close to the lower margin of the sternal notch. RESULTS: Guided by the MIBI-SPECT-CT fusion images, the surgeon performed a limited median sternotomy and easily removed the PA that was revealed before operation. To confirm the completeness of resection, a bilateral neck exploration was performed through the same incision, with identification of three normally sized parathyroid glands. CONCLUSIONS: Our experience suggests the utility of multimodality imaging procedures for the accurate preoperative localization of PAs, particularly when they are present in ectopic mediastinal locations. Such procedures, including the MIBI-SPECT-CT image fusion study, can be performed in a single day.

Adenoma↗

Different chelators and different peptides together influence the in vitro and mouse in vivo properties of 99Tcm.

Relatively few studies comparing different methods of labelling peptides with 99Tcm have been reported. In this investigation, we evaluated the influence of three chelators on the in vitro and in vivo properties of two small, similar peptides (HNE2 and HNE4) labelled with 99Tcm. Both peptides were labelled with hydrazinonicotinamide (HYNIC) (tricine) at pH 5-6 and with diethylenetriaminepentaacetic acid (DTPA) and mercaptoacetyltriglycine (MAG3) at both pH 5-6 and 7-8. All ten preparations were brought to pH 7.2 immediately after labelling. Each preparation labelled well and control labelling showed each label to be attached specifically at chelation sites. Analysis of 37 degrees C human serum incubates showed little evidence of label instability but high protein binding in several cases. The stability of 99Tcm to cysteine challenge for labelled DTPA- and MAG3-peptides was similar but lower than that for the HYNIC-peptides. Reverse phase HPLC of the DTPA-peptides, but not the MAG3-peptides, showed different 99Tcm species depending on labelling pH. The 3 h biodistributions in normal mice were generally independent of labelling pH for both MAG3-peptides but were heavily influenced by labelling pH for both DTPA-peptides. While significant differences in biodistribution for the same labelling method were evident between peptides, as expected, far larger differences in the case of both peptides resulted from changing chelators and, in the case of DTPA, changing the labelling method. In summary, the chelators and labelling methods influenced the biodistribution of 99Tcm in a characteristic fashion common to both peptides. Differences in biodistribution due to the different peptides were relatively small and generally lost in the much larger differences due to chelator and labelling method. In conclusion, it may be important to compare chelators and labelling methods before selecting a 99Tcm labelling method for any particular peptide.

Animals↗