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Synthesis, characterization, and in vitro evaluation of nitroimidazole--BATO complexes: new technetium compounds designed for imaging hypoxic tissue.

Several technetium-99 BATO (boronic acid adduct of technetium dioximes) complexes TcX(dioxime)3BR (X = Cl) that contain a boron cap R which bears a 2- or 4-nitroimidazole moiety have been prepared from either TcCl(dioxime)3 or from Tc(dioxime)3(mu-OH)SnCl3 [dioxime = dimethyl glyoxime (DMG) or cyclohexanedione dioxime (CDO)]. Two hydroxy analogs (X = OH) were isolated by treatment of the corresponding chloro complexes with aqueous NaOH. The complexes have been characterized by elemental analysis, mass spectrometry, NMR, UV/vis spectroscopy, and high-performance liquid chromatography. These complexes have the potential for selective retention in hypoxic tissue, by a mechanism believed to be the result of nitro reduction. The electrochemistry and enzymatic reduction of these complexes was studied to assess the potential for reduction in vivo. The nitroreductase enzyme xanthine oxidase was shown to reduce the nitroimidazole group on the complexes 99TcOH(DMG)3BBNO2 and 99TcOH(DMG)3BprenNO2 under anaerobic conditions in the presence of hypoxanthine. However, the results indicated that the rate of reduction might be slow in vivo, limiting the suitability of these compounds for imaging of regions of hypoxia.

Anaerobiosis

Single image pericardial effusion evaluation with technetium compounds.

Three cases of suspected pericardial effusion were evaluated with rapid, noninvasive procedure, combined use of macroaggregated albumin technetium 99m and human serum albumin technetium 99m to produce a single radiography showing the heart, liver, and lung perfusion simultaneously. This technic confirmed the diagnosis of pericardial effusion in two cases and ruled out this possibility in the third case.

Adult

On the nature of technetium compounds. 1. A semiquantitative biological model system to assay 99mTc-complexes/radiopharmaceuticals.

Eleven different 99mTc compounds having some relevance in clinical nuclear medicine have been classified according to their localizing properties. The following classes of 99mTc compounds have been compared in a semiquantitative manner, using a Wistar strain rat model: liver and hepatobiliary agents such as Tc-phytate, Tc-sulfur colloid, reduced (SnII) TcO-4, and 99mTc-LIDA (dimethyl-IDA); bone agents like Tc-pyrophosphate, Tc-HEDP, Tc-EDTMP; kidney and bladder agents comprising Tc-DTPA, Tc-glucoheptonate, Tc-citrate, and TcO-4. The in vivo pharmacokinetic behavior lends itself to unified approach with respect to nature of 99mTc compounds. Most of the 99mTc complexes display an excretory type of pathway. These compounds were found to be relatively stable in aqueous solutions at room temperature (25 degrees-28 degrees C) for at least 2 h without any additives. Both paper chromatographic and biologic (tissue distribution) criteria, commonly used for quality assurance and control of 99mTc compounds, were employed to study these compounds.

Animals

Imaging of acute myocardial infarction using technetium 99m labelled phosphate compounds.

Technetium 99m pyrophosphate or polyphosphate administered intravenously soon after acute myocardial infarction produces positive images of the area and extent of myocardial necrosis. Forty-four patients have been studied of whom 39 had myocardial infarction. There was good correlation of the site and extent of infarction as indicated by the scintigram with electrocardiogram and cardiac enzyme criteria.

Acute Disease

Extraosseous tumor uptake of 99m technetium phosphate compounds in children with abdominal neuroblastoma.

Sixteen patients with abdominal neuroblastoma had 99m Technetium Phosphate Compounds (99m TC-PC) bone scans as a preoperative evaluation for metastatic disease. Ten patients (62%) had extraosseous tumor uptake while six patients (38%) did not. There was no difference in the incidence of tumor calcification, tumor necrosis or hydronephrosis in the two groups. However, VMA levels were significantly higher in the group with extraosseous tumor uptake. Various bone seeking radionuclides are compared to 99m TC-PC and possible mechanism for extraosseous uptake of such radionuclides are postulated. Awareness of the frequency of such uptake should reduce the possibility of errors in the interpretation of bone scans in patients with neuroblastoma.

Abdominal Neoplasms

99m-Technetium phosphate compound joint scintigraphy in the management of juvenile osteochondritis dissecans of the femoral condyles.

The known sensitivity of joint scintigraphy in following the course of fracture healing caused the authors to believe that this radiologic technique might be valuable in the management of osteochondritis dissecans (OCD). Accordingly, 99mTc-diphosphonate joint scintigraphy was used on 18 patients with OCD of the knee. The average age was 13 1/2 years. The scintigrams were repeated at 6-week intervals until healing had occurred. When the diagnosis of OCD was established by standard roentgenograms and joint scintigraphy, the patients were placed on an activity restriction program, attempting to reach a symptom-free level. The patients were followed for an average of 18 months. Ninety-five scans were categorized according to their level of scintigraphic activity. This led to a discrete four-part scintigraphic classification that is indicative of the extent of healing or progression of this condition, and precedes changes seen on standard x-rays by months. Joint scintigraphy also rules out anomalies of ossification in the diagnosis of OCD since an anomaly should have a normal scintigraphic appearance. We have concluded that joint scintigraphy is valuable in the management of OCD because of its superior sensitivity to changes in the activity of the lesion. As experience is gained with this technique, those cases that should be prophylactically surgically stabilized may be indicated.

Adolescent

Is image subtraction necessary in the clinical interpretation of single-day split-dose stress cerebral perfusion single-photon emission tomography using technetium-99m compounds?

The aim of this study was to validate a simplified semiquantitative method of evaluating a single-day stress cerebral perfusion test to obtain cerebrovascular reserve capacity (CVRC) for routine clinical uses. A split-dose protocol was tested in 36 pairs of technetium-99m hexamethylpropylene amino oxime baseline (low dose) and acetazolamide (high dose) stress brain single-photon emission tomographic (SPET) studies from 16 patients with cerebrovascular disease. The images were displayed on a semiquantitative color scale with (corrected) and without (uncorrected) image subtraction, dose adjustment, and decay correction. The representative CVRC was determined by placing 3x3 pixel regions of interest on midthalamic and midcerebellar slices. The corrected and uncorrected relative changes in CVRC were correlated using linear regression. The relative changes of corrected (x) and uncorrected (y) CVRC by quantitative analysis were highly correlated in a linear fashion (y=0.67x+0.002, r=0.998, P<0.0005). As predicted by theory, the slope was related to the ratio of split dose and independent of ROI sampling. Single-day split-dose stress brain SPET can be accurately performed without image subtraction and complicated dose adjustment or decay correction for clinical studies.

Acetazolamide

Biological studies of a new class of technetium complexes: the hexakis(alkylisonitrile)technetium(I) cations.

This study describes the preparation and synthesis of a new class of cationic technetium compounds, the hexakis(alkylisonitrile)technetium(+ 1) complexes, at both carrier added and no carrier added concentrations in aqueous media from pertechnetate. Biological distribution and imaging data in animals indicate that certain members of this class may be effective for cardiac imaging in man. The usefulness of these lipophilic water-soluble species for labeling mammalian cells is also reported.

Animals

Acute intrahepatic biliary obstruction caused by hydatid cysts. Correlation between various imaging techniques.

An 18-year-old male was evaluated for recurrent attacks of right abdominal pain and intermittent jaundice caused by hydatid cysts of the liver. The case illustrates the value of dynamic functional information provided by Tc-99m-HIDA imaging over noninvasive modalities that demonstrate structural changes, such as ultrasound, computed tomography, and tin colloid liver imaging.

Adolescent

Medicinal applications of heavy-metal compounds.

A brief summary of the key role for certain heavy-metal compounds in medicine is discussed, with a special focus on very recent findings in the following four topics: platinum anti-tumor compounds (novel mononuclear compounds, dinuclear compounds and trinuclear compounds with promising activity); ruthenium anti-tumor compounds (the first clinical trial for a Ru compound has begun); gadolinium NMR-imaging compounds (association with biomacromolecules is now possible); technetium compounds (the use of organometallic precursors opens a plethora of new species and enables the labeling of, for example, neurotransmitter molecules).

Antineoplastic Agents

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

[The radiation dose to the foetus during isotope investigations of the mother].

The radiation dose to the foetus from the application of five different 99mTechnetium compounds during isotope investigation of the mother was investigated. After i-v injection of 100 muCi (3.7 MBq) of 99mTc-compounds into pregnant rats, these were sacrificed during the first, second and third week of pregnancy and radioactivity was determined in the foetuses and in the blood and organs of the mother. From these measurements the proportion of total body activity in individual organs and their specific activity was calculated. From this data the radiation burden to the rat foetuses from the various 99mTc compounds could be evaluated. Making use of phantom studies and the known biokinetic data of technetium compounds in man it was possible to calculate the radiation dose to the human foetus during isotope investigations of the mother.

Animals

Sources and behavior of technetium in the environment.

Technetium is a man-made element produced in increasing amounts during the last decades. The chemical and physical properties of some technetium compounds are considered, and a discussion of possible source terms is included. Literature on the environmental behavior of technetium is reviewed to evaluate its transfer and equilibrium distribution in aquatic and terrestrial ecosystems. Considerable effort has been expended in the last years in order to understand the biogeochemical processes responsible for the long-term behavior of technetium in the environment and its transfer through food chains as well as to identify critical pathways of the long-lived radioisotope Tc-99 from the environment to man.

Environmental Pollution