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M Bergström

Publications and source records attributed to M Bergström.

At least 91 records · Page 5Linked to original sources
PubMed1998

In vitro and animal validation of bromine-76-bromodeoxyuridine as a proliferation marker.

UNLABELLED: The potential of 76Br-bromodeoxyuridine as a PET tracer for characterizing proliferation potential was investigated in multicellular tumor aggregates and in healthy rats and pigs. METHODS: Bromine-76-bromide was produced by proton irradiation of a 76Se-enriched target using a 17-MeV cyclotron and recovered by thermal diffusion. Bromine-76-BrdU was prepared from the corresponding trimethylstannate by an oxidative bromination. Multicellular aggregates from a carcinoid cell line and two bladder cancer cell lines were co-incubated with 76Br-BrdU and 3H-thymidine and the uptake and DNA incorporation analyzed. About 0.5 MBq 76Br-BrdU were injected in the tail vein of unanaesthetised Sprague-Dawley rats. Two to 36 hr later they were decapitated and the radioactivity concentration and fraction of radioactivity incorporated into DNA determined in five different organs and the blood. Parallel studies were performed in animals pretreated with hydroxyurea. In separate experiments, rats were given an injection of 76Br-bromide and organ uptake was evaluated after 20 hr. PET studies were performed in two pigs and the uptake in different organs was investigated after injection of 76Br-BrdU. In these studies, diuresis was induced by furosemide and mannitol and radioactivity in blood and organs was followed during 10 hr. RESULTS: In the cell aggregates, 30%-90% of the radioactivity was extracted in the DNA fraction. A good correlation was found between 76Br-BrdU and 3H-thymidine with respect to total uptake and DNA fraction. The DNA fraction increased from 2-10 hr after incubation. With in vivo injection in the rat, relatively high uptake of radioactivity was found in all organs, unrelated to the degree of DNA synthesis. However, inhibition by hydroxyurea occurred only in the spleen and intestines, organs which also showed a high degree of incorporation of 76Br-BrdU into DNA. In the pig, the highest in vivo uptake was observed in the red bone marrow and the intestines. In these organs, 70%-80% of the radioactivity was recovered in the DNA fraction. The concentration of radioactivity in the heart, liver and kidney was 3-10 times lower, and here the DNA fraction accounted for 10%-20% of the radioactivity. The decay-corrected radioactivity in blood and nonproliferating organs decreased with diuresis with a half-life of 13 and 16 hr, respectively. CONCLUSION: It is suggested that the radioactivity uptake as seen after the administration of 76Br-BrdU, is constituted by two parts: one relating to incorporation into DNA and one existing as free 76Br- or metabolites of 76Br-BrdU. If sufficient time has passed, 76Br- dominates other metabolites. A correct assessment of DNA-incorporated radioactivity using PET with 76Br-BrdU is not trivial and can only be made with due correction for 76Br-, using either a complementary investigation after hydroxyurea pretreatment (in animal studies) or a separate 76Br-bromide investigation. Alternatively, the free bromide can be eliminated partially through forced diuresis.

Animals↗
PubMed1998

[PET as a tool in pharmacologic development].

Positron emission tomography (PET) allows the in vivo recording of tracer compounds with respect to anatomical distribution, time course and absolute concentration. These features has proven of great value in drug development, especially in the phase of early clinical trials. PET can be used to assess the tissue kinetics of a new drug, or to evaluate a drugs interaction with a target system and thereby aid in decisions regarding dosing regimes.

Dose-Response Relationship, Drug↗
PubMed1998

[Positron emission tomography in oncology--an introduction].

Positron emission tomography has developed very much since the start in the late 1970s, especially with the development of new labelling procedures for PET-tracers. With the development of whole body imaging and the discovery that 18F-FDG allows a high sensitivity for the detection of soft tissue tumors, the clinical use has increased remarkably. The cost-effectiveness of this modality, when properly used, has been demonstrated and 18F-FDG-PET should be considered as an early alternative in patient evaluation.

Humans↗
PubMed1998

[Differential diagnosis in adrenal gland tumors using PET and 11C-metomidate].

We have investigated 13 patients with incidentaloma using PET with 11C-metomidate. The patients included six adrenocortical adenomas, one adrenal cancer, two pheochromocytomas, one myelolipoma, one benign cyst and two metastases. A very high tracer uptake was observed in all tumors originating from the adrenal cortex, allowing excellent visualisation, whereas all other processes were negative. PET with 11C-metomidate is a very promising method for the characterisation of incidentalomas and is suggested to be included very early in the evaluation of these patients.

Adrenal Cortex Neoplasms↗
PubMed1998

[PET in neuroendocrine tumors].

With the radionuclide tracers available today, 50-90 per cent of neuroendocrine tumours of the gastro-intestinal tract can be visualised with PET (positron-emission tomography). PET also enables the effect of tumour treatment to be monitored in terms of biochemical and functional variables, which is not possible with other radiological techniques. Owing to the very good tumour resolution possible with PET, it serves as a complement to other routine methods such as computed tomography and ultrasonography, and can be used to screen the chest and abdomen for small primary tumours that can not be detected with other methods. In several pre-operative trials PET has been shown to demonstrate more changes in the pancreas and liver than was possible with other methods. In the near future it will be possible to demonstrate the presence of and quantify growth factor receptors, hormones, enzymes, DNA synthesis, mRNA synthesis and protein synthesis. Access to these tumour biological data will be of crucial importance to the individualisation of treatment.

Forecasting↗
PubMed1997

Supercritical fluid extraction of 11C-labeled metabolites in tissue using supercritical ammonia.

Supercritical fluid extraction (SFE) of 11C-labeled tracer compounds and their metabolites from biological tissue was performed using supercritical ammonia in an attempt to develop a rapid extraction procedure that allowed subsequent analysis of the labeled metabolites. Metabolites were extracted from kidneys and brain in rats given in vivo injections of the radiotracers O-[2-11C]acetyl-L-carnitine and N-[11C]methylpiperidyl benzilate, respectively. Only a minimal sample pretreatment of the tissue was necessary, i.e., cutting into 10-20 pieces and mixing with the drying agent Hydromatrix, before it was loaded into the extraction vessel. Extraction efficiency was measured for SFE at temperatures over the range of 70-150 degrees C and a pressure of 400 bar. For O-[2-11C]acetyl-L-carnitine, 66% of the radioactivity was trapped in the collected fractions and 12% remained in the extraction vessel. For the more lipophilic N-[11C]methylpiperidyl benzilate, 93% of the activity was collected and less than 1% remained in the extraction vessel. Labeled metabolites were analyzed by LC and also, in the case, of O-[2-11C]acetyl-L-carnitine by LC/MS. The complete extraction procedure, from removal of the biological tissue until an extract was ready for analysis, was 25 min, corresponding to about one half-life of the radionuclide 11C.

Acetylcarnitine↗
PubMed1997

Use of monoclonal antibodies for weak affinity chromatography.

Weak monoclonal antibodies were used as ligands in a high-performance liquid affinity chromatography system. Isocratic weak affinity chromatography was achieved when similar carbohydrate antigens were separated according to their weak binding to the immobilized monoclonal antibody. These chromatographic systems were studied in detail in terms of affinity, specificity and efficiency. The influence of the physico-chemical factors of temperature, pH, ionic strength and organic solvents was also evaluated. The issue of specificity was specially considered, as non-specific interactions are prevalent and usually of a weak affinity nature. This study clearly demonstrates the potential to use weak affinity biological interactions as the basis of chromatographic analysis and separation.

Animals↗
PubMed1997

MAO-A inhibition in brain after dosing with esuprone, moclobemide and placebo in healthy volunteers: in vivo studies with positron emission tomography.

OBJECTIVE: The aim of the study was to investigate whether or not esuprone binds substantially to MAO-A in the human brain. METHODS: In a randomised double-blind placebo-controlled study 16 male healthy volunteers were examined with positron emission tomography (PET) with [11C]harmine. Eight of the volunteers were given daily doses of 800 mg esuprone, four were given bi-daily doses of 300 mg moclobemide, and four volunteers were given placebo tablets. PET was performed before initiation of a 7-day treatment period. On day 7, one investigation was made immediately before administration of the drug, representing 23 h after the previous day's treatment for esuprone and 11 h after the last tablets of moclobemide. Further investigations were made 4 h and 8 h after the morning dose on day 7. RESULTS: PET showed a high degree of binding of [11C]harmine, a high-affinity ligand for MAO-A, before the start of treatment, and a marked and similar reduction after treatment with esuprone and moclobemide. A slight tendency for normalisation of enzyme binding was observed at the last time point. In the placebo group no change was observed. Plasma kinetics of esuprone showed a rapid elimination with a half-life of about 4 h. CONCLUSION: The study demonstrates that esuprone was comparable to moclobemide in its effect on MAO-A inhibition in the brain at the doses given. This is an illustration of the potential of PET to monitor drug effects directly on target biochemical systems in the brain in human volunteers, and the possibility of using these data, rather than pharmacokinetic data, for the determination of dosing intervals.

Adult↗
PubMed1997

Modulation of organ uptake of 11C-labelled L-DOPA.

The present study was undertaken to investigate if pretreatment with pharmacological agents could change the organ uptake of 11C-labelled L-DOPA, and especially if the urinary excretion could be decreased. L-[beta-11C]DOPA was injected IV into unanesthetized Sprague-Dawley rats. After 20 min the rats were decapitated and organs taken out for radioactivity measurements. The uptake in the organs was investigated in animals only given the tracer, and in animals pretreated with drugs such as decarboxylase inhibitors carbidopa and benserazide as well as the monoamine oxidase inhibitors deprenyl, clorgyline, and the COMT inhibitor OR-486. A marked decrease in the urinary radioactivity was observed after carbidopa and benserazide administration. HPLC analysis revealed that under native conditions the major part of urinary radioactivity existed as dopamine, which was eliminated by the decarboxylase inhibitors. After pretreatment with the COMT inhibitor OR-486, the radioactivity uptake in the pancreas increased fourfold as compared to non-treated animals. HPLC analysis showed that this correlated with a marked increase in radiolabelled DOPAC. In the other organs and with the other drugs, only small effects were observed. With L-[beta-11C]fluoroDOPA as a tracer, similar results were observed although the increase in the pancreas by OR-486 had a lower magnitude. These studies suggest that it might be possible to improve the diagnostic ratio of L-[beta-11C]DOPA or L-[18F]fluoroDOPA in whole-body PET studies by pretreating the patient with decarboxylase inhibitor for reducing the urinary excretion and potentially increase the target organ uptake by COMT inhibition.

Animals↗
PubMed1997

11C-harmine as a tracer for monoamine oxidase A (MAO-A): in vitro and in vivo studies.

Frozen-section autoradiography in rat brain sections as well as in vivo positron emission tomography (PET) studies in monkey brain were used for the determination of binding characteristics of O-[methyl-11C]harmine in an attempt to validate this ligand for the assessment of monoamine oxidase A (MAO-A). In frozen sections, the binding of [11C]harmine showed an apparent KD of the binding of 2 nM. The specific binding was inhibited by nanomolar concentrations of clorgyline, esuprone, brofaromine, and Ro 41-1049. The in vivo kinetic pattern in the monkey brain indicated a significant trapping, which was inhibited by pretreatment with clorgyline, moclobemide, or harmine. Different approaches for a quantitative determination of MAO-A enzyme binding were attempted and demonstrated an IC50 dose of harmine in the range of 0.05-0.1 mg/kg. The studies give strong indications for the validity of [11C]harmine as an in vivo tracer for the assessment of MAO-A enzyme binding in the brain.

Animals↗
PubMed1997

Synthesis of L-2,4-diamino[4-11C]butyric acid and its use in some in vitro and in vivo tumour models.

L-2,4-Diamino[4-11C]butyric acid (DAB) was synthesized by an enzyme catalysed carrier added (0.1 micromol KCN) reaction of hydrogen [11C]cyanide with O-acetyl-L-serine followed by reduction. L-[11C]DAB was obtained with a radiochemical purity higher than 96% and with a decay corrected radiochemical yield of 30-40% within a 32 min reaction time. The enantiomeric excess was 98%. The uptake of L-[11C]DAB was investigated in multicellular aggregates of six different cell lines and animal tumour models. L-[11C]DAB is potentially useful for the assessment of pharmacokinetics of L-DAB in vivo for part of its evaluation as an antitumoural agent, although its use for diagnostic purposes seems limited.

Aminobutyrates↗
PubMed1997

Positron emission tomography (PET) with 11C-5-hydroxytryptophan (5-HTP) in patients with metastatic hormone-refractory prostatic adenocarcinoma.

The discovery of neuroendocrine differentiation in hormone-refractory prostatic adenocarcinoma has opened a potentially new therapeutic approach in this group of patients with a poor prognosis and few effective therapy modalities. Based on previous findings of increased uptake of 11C-5-hydroxytryptophan (11C-5-HTP) in neuroendocrine tumours using the PET technique, this tracer was applied in the study of 10 patients with metastatic hormone-refractory prostatic adenocarcinoma. In three patients, the study was repeated after treatment. An increased uptake of 11C-5-HTP was observed in all investigated skeletal lesions, although the magnitude of the uptake was moderate. The difference between the standard uptake values (SUV) in normal bone and metastatic lesions was significant (p < 0.001). A kinetic analysis of the uptake of 11C-5-HTP demonstrates an increase during the first minutes followed by a wash-out and a stabilization of the tissue/blood ratio at about 2. The Patlak plots demonstrated a gradual increase in the transport rate during the first 20 to 30 min, after which a constant level was observed. The SUV varied between patients and between lesions over time and treatment. The uptake of 11C-5-HTP discriminates metastatic lesions from normal bone and may thus aid in the diagnosis and, potentially, in treatment monitoring of metastatic hormone-refractory prostatic adenocarcinoma. Uptake kinetics are characterized by a wash-out and cannot alone be used as proof of neuroendocrine differentiation in hormone-refractory prostatic adenocarcinoma.

5-Hydroxytryptophan↗
PubMed1997

Methodological aspects for in vitro characterization of receptor binding using 11C-labeled receptor ligands: a detailed study with the benzodiazepine receptor antagonist [11C]Ro 15-1788.

As a complement to in vivo studies with positron emission tomography (PET), it is desirable to perform in vitro characterization of newly developed 11C tracers. In this report we describe the technique for determination of receptor-ligand kinetics utilizing ligands labeled with the short-lived radionuclide 11C. The limitations and advantages are discussed. The benzodiazepine antagonist [11C]Ro 15-1788 was used as a model substance, and the use of storage phosphor plates for quantification of radioactivity was validated. Storage phosphor plates showed an excellent linear range (approximately 10[3]) and acceptable resolution (approximately 0.5 mm). Receptor-ligand kinetics, including depletion, association and dissociation, saturation and displacement were evaluated with good results through the use of short-lived radiotracers and storage phosphor plates.

Animals↗
PubMed1997

Synthesis of some 11C-labelled MAO-A inhibitors and their in vivo uptake kinetics in rhesus monkey brain.

Five potential MAO-A inhibitors--harmine, N-methyl-harmine, harmaline, brofaromine, and clorgyline--were labelled with 11C and their brain kinetics evaluated in vivo in rhesus monkey using PET. The compounds were synthesized by alkylation with 11C methyl iodide and obtained in 48-89% radiochemical yield within 40 to 45 min synthesis time and with specific radioactivities in the region of 0.49-2.4 Ci mumol-1 (18-87 GBq mumol-1) at the end of synthesis. The kinetic pattern after administration of MAO-A inhibitors was comparable to that seen in the tracer study when using 11C-brofaromine, 11C-harmaline, or 11C-clorgyline, although the magnitude of uptake markedly increased in the case of brofaromine and harmaline. Both 11C-methylharmine and 11C-harmine showed a significant washout in the inhibition studies. The kinetics of brain uptake with and without MAO-A inhibition is compatible with a significant fraction of the tracer bound to MAO-A for 11C-methylharmine and 11C-harmine, whereas 11C-brofaromine, 11C-harmaline, or 11C-clorgyline did not seem to show specific enzyme binding.

Animals↗
PubMed1997

Possible effects of tetrahydrobiopterin treatment in six children with autism--clinical and positron emission tomography data: a pilot study.

Six children, between 3 and 5 years of age, having infantile autism according to DSM-III-R, were treated for 3 months with 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (R-BH4), a cofactor for tyrosine hydroxylases in the biosynthetic pathway of catecholamines and serotonin. A criterion for inclusion in the study was a relatively low level of R-BH4 in the cerebrospinal fluid. For clinical evaluation, the Parental Satisfaction Survey (PASS) was used every fourth week and the Griffiths Developmental Scales were used before starting and 3 months after completing the treatment. During the treatment period, all parents reported improvements in the child's social functioning-mainly eye contact and desire to interact-and in the number of words or sounds which the child used. Small positive changes were noted on the Griffiths Developmental Scales between the two testing occasions. R-BH4 levels in CSF increased significantly after treatment. The positron emission tomography (PET) study showed that the high value of dopamine D2 receptor binding in the caudate and putamen decreased by about 10% towards the normal level after treatment with R-BH4. The observations in this open study indicate that the drug might be useful for a subgroup of children with autism, but there is a need for a larger double-blind study with a longer treatment period.

Antioxidants↗
PubMed1997

Diagnosis of hypoglycaemia: effects of blood sample handling and evaluation of a glucose photometer in the low glucose range.

Hypoglycaemia is a dangerous condition. Rapid and reliable blood glucose measurements are necessary for the initiation of treatment to reduce the risk of neurological sequelae. The aim of this study was to compare a bedside glucose photometer (HemoCue) with three methods of handling blood glucose measurements in a routine chemistry laboratory and to estimate the reliability of glucose measurements in the low glucose range during controlled hypoglycaemia. Nine children underwent an arginine-insulin tolerance test as part of a growth hormone deficiency investigation. Only blood samples below 4.0 mmol l-1 were included (n = 35). Significant (0.3-1.0 mmol l-1) differences in blood glucose measurements were found, depending on the handling of the blood sample. The differences seem primarily to be due to glycolysis which occurred in spite of the addition of the glycolysis inhibitor NaF to the blood samples. Immediate centrifugation and analysis of the supernatant or immediate analysis with the HemoCue results in higher, and presumably more correct, values than routine procedures and permits a more accurate diagnosis of hypoglycaemia.

Arginine↗
PubMed1997

PET-methionine of skull base neuromas and meningiomas.

Eighteen patients with intracranial skull base tumours diagnosed at CT or MR as neuromas or meningiomas were studied with positron emission tomography (PET) using L-(methyl-11C) methionine. Compared with normal cerebellar tissue, the uptake of methionine in the tumours increased more rapidly and reached a higher level, and showed a slow decline after a peak occurring about 5 min after the injection. All the meningiomas exhibited considerably higher accumulation of the tracer compared with the surrounding cerebellar tissue, which made the tumour easy to identify and to demarcate from the surrounding cerebellar tissue, which made the tumour easy to identify and to demarcate from the surrounding structures (tumour to cerebellum ratios 2.62-5.37, mean 3.63). The uptake was homogeneous in all meningiomas, which were all of the syncytial type. The neuromas showed lower contrast against the cerebellum (tumour to cerebellum ratios 1.1-1.87, mean 1.48). Some neuromas displayed an irregular pattern with regions of decreased tracer uptake corresponding to small cystic areas within the neuroma. There was no overlap in methionine uptake between the two tumour groups. The results indicate that PET-methionine may contribute to the evaluation, treatment planning and follow-up of patients with skull base meningiomas and neuromas.

Adult↗