Mats Bergström

Uppsala University, Uppsala, Uppsala, Sweden

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Publications (298)757.5 Total impact

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    ABSTRACT: Tesofensine (TE) is a novel triple monoamine re-uptake inhibitor inducing a potent inhibition of the re-uptake process in the synaptic cleft of the neurotransmitters dopamine, norepinephrine, and serotonin. In recent preclinical and clinical evaluations TE showed a robust anti-obesity effect, but the specific mechanism of this triple monoamine re-uptake inhibitor still needs to be further elucidated. This positron emission tomography (PET) study, using [(11)C]βCIT-FE, aimed to assess the degree of the dopamine transporter (DAT) occupancy, at constant TE plasma levels, following different oral, multiple doses of TE during totally 8-12 days. In addition, the relationships between DAT occupancy and TE plasma concentrations, or doses, were investigated to enable assessment of DAT occupancies in subsequent clinical trials. The results demonstrated that TE induced a dose-dependent blockade of DAT following multiple doses of 0.125-1mg TE at anticipated steady-state conditions. The mean striatal DAT occupancy varied dose-dependently between 18% and 77%. A sigmoid Emax model well described the relationship between striatal DAT occupancy and TE plasma concentrations or doses. It was estimated that the maximum achievable DAT occupancy was about 80% and that half of this effect was accomplished by approximately 0.25mg TE and a plasma drug concentration of 4ng/ml. The results indicated an important mechanism of action of TE on DAT. Further, these results suggest that the previously reported dose-dependent weight loss, in TE treated subjects, was in part mediated by an up-regulation of dopaminergic pathways due to enhanced amounts of synaptic dopamine after blockade of DAT.
    No preview · Article · Oct 2013 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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    ABSTRACT: Zolmitriptan is a serotonin 5-HT(1B/1D) receptor agonist that is an effective and well-tolerated drug for migraine treatment. In a human positron emission tomography study, [(11)C]zolmitriptan crossed the blood-brain barrier but no clear pattern of regional uptake was discernable. The objective of this study was to map the binding of [(11)C]zolmitriptan in Rhesus monkey brain using whole hemisphere in vitro autoradiography with [(11)C]zolmitriptan as a radioligand. In saturation studies, [(11)C]zolmitriptan showed specific (90%) binding to a population of high-affinity binding sites (Kd 0.95-5.06 nM). There was regional distribution of binding sites with the highest density in the ventral pallidum, followed by the external globus pallidus, substantia nigra, visual cortex, and nucleus accumbens. In competitive binding studies with 5-HT(1) receptor antagonists, [(11)C]zolmitriptan binding was blocked by selective 5-HT(1B) and 5-HT(1D) ligands in all target areas. There was no appreciable change in binding with the addition of a 5-HT(1A) receptor antagonist.
    Full-text · Article · Oct 2011
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    ABSTRACT: In an earlier study in rodents, we showed that the aromatase that converts androgens to estrogens in the preoptic area and bed nucleus of stria terminalis was significantly increased in concentration after exposure to anabolic-androgenic steroids. To confirm whether this occurs in primates, we conducted a positron emission tomographic study using macaque monkeys. Male rhesus monkeys were treated with nandrolone decanoate for 3 weeks. To measure aromatase concentrations, we performed positron emission tomographic imaging using a 11C-labeled specific aromatase inhibitor, [11C]vorozole. After treatment with nandrolone, significant increase in [11C]vorozole binding was observed in the hypothalamus but not other areas including the amygdala, which is also aromatase enriched. These findings in monkeys are consistent with those we obtained earlier in rats. These findings strongly suggest that aromatase in the hypothalamus may play a crucial role in the emotional instability of anabolic-androgenic steroids abusers.
    No preview · Article · Mar 2011 · Neuroreport

  • No preview · Article · Aug 2010 · Nuclear Medicine and Biology
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    ABSTRACT: The aim of this pilot study was to explore the impact of peptide mass on binding of [(68)Ga]-DOTATOC to neuroendocrine tumour somatostatin receptors in vivo using a tracer of variable specific radioactivity (SRA) and to show the logistic feasibility of sequential PET scans in the same patient. Nine patients with gastroenteropancreatic neuroendocrine tumours were included. Six of them underwent three sequential PET-CT examinations with intravenous injections of [(68)Ga]-DOTATOC proceeded by 0, 50 and 250 or 500 microg of octreotide, administered 10 min before the tracer. Three patients were examined by dynamic and static PET/CT for pharmacokinetic and dosimetric calculations. The [(68)Ga]-DOTATOC synthesis included preconcentration and purification of the generator eluate and microwave heating in a semi-automated in-house procedure. [(68)Ga]-DOTATOC synthesis and quality control were accomplished within 30 min and radiochemical purity was >95%. The tracer accumulation in the tumours varied and depended on the total amount of the administered peptide. In five of six patients, the highest tumour-to-normal tissue ratio was found when 50 microg of octreotide was preadministered. One patient showed a continuously increasing tumour uptake. Dosimetrically, a large variation in organ doses was found (kidney: 0.086-0.168 mSv/MBq; liver: 0.026-0.096 mSv/MBq; spleen: 0.046-0.226 mSv/MBq). The effective dose (0.015, 0.0067 and 0.0042 mSv/MBq) was correlated to the total amount of decays. Three sequential PET-CT examinations using (68)Ga-based tracer was carried out in 1 day. The use of high SRA [(68)Ga]-DOTATOC and unlabelled octreotide indicates an optimal mass leading to better image contrast. [(68)Ga]-DOTATOC-PET-CT employing variable SRA may be utilised for accurate quantification of tumour uptake with subsequent dosimetry for personalized therapy management.
    No preview · Article · Apr 2010 · Nuclear Medicine and Biology
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    ABSTRACT: Five patients with glioma were examined with positron emission tomography after the administration of 11C-L-methionine and at a following day with 11C-D-methionine. The rates of accumulation of the tracers were determined in the tumor and in the normal brain tissue according to a graphical technique of Patlak et coll. The accumulation rates for L-methionine were on the average 2.4 times higher than those of D-methionine in the tumors. The corresponding ration for normal brain tissue was 2.3. It is concluded that in this group of tumors without obvious blood-tumor-barrier breakdown, a stereospecific process with similar properties as in the normal brain tissue, is responsible for the accumulation of the labelled methionine.
    No preview · Article · Jan 2010 · Acta Radiologica
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    ABSTRACT: Oligonucleotides (ODN) are key molecules for the aim of preventing translation of a gene product or monitoring gene expression in tissues. However, multiple methodological and biological hurdles need to be solved before in vivo application in humans will be possible. For positron emission tomography (PET) investigations, a 20-mer DNA-locked nucleic acid (LNA) mixmer ODN specific for rat chromogranin-A mRNA was labeled with (68)Ga and its uptake was examined in vivo in rats with and without blocking of scavenger receptors by polyribonucleotides. In addition, uptake studies of (68)Ga-LNA were performed with respect to time and concentration in human and rat cell lines. The human cell lines did not express the target mRNA. Both polyinosinic acid (poly-I) and polyadenylic acid (poly-A) reduced the uptake in rat tissues and in human cell lines. Poly-I was found to be more effective in the liver whereas poly-A was more effective in the kidney. In addition, the blockade by poly-I was statistically significant in the pancreas, adrenal gland, bone marrow, intestine, testis, urinary bladder, muscle, parotid gland, and heart, whereas poly-A also caused significant reduction in pancreas, adrenal gland, and bone marrow but not as much as in kidney. Cell culture study showed a 2-phase dose-dependent uptake characteristic with a saturable and a passive diffusion-like phase; however, these 2 phases were not so well expressed in the rat cell line. The results suggest that scavenger receptors or other saturable processes unrelated to hybridization may be involved in the tissue uptake of (68)Ga-LNA and in the clearance of antisense ODN through the liver, kidney, spleen, and bone marrow. The fact that these processes may be sequence-dependent suggests that proof of in vivo hybridization through imaging may not be obtained by only comparing sense and antisense sequences and proving dose-dependency.
    No preview · Article · Oct 2009 · Oligonucleotides

  • No preview · Article · Oct 2009 · Biological psychiatry
  • G Lendvai · S Estrada · M Bergström
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    ABSTRACT: Our understanding of altered patterns of gene expression being responsible for many diseases has been growing thanks to modern molecular biological methods. Today, these changes can only be identified when tissue samples are available. Therefore, a noninvasive method allowing us to monitor gene expression in vivo would be valuable, not only as a research tool, but also for patient stratification before treatment and for treatment follow-up. Antisense oligonucleotides (ODN) have been considered to be suitable molecules to trace active genes in vivo, as well as to treat diseases by hybridising to its complementary messenger RNA (mRNA) sequence in the cells thereby preventing the synthesis of the peptide. However, the use of ODNs in the organisms are endangered by many hurdles such as physical barriers to pass and enzyme attack to be avoided. Positron emission tomography (PET) provides a most advanced in vivo imaging technology that allows the exploration of the fate of radionuclide-labelled antisense ODNs in the body; thereby providing information about biodistribution and quantitative accumulation in tissues to assess pharmacokinetic properties of ODNs. This kind of evaluation is important as part of the characterisation of antisense therapeutics but also as part of the development of antisense imaging agents. This review provides a general summary about the antisense concept and displays the present status of the antisense imaging field with the major achievements and remaining challenges on the long journey towards accomplishing in vivo monitoring of gene expression using PET.
    No preview · Article · Oct 2009 · Current Medicinal Chemistry
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    ABSTRACT: Following experimental and clinical traumatic brain injury (TBI), the local cerebral metabolic rate of glucose (1CMR(G1c)) is commonly estimated using the 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) method. The adequate estimation of 1CMR(G1c) using FDG requires a correction factor, the lumped constant (LC), to convert FDG net uptake into 1CMR(G1c). The LC, and thus 1CMR(G1c) calculations, require a steady-state that may be disrupted following TBI. In the present report, we hypothesized that [1-(14)C] glucose uptake would accurately reflect glucose dynamics early post-injury, and was compared to the regional uptake of FDG in 44 rats subjected to moderate (2.4-2.6 atm) lateral fluid percussion brain injury (FPI) or sham injury. Cortical energy state and adenylate (ATP, ADP, and AMP) levels were also measured. Early (7-42 min) after FPI, FDG uptake was increased in the ipsilateral cortex and hippocampus (p< 0.05). In contrast, no change in [1-(14)C] glucose uptake (7 and 17 min post-injury) or cortical adenylate content (42 min post-injury) was observed. At 12 h following FPI, the ipsilateral FDG and [1-(14)C] glucose uptake were decreased in the cortex and hippocampus, and the ipsilateral cortical ATP concentration was decreased in comparison to sham-injured controls (p< 0.05). Under the present experimental conditions, the rate of cerebral uptake of FDG and of [1-(14)C] glucose differed, and indicated that following TBI, regional changes in the LC may occur in the immediate, but not in the late, post-injury phase. These results should be considered when interpreting results obtained using FDG for the estimation of 1CMR(G1c) early following experimental TBI.
    No preview · Article · Aug 2009 · Journal of Neurotrauma
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    ABSTRACT: This study introduces a new approach for the application of principal component analysis (PCA) with pre-normalization on dynamic positron emission tomography (PET) images. These images are generated using the amyloid imaging agent N-methyl [(11)C]2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole ([(11)C]PIB) in patients with Alzheimer's disease (AD) and healthy volunteers (HVs). The aim was to introduce a method which, by using the whole dataset and without assuming a specific kinetic model, could generate images with improved signal-to-noise and detect, extract and illustrate changes in kinetic behavior between different regions in the brain. Eight AD patients and eight HVs from a previously published study with [(11)C]PIB were used. The approach includes enhancement of brain regions where the kinetics of the radiotracer are different from what is seen in the reference region, pre-normalization for differences in noise levels and removal of negative values. This is followed by slice-wise application of PCA (SW-PCA) on the dynamic PET images. Results obtained using the new approach were compared with results obtained using reference Patlak and summed images. The new approach generated images with good quality in which cortical brain regions in AD patients showed high uptake, compared to cerebellum and white matter. Cortical structures in HVs showed low uptake as expected and in good agreement with data generated using kinetic modeling. The introduced approach generated images with enhanced contrast and improved signal-to-noise ratio (SNR) and discrimination power (DP) compared to summed images and parametric images. This method is expected to be an important clinical tool in the diagnosis and differential diagnosis of dementia.
    No preview · Article · Jul 2009 · Physics in Medicine and Biology
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    ABSTRACT: Molecular targeting has become a prominent concept in cancer treatment and heat shock protein 90 (Hsp90) inhibitors are suggested as promising anticancer drugs. The Hsp90 complex is one of the chaperones that facilitate the refolding of unfolded or misfolded proteins and plays a role for key oncogenic proteins such as Her2, Raf-1, Akt/PKB, and mutant p53. NVP-AUY922 is a novel low-molecular Hsp90 inhibitor, currently under clinical development as an anticancer drug. Disruption of the Hsp90-client protein complexes leads to proteasome-mediated degradation of client proteins and cell death. The aim of the current study was to use a combination of the multicellular tumour spheroid (MTS) model and positron emission tomography (PET) to investigate the effects of NVP-AUY922 on tumour growth and its relation to PET tracer uptake for the selection of appropriate PET tracer. A further aim was to evaluate the concentration and time dependence in the relation between growth inhibition and PET tracer uptake as part of translational imaging activities. MTS of two breast cancer cell lines (MCF-7 and BT474), one glioblastoma cell line (U87MG) and one colon carcinoma cell line (HCT116) were prepared. Initially, we investigated MTS growth pattern and (3)H-thymidine incorporation in MTS after continuous exposure to NVP-AUY922 in order to determine dose response. Then the short-term effect of the drug on the four PET tracers 2-[(18)F] fluoro-2-deoxyglucose (FDG), 3'-deoxy-3'-fluorothymidine (FLT), methionine and choline was correlated to the long-term effect (changes in growth pattern) to determine the adequate PET tracer with high predictability. Next, the growth inhibitory effect of different dose schedules was evaluated to determine the optimal dose and time. Finally, the effect of a 2-h exposure to the drug on growth pattern and FDG/FLT uptake was evaluated. A dose-dependent inhibition of growth and decrease of (3)H-thymidine uptake was observed with 100% growth cessation in the dose range 7-52 nM and 50% (3)H-thymidine reduction in the range of 10-23 nM, with the most pronounced effect on BT474 cells. The effect of the drug was best detected by FLT. The results suggested that a complete cessation of growth of the viable cell volume was achieved with about 50% inhibition of FLT uptake 3 days after continuous treatment. Significant growth inhibition was observed at all doses and all exposure time spans. Two-hour exposure to NVP-AUY922 generated a growth inhibition which persisted dose dependently up to 10 days. The uptake of FDG per viable tumour volume was reduced by just 25% with 300 nM treatment of the drug, whereas the FLT uptake decreased up to 75% in correlation with the growth inhibition and recovery. Our results indicate a prolonged action of NVP-AUY922 in this cell culture, FLT is a suitable tracer for the monitoring of the effect and a FLT PET study within 3 days after treatment can predict the treatment outcome in this model. If relevant in vivo, this information can be used for efficient planning of animal PET studies and later human PET trial.
    No preview · Article · May 2009 · Nuclear Medicine and Biology
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    ABSTRACT: Following experimental and clinical traumatic brain injury (TBI), the local cerebral metabolic rate of glucose (lCMR(Glc)) is commonly estimated using the 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) method. The adequate estimation of lCMR(Glc) using FDG requires a correction factor, the lumped constant (LC), to convert FDG net uptake into lCMR(Glc). The LC, and thus lCMR(Glc) calculations, require a steady-state that may be disrupted following TBI. In the present report, we hypothesized that [1-(14)C]glucose uptake would accurately reflect glucose dynamics early post-injury, and was compared to the regional uptake of FDG in 44 rats subjected to moderate (2.4-2.6 atm) lateral fluid percussion brain injury (FPI) or sham injury. Cortical energy state and adenylate (ATP, ADP, and AMP) levels were also measured. Early (7-42 min) after FPI, FDG uptake was increased in the ipsilateral cortex and hippocampus (p < 0.05). In contrast, no change in [1-(14)C]glucose uptake (7 and 17 min post-injury) or cortical adenylate content (42 min post-injury) was observed. At 12 h following FPI, the ipsilateral FDG and [1-(14)C]glucose uptake were decreased in the cortex and hippocampus, and the ipsilateral cortical ATP concentration was decreased in comparison to sham-injured controls (p < 0.05). Under the present experimental conditions, the rate of cerebral uptake of FDG and of [1-(14)C]glucose differed, and indicated that following TBI, regional changes in the LC may occur in the immediate, but not in the late, post-injury phase. These results should be considered when interpreting results obtained using FDG for the estimation of lCMR(Glc) early following experimental TBI.
    No preview · Article · May 2009 · Journal of neurotrauma
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    ABSTRACT: Multivariate image analysis tools are used for analyzing dynamic or multidimensional Positron Emission Tomography, PET data with the aim of noise reduction, dimension reduction and signal separation. Principal Component Analysis is one of the most commonly used multivariate image analysis tools, applied on dynamic PET data. Independent Component Analysis is another multivariate image analysis tool used to extract and separate signals. Because of the presence of high and variable noise levels and correlation in the different PET images which may confound the multivariate analysis, it is essential to explore and investigate different types of pre-normalization (transformation) methods that need to be applied, prior to application of these tools. In this study, we explored the performance of Principal Component Analysis (PCA) and Independent Component Analysis (ICA) to extract signals and reduce noise, thereby increasing the Signal to Noise Ratio (SNR) in a dynamic sequence of PET images, where the features of the noise are different compared with some other medical imaging techniques. Applications on computer simulated PET images were explored and compared. Application of PCA generated relatively similar results, with some minor differences, on the images with different noise characteristics. However, clear differences were seen with respect to the type of pre-normalization. ICA on images normalized using two types of normalization methods also seemed to perform relatively well but did not reach the improvement in SNR as PCA. Furthermore ICA seems to have a tendency under some conditions to shift over information from IC1 to other independent components and to be more sensitive to the level of noise. PCA is a more stable technique than ICA and creates better results both qualitatively and quantitatively in the simulated PET images. PCA can extract the signals from the noise rather well and is not sensitive to type of noise, magnitude and correlation, when the input data are correctly handled by a proper pre-normalization. It is important to note that PCA as inherently a method to separate signal information into different components could still generate PC1 images with improved SNR as compared to mean images.
    Full-text · Article · Feb 2009 · The Open Neuroimaging Journal
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    ABSTRACT: This article describes the experimental set-up and pharmacokinetic modeling of P-glycoprotein function in the rat blood-brain barrier using [(11)C]verapamil as the substrate and cyclosporin A as an inhibitor of P-gp. [(11)C]verapamil was administered to rats as an i.v. bolus dose followed by graded infusions to obtain steady-state concentrations in the brain during 70 min. CsA was administered as a bolus followed by a constant infusion 20 min after the start of the [(11)C]verapamil infusion. The brain uptake of [(11)C]verapamil over 2 h was portrayed in a sequence of PET scans in parallel with measurement of [(11)C]verapamil concentrations in blood and plasma and CsA concentrations in blood. Mixed effects modeling in NONMEM was used to build a pharmacokinetic model of CsA-induced P-gp inhibition. The brain pharmacokinetics of [(11)C]verapamil was well described by a two-compartment model. The effect of CsA on the uptake of [(11)C]verapamil in the brain was best described by an inhibitory indirect effect model with an effect on the transport of [(11)C]verapamil out of the brain. The CsA concentration required to obtain 50% of the maximal inhibition was 4.9 microg/mL (4.1 microM). The model parameters indicated that 93% of the outward transport of [(11)C]verapamil was P-gp mediated.
    Full-text · Article · Dec 2008 · Journal of Pharmaceutical Sciences
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    ABSTRACT: 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.
    Full-text · Article · Sep 2008 · Developmental Medicine & Child Neurology
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    ABSTRACT: The use of (68)Ga-labeled peptides in diagnosis, dosimetry, therapy planning and follow-up of response to chemo- and radiotherapy requires accurate quantification of tracer binding characteristics in vivo, which may be influenced by the specific radioactivity (SRA) of the tracer. Systematic study of the complexation reaction of DOTA-D-Phe(1)-Tyr(3)-Octreotide (DOTATOC, where DOTA is the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) with (67)Ga, (68)Ga, (69,71)Ga and in the presence of competing metal cations [Al(III), Fe(III), In(III)] was performed using conventional and microwave heating techniques and assessed by mass spectrometry. Saturation binding of (68)Ga-DOTATOC to Rhesus monkey brain slices was performed using frozen section autoradiography. High SRA was necessary in order to characterize the saturation binding of (68)Ga-DOTATOC to somatostatin receptors in Rhesus monkey brain sections. The complexation of Ga(III) with DOTATOC suggested more favorable formation compared to Fe(III) and In(III). The microwave heating mode might influence the selectivity of the complexation reaction, especially when comparing the behavior of Ga(III) and In(III). Al(III) was less critical with contamination and could be tolerated up to a concentration equal to that of the peptide bioconjugate. The SRA of (67)Ga-DOTATOC and (67)Ga-NODAGA-TATE (NODAGA-Tyr(3)-Octreotate, where NODAGA is 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid) exceeded literature data by a factor of 7 and 5-15, respectively. High SRA was critical for providing sufficient contrast and accurate quantification of PET images. Microwave heating mode apart from the acceleration of the labeling reaction also improved the selectivity of the complexation reaction towards gallium. Fe(III) was shown to be the most critical competitor deteriorating the (68)Ga-labeling efficiency.
    No preview · Article · Aug 2008 · Nuclear Medicine and Biology
  • Olof Eriksson · Ray Josephsson · Bengt Långstrom · Mats Bergström
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    ABSTRACT: There are several instances when it is desirable to control brain concentration of pharmaceuticals, e.g., to modulate the concentration of anesthetic agents to different desired levels fitting to different needs during the course of surgery. This has so far only been possible using indirect estimates of drug concentration such as assuming constant relation between tissue and blood including extrapolations from animals. A system for controlling target tissue concentration (UIPump) was used to regulate whole-brain concentrations of a central benzodiazepine receptor antagonist at therapeutic levels with input from brain kinetics as determined with PET. The system was tested by using pharmacological doses of flumazenil mixed with tracer amounts of [11C]flumazenil. Flumazenil was used as a model compound for anesthesia. An infusion scheme to produce three different steady-state levels in sequence was designed based on kinetic curves obtained after bolus injection. The subjects (Sprague-Dawley rats, n=6) were monitored in a microPET scanner during the whole experiment to verify resulting brain kinetic curves. A steady-state brain concentration was rapidly achieved corresponding to a whole-brain concentration of 118+/-6 ng/ml. As the infusion rate decreased to lower the exposure by a factor of 2, the brain concentration decreased to 56+/-4 ng/ml. A third increased steady-state level of anesthesia corresponding to a whole-brain concentration of 107+/-7 ng/ml was rapidly achieved. The experimental setup with computerized pump infusion and PET supervision enables accurate setting of target tissue drug concentration.
    No preview · Article · May 2008 · Nuclear Medicine and Biology
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    ABSTRACT: In a previous study, we demonstrated that androgenic-anabolic steroids increased aromatase expression in the bed nucleus of stria terminalis and preoptic area in rat brain, as evaluated using autoradiography with [11C]vorozole, a potential positron emission tomography tracer for aromatase. In this study, we explored whether the increase in aromatase binding is mediated via androgen receptors and whether this increase occurs in neurons or glial cells. Rats were given nandrolone decanoate (15 mg/kg body weight once every 3 days) and flutamide (20 mg/kg/day) alone or in combination for 20 days. Results indicated a significant increase of [11C]vorozole binding by nandrolone decanoate in the bed nucleus of the stria terminalis and preoptic area, as in our previous study. Flutamide treatment, on the other hand, decreased [11C]vorozole binding in the bed nucleus of the stria terminalis, preoptic area, and medial amygdala. Immunohistochemical examination demonstrated that upregulation of aromatase expression occurred in neurons. Our findings suggest that aromatase is regulated through an androgen receptor-mediated system. This aromatase-specific tracer and the positron emission tomography technique could be useful for exploring the role of aromatase in anabolic androgenic steroids abusers.
    No preview · Article · Apr 2008 · Neuroreport
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    ABSTRACT: In vivo monitoring of gene expression may be accomplished using a most advanced imaging technology such as positron emission tomography (PET). However, a range of methodological and biological hurdles needs exploration. In the present study, 20-mer DNA-LNA (locked nucleic acid) mixmer oligonucleotides specific for rat Chromogranin-A (Chg-A) mRNA were labeled with 68Ga and their biodistribution were investigated in rats; namely, two Antisense (LNA1, LNA2--differing only in the positioning of LNA modification), Mismatched, and Sense sequences. In addition, in vivo and in vitro metabolite analysis of LNA1 and LNA2 was compared, and hybridization in solution was performed to verify the hybridization ability after labeling. Furthermore, semiquantitative polymerase chain reaction was carried out to find organs expressing Chg-A mRNA in the rat. The biodistribution patterns altered according to the sequence and the positioning of LNA modification. The pattern of Mismatched--differing only in two nucleotides from the two Antisenses--was similar to that of Sense, whereas the pattern of LNA1 and LNA2 showed differences. Uptake in the adrenal gland was twofold higher with LNA2 compared to the other three oligonucleotides. Intact LNA2 could be observed in the 60-minute sample in vivo, whereas in vitro, the intact compound of both Antisenses could also be detected after 2 hours. Hybridization in solution revealed that the two Antisenses retained their hybridization abilities after 68Ga-labeling. With decreasing magnitude, Chg-A mRNA was expressed in the adrenal gland, intestine, testis, and pancreas. This study further supported LNA-DNA mixmer to be a favorable modification for antisense targeting approach with respect to hybridization and longer plasma residence; however, the organ uptake was dominated by processes irrelevant to specific hybridization.
    No preview · Article · Feb 2008 · Oligonucleotides

Publication Stats

10k Citations
757.50 Total Impact Points


  • 1983-2013
    • Uppsala University
      • • Department of Pharmaceutical Biosciences
      • • Department of Neuroscience
      Uppsala, Uppsala, Sweden
  • 2006-2009
    • Uppsala Monitoring Centre
      Uppsala, Uppsala, Sweden
  • 1986-2006
    • Uppsala University Hospital
      • • Department of Neuroscience
      • • PET Centre
      • • Department of Internal Medicine
      • • Department of Neurology
      Uppsala, Uppsala, Sweden
  • 2005
    • Novartis
      Bâle, Basel-City, Switzerland
  • 2004
    • HAMAMATSU Photonics K.K.
      Hamamatu, Shizuoka, Japan
  • 2002
    • Cliniques Universitaires Saint-Luc
      • Division of Nuclear Medicine
      Bruxelles, Brussels Capital, Belgium
  • 1988-1998
    • Akademiska Sjukhuset
      Uppsala, Uppsala, Sweden
  • 1980-1987
    • Karolinska University Hospital
      • Department of Clinical Pharmacology
      Tukholma, Stockholm, Sweden
  • 1977-1986
    • Karolinska Institutet
      • Department of Neurosurgery
      Solna, Stockholm, Sweden
  • 1978
    • Stockholm University
      • Department of Physics
      Tukholma, Stockholm, Sweden