| 1. |
- Forsberg, Anton, et al.
(författare)
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Low background and high contrast PET imaging of amyloid-β with [11C]AZD2995 and [11C]AZD2184 in Alzheimer's disease patients
- 2013
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer-Verlag New York. - 1619-7070 .- 1619-7089. ; 40:4, s. 580-593
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-β in Alzheimer's disease (AD).METHODS: In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-β PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [(11)C]AZD2995 and [(11)C]AZD2184 in three healthy control subjects and seven AD patients.RESULTS: AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-β. [(3)H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [(11)C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [(11)C]AZD2995 was greater in areas with lower amyloid-β load, e.g. the hippocampus.CONCLUSION: Both AZD2995 and AZD2184 detect amyloid-β with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [(11)C]AZD2184 seems to be an amyloid-β radioligand with higher uptake and better group separation when compared to [(11)C]AZD2995. However, the very low nonspecific binding of [(11)C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-β. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy.
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| 2. |
- Kågedal, Matts, et al.
(författare)
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A positron emission tomography study in healthy volunteers to estimate mGluR5 receptor occupancy of AZD2066-Estimating occupancy in the absence of a reference region
- 2013
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 82, s. 160-169
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Tidskriftsartikel (refereegranskat)abstract
- AZD2066 is a new chemical entity pharmacologically characterized as a selective, negative allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). Antagonism of mGluR5 has been implicated in relation to various diseases such as anxiety, depression, and pain disorders. To support translation from preclinical results and previous experiences with this target in man, a positron emission tomography study was performed to estimate the relationship between AZD2066 plasma concentrations and receptor occupancy in the human brain, using the mGluR5 radioligand [C-11]-ABP688. The study involved PET scans on 4 occasions in 6 healthy volunteers. The radioligand was given as a tracer dose alone and following oral treatment with different doses of AZD2066. The analysis was based on the total volume of distribution derived fro m each PET-assessment. A non-linear mixed effects model was developed where ten delineated brain regions of interest from all PET scans were included in one simultaneous fit. For comparison the analysis was also performed according to a method described previously by Lassen et al. (1995). The results of the analysis showed that the total volume of distribution decreased with increasing drug concentrations in all regions with an estimated Kipl of 1170 nM. Variability between individuals and occasions in non-displaceable volume of distribution could explain most of the variability in the total volume of distribution. The Lassen approach provided a similar estimate for Kipl, but the variability was exaggerated and difficult to interpret.
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| 3. |
- Kågedal, Matts, et al.
(författare)
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Estimation of drug receptor occupancy when non-displaceable binding differs between brain regions : extending the simplified reference tissue model
- 2015
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 80:1, s. 116-127
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The simplified reference tissue model (SRTM) is used for estimation of receptor occupancy assuming that the non-displaceable binding in the reference region is identical to the brain regions of interest. The aim of this work was to extended the SRTM to also account for inter-regional differences in non-displaceable concentrations, and to investigate if this model allowed estimation of receptor occupancy using white matter as reference. It was also investigated if an apparent higher affinity in caudate compared to other brain regions, could be better explained by a difference in the extent of non-displaceable binding.METHODS: The analysis was based on a PET study in 6 healthy volunteers using the 5-HT1B receptor radioligand [(11) C]AZ10419369. The radioligand was given intravenously as a tracer dose alone and following different oral doses of the 5-HT1B receptor antagonist AZD3783. Nonlinear mixed effects models were developed where differences between regions in non-specific concentrations were accounted for. The properties of the models were also evaluated by means of simulation studies.RESULTS: The estimate (95% CI) of KiPL was 10.2 ng/ml (5.4-15) and 10.4 ng/ml (8.1-13.6) based on the extended SRTM with white matter as reference and based on the SRTM using cerebellum as reference respectively. The estimate (95% CI) of KiPL for caudate relative to other brain regions was 55% ( 48% -62%).CONCLUSIONS: The extended SRTM allows consideration of white matter as reference region when no suitable grey matter region exists. The AZD3783 affinity appears to be higher in caudate compared with other brain regions.
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| 4. |
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| 5. |
- Nag, Sangram, et al.
(författare)
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Synthesis, Biodistribution, and Radiation Dosimetry of a Novel mGluR5 Radioligand : F-18-AZD9272
- 2020
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Ingår i: ACS Chemical Neuroscience. - : AMER CHEMICAL SOC. - 1948-7193. ; 11:7, s. 1048-1057
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Tidskriftsartikel (refereegranskat)abstract
- The metabotropic glutamate receptor subtype mGluR5 has been proposed as a potential drug target for CNS disorders such as anxiety, depression, Parkinson's disease, and epilepsy. The AstraZeneca compound AZD9272 has previously been labeled with carbon-11 and used as a PET radioligand for mGluR5 receptor binding. The molecular structure of AZD9272 allows one to label the molecule with fluorine-18 without altering the structure. The aim of this study was to develop a fluorine-18 analogue of AZD9272 and to examine its binding distribution in the nonhuman primate brain in vivo as well as to obtain whole body radiation dosimetry. F-18-AZD9272 was successfully synthesized from a nitro precursor. The radioligand was stable, with a radiochemical purity of >99% at 2 h after formulation in a sterile phosphate buffered solution (pH = 7.4). After injection of F-18-AZD9272 in two cynomolgus monkeys, the maximum whole brain radioactivity concentration was 4.9-6.7% of the injected dose (n = 2) and PET images showed a pattern of regional radioactivity consistent with that previously obtained for C-11-AZD9272. The percentage of parent radioligand in plasma was 59 and 64% (n = 2) at 120 min after injection of F-18-AZD9272, consistent with high metabolic stability. Two whole body PET scans were performed in nonhuman primates for a total of 231 min after injection of F-18-AZD9272. Highest uptakes were seen in liver and small intestine, followed by brain and kidney. The estimated effective dose was around 0.017 mSv/MBq. F-18-AZD9272 shows suitable properties as a PET radioligand for in vivo imaging of binding in the primate brain. F-18-labeled AZD9272 offers advantages over C-11-AZD9272 in terms of higher image resolution, combined with a longer half-life. Moreover, based on the distribution and the estimated radiation burden, imaging of F-18-AZD9272 could be used as an improved tool for quantitative assessment and characterization of AZD9272 binding sites in the human brain by using PET.
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| 6. |
- Nyberg, Svante, et al.
(författare)
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Detection of amyloid in Alzheimer's disease with positron emission tomography using [11C]AZD2184
- 2009
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer. - 1619-7070 .- 1619-7089. ; 36:11, s. 1859-1863
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Current positron emission tomography (PET) radioligands for detection of Aβ amyloid in Alzheimer's disease (AD) are not ideal for quantification. To improve the signal to noise ratio we have developed the radioligand [11C]AZD2184 and report here the first clinical evaluation.METHODS: Eight AD patients and four younger control subjects underwent 93-min PET measurements with [11C]AZD2184. A ratio approach using the cerebellum as reference region was applied to determine binding parameters.RESULTS: Brain uptake of [11C]AZD2184 peaked within 1 min at 3-4% of injected radioactivity. AD patients had high radioactivity in cortical regions while controls had uniformly low radioactivity uptake. Specific binding peaked within 30 min at which time standardized uptake value ratios (SUVR) ranged between 1.19 and 2.57.CONCLUSION: [11C]AZD2184 is a promising radioligand for detailed mapping of Aβ amyloid depositions in Alzheimer's disease, due to low non-specific binding, high signal to background ratio and reversible binding as evident from early peak equilibrium.
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| 7. |
- Schain, Martin, et al.
(författare)
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Arterial input function derived from pairwise correlations between PET-image voxels
- 2013
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : Nature Publishing Group. - 0271-678X .- 1559-7016. ; 33:7, s. 1058-1065
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Tidskriftsartikel (refereegranskat)abstract
- A metabolite corrected arterial input function is a prerequisite for quantification of positron emission tomography (PET) data by compartmental analysis. This quantitative approach is also necessary for radioligands without suitable reference regions in brain. The measurement is laborious and requires cannulation of a peripheral artery, a procedure that can be associated with patient discomfort and potential adverse events. A non invasive procedure for obtaining the arterial input function is thus preferable. In this study, we present a novel method to obtain image-derived input functions (IDIFs). The method is based on calculation of the Pearson correlation coefficient between the time-activity curves of voxel pairs in the PET image to localize voxels displaying blood-like behavior. The method was evaluated using data obtained in human studies with the radioligands [11C]flumazenil and [11C]AZ10419369, and its performance was compared with three previously published methods. The distribution volumes (VT) obtained using IDIFs were compared with those obtained using traditional arterial measurements. Overall, the agreement in VT was good (~3% difference) for input functions obtained using the pairwise correlation approach. This approach performed similarly or even better than the other methods, and could be considered in applied clinical studies. Applications to other radioligands are needed for further verification.
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| 8. |
- Tangen, Ämma, et al.
(författare)
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Associations between cognition and serotonin receptor 1B binding in patients with major depressive disorder : a pilot study
- 2017
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Ingår i: Psychiatry Research: Neuroimaging. - Stockholm : Karolinska Institutet, Dept of Clinical Neuroscience. - 0925-4927 .- 1872-7506.
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Tidskriftsartikel (refereegranskat)abstract
- The neurotransmitter serotonin has been widely implicated in the pathophysiology of major depressive disorder (MDD). In animal studies and human neuroimaging studies, involvement of the serotonin receptor 1B (5-HT1BR) in MDD and memory performance has been reported. However, the role of the 5-HT1BR in cognitive functions affected in MDD remains to be clarified. Ten patients with MDD diagnosis were examined with positron emission tomography (PET) and a battery of cognitive tests before and after Internet-based Cognitive Behavioral Therapy (ICBT). The results were compared to ten matched control subjects in order to investigate putative changes in 5-HT1BR availability and cognitive performance. Patients treated with ICBT showed statistically significant improvement relative to baseline in Verbal fluency, both letter and category production. Significant correlations were found between improvement in letter production and changes in 5-HT1BR availability in ventral striatum, between category production and amygdala, as well as between the improvement in Trailmaking test B and change in 5-HT1BR binding in dorsal brainstem, in amygdala and in hippocampus. The results suggest an association between 5-HT1BR binding and improvement in cognitive functioning. Replications in larger-scale studies are required to confirm these findings.
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| 9. |
- Varnäs, Katarina
(författare)
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Distribution of serotonin receptors and transporters in the human brain : implications for psychosis
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The serotonin (5-HT) system is thought to be involved in different psychiatric disorders, including depression and anxiety disorders, and is a major target for the pharmacological treatment of these conditions. The involvement of the 5-HT system in psychosis has been suggested, as 5-HT receptor agonism is a common mechanism of different classes of hallucinogenic drugs and several antipsychotics are 5-HT receptor antagonists. In this study, the distribution of 5-HT transporters and G-protein-coupled 5-HT receptors in the human brain was characterized using whole hemisphere autoradiographic techniques. In addition, a pilot investigation was performed to compare the densities of 5-HT binding sites in brain tissue from patients who suffered from schizophrenia-like psychosis and control subjects. We found higher levels of 5-HT transporters in several regions of the greater limbic lobe (subcallosal area, anterior cingulate gyrus, posterior uncus, insular and entorhinal cortices, and the temporal pole) as compared to the isocortex. Higher levels of 5-HT1A receptors were also found in limbic cortices (subcallosal area, temporal pole, hippocampus, and entorhinal cortex) compared to isocortical structures. Dense binding to 5-HT1B receptors was found in the ventral striato-pallidal system of the human brain. 5-HT1B receptor mRNA expression was detected in the striatum with the highest levels in ventral striatal regions. We found no evidence for mRNA expression in the substantia nigra and pallidum, where the highest levels of receptor binding sites were found, in support of the localization of 5-HT1B receptors in axon terminals in these regions. Conversely, high levels of mRNA expression was identified in thalamic nuclei, where binding to 5-HT1B receptors was very low or absent, suggesting the localization of these receptors in thalamic projections. 5-HT1B receptor binding sites and mRNA expression were detected in the isocortex with a region- and layer-specific distribution pattern. 5-HT1D receptors seemed to be confined to the substantia nigra and pallidum, where densities were markedly lower as compared to 5-HT1B receptor densities. The use of a high sensitivity radioligand allowed the detection of 5-HT4 receptors in low-density regions, including thalamus and raphe nuclei. Our results demonstrate that 5-HT6 receptors are concentrated in nigrostriatal regions, whereas 5-HT7 receptors are densely localized in the anterior thalamus, hippocampal formation and the anterior cingulate gyrus, regions involved in the modulation of learning and memory and affective behavior, respectively. There was a trend towards lower levels of 5-HT transporters in the striatum and the temporal cortex, as well as lower levels of 5-HT2A receptors in cortical regions and 5-HT7 receptors in the lateral frontal cortex and pulvinar thalamus of psychotic patients compared to controls. Data also indicated lower levels of 5-HT1A and 5-HT1B receptors in the hippocampal formation, and in the ventral pallidum and orbitofrontal cortex, respectively. Future large-scale studies are required to verify these findings. It can be concluded that the different 5-HT receptors have unique distribution patterns in the human brain, reflecting their different physiological effects. The general localization in regions belonging to limbic cortico-striato-pallido-thalamic circuits is consistent with the documented role for 5-HT in the modulation of mood and emotion, as well as with the suggested involvement of this system in the pathophysiology of psychiatric disorders.
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| 10. |
- Varrone, Andrea, et al.
(författare)
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Positron emission tomography imaging of 5-hydroxytryptamine(1B) receptors in Parkinson's disease
- 2014
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 35:4, s. 867-875
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Tidskriftsartikel (refereegranskat)abstract
- Impairment of the central serotonin system in Parkinson's disease (PD) has been shown postmortem and in vivo with positron emission tomography (PET). The aim of this PET study was to examine and compare the availability of the 5-hydroxytryptamine (5-HT)(1B)-receptor subtype in patients with PD and age-matched control subjects. Twelve control subjects and 12 PD patients were examined with PET using the 5-HT1B-radioligand [C-11]AZ10419369. In PD patients, 5-HT1B-receptor availability in the right orbitofrontal cortex was lower than in control subjects. A statistically significant negative correlation between 5-HT1B-receptor availability and age was obtained for the right temporal cortex in control subjects and for the right midbrain and left parahippocampal gyrus in PD patients. The lower regional 5-HT1B-receptor availability is in line with previous studies showing a decrease of serotonin imaging markers in PD and corroborates a role of the serotonin system in the pathophysiology of PD. The demonstrated age effect on 5-HT1B receptors suggest a physiologic and PD-related decline of serotonin function, indicating the importance of controlling for age in clinical studies.
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