| 1. |
- Erlandsson, Maria, 1980-, et al.
(författare)
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18F-Labelled Metomidate Analogues as Adrenocortical Imaging Agents
- 2009
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 36:4, s. 435-445
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Two- and one-step syntheses of 18F-labelled analogues of Metomidate, such as 2-[18F]fluoroethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (1), 2-[18F]fluoroethyl 1-[(1R)-1-(4-chlorophenyl)ethyl]-1H-imidazole-5-carboxylate (2), 2-[18F]fluoroethyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (3), 3-[18F]fluoropropyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (4) and 3-[18F]fluoropropyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (5) are presented.Methods: Analogues 1-5 were prepared by a two-step reaction sequence that started with the synthesis of either 2-[18F]fluoroethyl 4-methylbenzenesulfonate or 3-[18F]fluoropropyl 4-methylbenzenesulfonate. These were used as 18F-alkylating agents in the second step, in which they reacted with the ammonium salt of a 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylic acid. One-step-labelling syntheses of 1, 2 and 5 were also explored. Analogues 1-4 were biological validated by frozen-section autoradiography and organ distribution. Metabolite analysis was performed for 2 and 3.Results: The radiochemical yield of the two-step synthesis was in the range of 10-29%, and thatof the one-step synthesis was 25-37%. Using microwave irradiation in the one-step synthesis of 1 and 2 increased the radiochemical yield to 46 ± 3 and 79 ± 30%, respectively.Conclusion: Both the frozen-section autoradiography and organ distribution results indicated that analogue 2 has a potential as an adrenocortical imaging agent, having the highest degree of specific adrenal binding and best ratio of adrenal to organ uptake among the compounds studied.
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| 2. |
- Hennings, Joakim, et al.
(författare)
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[11C]metomidate positron emission tomography of adrenocortical tumors in correlation with histopathological findings
- 2006
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 91:4, s. 1410-4
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Adrenal incidentalomas are common findings necessitating extensive laboratory work-up and repetitive radiological examinations. Positron emission tomography (PET) using (11)C-labeled metomidate (MTO) has previously been described as a tool for specific adrenocortical imaging. OBJECTIVE: We evaluated 212 MTO-PET examinations in 173 patients to identify its role in the management of adrenal tumors. DESIGN: Seventy-five histopathological examinations from 73 patients were retrospectively analyzed. SETTING: All examinations were performed at a referral center. PATIENTS: Patients who were operated or biopsied due to adrenal tumors had histopathological diagnoses of adrenocortical adenoma (n = 26), adrenocortical cancer (ACC; n = 13), adrenocortical hyperplasia (n = 8), pheochromocytoma (n = 6), metastasis (n = 3), and tumors of nonadrenal origin (n = 19). MAIN OUTCOME MEASURES: The main outcome measures were statistical analyses and findings while scrutinizing images. The hypothesis that MTO-PET is of value in the management of adrenal tumors, especially incidentaloma, was stated before data collection. RESULTS: Sensitivity was 0.89 and specificity was 0.96 for MTO-PET in proving adrenocortical origin of the lesions. Pheochromocytomas, metastases to the adrenal gland, and nonadrenal masses were all MTO negative. PET measurements using standardized uptake values (SUV) in pathological adrenocortical tissue could differentiate lesions larger than 1-1.5 cm from normal adrenocortical tissue. SUV was higher in aldosterone-hypersecreting adenomas, and the SUV ratio between the tumor and the contralateral gland was significantly higher in all hormonally hypersecreting adenomas as well as in ACC. CONCLUSION: MTO-PET is a specific and sensitive method for diagnosing adrenocortical tumors. MTO-PET is useful in the imaging work-up of adrenal incidentalomas and may be beneficial for the examination of patients with primary aldosteronism or ACC.
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| 3. |
- Karimi, Farhad, et al.
(författare)
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Synthesis of C-11-labelled metomidate analogues as adrenocortical imaging agents.
- 2008
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Ingår i: Journal of labelled compounds & radiopharmaceuticals. - : Wiley. - 0362-4803 .- 1099-1344. ; 51:6, s. 273-276:51, s. 273-276
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Tidskriftsartikel (refereegranskat)abstract
- Clinical findings using [C-11]methyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate ([C-11]MTO, 1) show high uptake in lesions of adrenocortical origin, including adenomas, but low uptake in lesions of non-adrenocortical origin. In this paper the synthesis and preclinical evaluation of two new C-11-labelled analogues of MTO, [C-11]methyl 1-[(1R)-1-(4-chlorophenyl)ethyl]-1H-imidazole-5-carboxylate ([C-11]CLM, 2) and [C-11]methyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate ([C-11]BRM, 3), using frozen-section autoradiography, organ distribution and a metabolic study are presented.
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| 4. |
- Lindhe, Örjan, et al.
(författare)
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[(18)F]Fluoroacetate is not a functional analogue of [(11)C]acetate in normal physiology
- 2009
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 36:9, s. 1453-1459
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: [(11)C]Acetate (C-AC) is a general PET tracer of cellular carbon flux and useful for clinical imaging in heart disease as well as prostate cancer and other tumours. C-AC has a high (70%) whole-body extraction fraction, proportional to blood flow in many organs. Trapping is related to organ-specific enzymatic activation and formation of [(11)C]-acetyl-CoA, the fate of which has been well characterized. Due to the logistic challenges with C-AC, 2-[(18)F]fluoroacetate (F-AC) has been proposed as a marker for prostate cancer imaging. METHOD: We evaluated the potential of F-AC as a tracer for imaging blood flow and early enzymatic steps in the intermediary metabolism. C-AC and F-AC were injected serially in three cynomolgus monkeys and one domestic pig and scanned using PET/CT. A dynamic scan covering heart and liver was followed by repeated whole-body imaging. Kinetic patterns were compared for the myocardium, liver, blood and other organs. RESULTS: C-AC kinetics and organ distribution in both species were similar to those previously established in man. In contrast, F-AC showed prolonged blood retention, no detectable trapping in myocardium or salivary glands, rapid clearance from liver and extensive excretion to bile and urine. Massive defluorination was seen in the pig, resulting in intense skeletal activity. CONCLUSION: 2-[(18)F]Fluoroacetate cannot be regarded as a functional analogue of 1-[(11)C]acetate in normal physiology and appears to be of little use for studies of organ blood flow, intermediary metabolism or lipid synthesis.
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| 5. |
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| 6. |
- Lindhe, Örjan, 1968-
(författare)
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Adrenal Bioactivation and Toxicity of 3-MeSO2-DDE, o,p´-DDD and DMBA Investigated in Tissue Slice Culture
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- I developed a precision-cut adrenal slice culture procedure to investigate cytochrome P450 (CYP) catalysed irreversible binding and adrenocorticolytic effects in human, rodent, and fish adrenal tissue, ex vivo. Autoradiography and radioluminography of exposed tissue slices showed that the potent adrenal toxicant 3-methylsulphonyl-2,2´-bis(4-chlorophenyl)-1,1´-dichloroethene (MeSO2-DDE) causes a selective metabolite binding in zona fasciculata (ZF), which is diminished by the CYP11B1 inhibitor metyrapone. MeSO2-DDE also reduces corticosterone secretion, increases 11-deoxycorticosterone secretion and causes mitochondrial degeneration in ZF cells in cultured mouse adrenal slices. ACTH treatment of mice induces CYP11B1 and increases irreversible MeSO2-DDE binding and toxicity in ZF cells. Metyrapone-sensitive binding of MeSO2-DDE is also observed in human zona fasciculata/reticularis (ZF/ZR) and 11-deoxycorti- sol/corticosterone secretion increases in MeSO2-DDE-exposed cultured human adrenal slices. The adrenocorticolytic drug 2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichlorethane (o,p´- DDD, Mitotane®) is also bound in ZF/ZR but does not to impair hormone secretion in human adrenal slices at equimolar concentration. A targeted, presumably CYP1B1-catalysed irreversible binding of the adrenocorticolytic carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) in ZF/ZR occurs in rat adrenal slices, whereas presumably CYP1A1-catalysed irreversible binding in endothelial cells is observed in CYP1-induced rats and mice. The rat-specific adrenocorticolytic activity of DMBA may rely on two independent pathological processes resulting in cell death and haemorrhage in the adrenal cortex. In Atlantic cod, selective binding of o,p´-DDD is observed in interrenal cells in cultured anterior kidney slices.In conclusion, precision-cut adrenal slice culture is a simple ex vivo test system with which to investigate CYP-catalysed metabolite binding, alteredsteroid hormone secretion and target cell ultrastructure in human, experimental and wild animal tissue. The results imply that organisms under stress could be at increased risk of MeSO2-DDE induced adrenal toxicity. MeSO2-DDE is an expected human adrenal toxicant, which should be evaluated as a possible alternative in the therapy of adrenocortical hypersecretion and tumour growth.
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| 7. |
- Lindhe, Örjan, et al.
(författare)
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Autoradiographic mapping of 5-HT1B/1D binding sites in the Rhesus monkey brain using [carbonyl-11C]zolmitriptan
- 2011
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Ingår i: International Journal of Molecular Imaging. - : Hindawi Publishing Corporation. - 2090-1712 .- 2090-1720.
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Tidskriftsartikel (refereegranskat)abstract
- Zolmitriptan is a serotonin 5-HT1B/1D receptor agonist that is an effective and well-tolerated drug for migraine treatment. In a human positron emission tomography study, [11C]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 [11C]zolmitriptan in Rhesus monkey brain using whole hemisphere in vitro autoradiography with [11C]zolmitriptan as a radioligand. In saturation studies, [11C]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-HT1 receptor antagonists, [11C]zolmitriptan binding was blocked by selective 5-HT1B and 5-HT1D ligands in all target areas. There was no appreciable change in binding with the addition of a 5-HT1A receptor antagonist.
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| 8. |
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| 9. |
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| 10. |
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| 11. |
- Lindhe, Örjan, et al.
(författare)
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Irreversible binding and adrenocorticolytic activity of the DDT metabolite 3-methylsulfonyl-DDE examined in tissue-slice culture
- 2001
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Ingår i: Journal of Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 109:2, s. 105-110
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Tidskriftsartikel (refereegranskat)abstract
- The persistent adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE (MeSO(2)-DDE) was originally identified in Baltic grey seals, a population suffering from adrenocortical hyperplasia. In mice, MeSO(2)-DDE induces mitochondrial degeneration and cellular necrosis in the adrenal zona fasciculata. In this study, we used precision-cut tissue slice culture to examine local CYP11B1-catalyzed irreversible binding of MeSO(2)-DDE in the murine adrenal cortex. We also examined effects on steroid hormone secretion, histology, and ultrastructure. As determined by microautoradiography, selective binding occurred in zona fasciculata of slices exposed to MeSO(2)-[(14)C]-DDE. Quantification of binding by phosphorautoradiography revealed a 3-fold reduction of binding in slices co-exposed to the CYP11B1 inhibitor metyrapone. As measured by HPLC, corticosterone and 11-deoxycorticosterone secretion to the medium increased linearly for at least 24 hr. Addition of the ACTH analog tetracosactide caused an 8-fold increase in corticosterone secretion. Addition of metyrapone reduced corticosterone secretion 4-fold. Exposure of slices to MeSO(2)-DDE (50 microM) reduced the rate of corticosterone secretion by 90% after 24 hr of incubation. As determined by electron microscopy, vacuolated mitochondria were present in zona fasciculata of slices exposed to MeSO(2)-DDE (50 microM) for 24 hr. Our findings show that all effects of MeSO(2)-DDE previously reported in vivo could be reproduced in adrenal slice culture ex vivo. This test system allows analysis of zone-specific irreversible binding and effects on steroid hormone secretion and target cell ultrastructure. We propose adrenal slice culture as a simple ex vivo test system with which to examine the adrenocorticolytic activity of xenobiotics in human and wild animal tissue.
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| 12. |
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| 13. |
- Lindhe, Örjan, et al.
(författare)
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Mitotane Effects in a H295R Xenograft Model of Adjuvant Treatment of Adrenocortical Cancer
- 2010
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Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 42:10, s. 725-730
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Tidskriftsartikel (refereegranskat)abstract
- Adrenocortical cancer is one of the most aggressive endocrine malignancies. Growth through the capsule or accidental release of cancer cells during surgery frequently results in metastatic disease. We investigated the antitumoral effect of 2 adrenocorticolytic compounds, o,p′-DDD and MeSO2-DDE, in the adrenocortical cell line H295R both in vitro and as a xenograft model in vivo. H295R cells were injected s. c. in nude mice. o,p′-DDD, MeSO2-DDE, or oil (control) was administered i. p., either simultaneously with cell injection at day 0 (mimicking adjuvant treatment), or at day 48 (established tumors). Accumulation of PET tracers [11C]methionine (MET), [11C] metomidate (MTO), 2-deoxy-2-[18F]fluoro-d-glucose (FDG), and [18F]-l-tyrosine (FLT) in the aggregates were assessed ± drug treatment in vitro. Tumor growth was significantly inhibited when o,p′-DDD was given at the same time as injection of tumor cells. No significant growth inhibition was observed after treatment with o,p′-DDD at day 48. A significant reduction in FLT uptake and an increased FDG uptake, compared to control, were observed following treatment with 15 μM o,p′-DDD (p<0.01) in vitro. MeSO2-DDE (15 μM) treatment gave rise to a reduced MET and an increased FLT uptake (p<0.01). Both compounds reduced the uptake of MTO compared to control (p<0.01). Treatment with o,p′-DDD simultaneously to inoculation of H295R cells in mice, imitating release of cells during surgery, gave a markedly better effect than treatment of established H295R tumors. We suggest that FLT may be a potential PET biomarker when assessing adrenocortical cancer treatment with o,p′-DDD. Further studies in humans are needed to investigate this.
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| 14. |
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| 15. |
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| 16. |
- Lindström, Veronica, et al.
(författare)
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Species differences in 3-methylsulphonyl-DDE bioactivation by adrenocortical tissue
- 2008
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 82:3, s. 159-163
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Tidskriftsartikel (refereegranskat)abstract
- The CYP11B1-activated adrenocortical toxicant 3-methylsulphonyl-DDE (3-MeSO2-DDE) is proposed as a lead compound for an improved chemotherapy for adrenocortical carcinoma. We compared the binding of 3-MeSO2-[C-14]DDE in the adrenal cortex of four rodent species; hamster, guinea pig, mouse and rat, using a precision-cut adrenal slice culture system ex vivo. Localization and quantification of the bound radioactivity were carried out using light microscopy autoradiography and radioluminography. The results revealed major species differences since 3-MeSO2-[C-14]DDE was extensively bound to the hamster adrenal tissue while the guinea pig adrenals were devoid of binding. A high binding in mouse adrenal cortex was confirmed while binding in rat adrenal cortex was very weak. The results support previous observations that metabolic activation of 3-MeSO2-DDE is highly species dependent. Since CYP11B1 could be expressed in tissues other than the adrenal cortex, final toxicological characterization should be carried out in a species that can bioactivate this compound.
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| 17. |
- Långström, Bengt, et al.
(författare)
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In vitro imaging techniques in neurodegenerative diseases
- 2007
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Ingår i: Molecular Imaging and Biology. - : Springer Science and Business Media LLC. - 1536-1632 .- 1860-2002. ; 9:4, s. 161-175
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Tidskriftsartikel (refereegranskat)abstract
- Neurodegeneration induces various changes in the brain, changes that may be investigated using neuroimaging techniques. The in vivo techniques are useful for the visualization of major changes, and the progressing abnormalities may also be followed longitudinally. However, to study and quantify minor abnormalities, neuroimaging of postmortem brain tissue is used. These in vitro methods are complementary to the in vivo techniques and contribute to the knowledge of pathophysiology and etiology of the neurodegenerative diseases. In vitro radioligand autoradiography has given great insight in the involvement of different neuronal receptor systems in these diseases. Data on the dopamine and cholinergic systems in neurodegeneration are discussed in this review. Also, the amyloid plaques are studied using in vitro radioligand autoradiography. Using one of the newer methods, imaging matrix-assisted laser desorption ionization mass spectrometry, the distribution of a large number of peptides and proteins may be detected in vitro on brain cryosections. In this overview, we describe in vitro imaging techniques in the neurodegenerative diseases as a complement to in vivo positron emission tomography and single photon emission computed tomography imaging.
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| 18. |
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| 19. |
- Monazzam, Azita, et al.
(författare)
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A new, fast and semi-automated size determination method (SASDM) for studying multicellular tumor spheroids
- 2005
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Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; :5, s. 32-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Considering the width and importance of using Multicellular Tumor Spheroids (MTS) in oncology research, size determination of MTSs by an accurate and fast method is essential. In the present study an effective, fast and semi-automated method, SASDM, was developed to determinate the size of MTSs. The method was applied and tested in MTSs of three different cell-lines. Frozen section autoradiography and Hemotoxylin Eosin (H&E) staining was used for further confirmation.RESULTS:SASDM was shown to be effective, user-friendly, and time efficient, and to be more precise than the traditional methods and it was applicable for MTSs of different cell-lines. Furthermore, the results of image analysis showed high correspondence to the results of autoradiography and staining.CONCLUSION:The combination of assessment of metabolic condition and image analysis in MTSs provides a good model to evaluate the effect of various anti-cancer treatments.
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| 20. |
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| 21. |
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| 22. |
- Syvänen, Stina, et al.
(författare)
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Species differences in blood-brain barrier transport of three positron emission tomography radioligands with emphasis on P-glycoprotein transport
- 2009
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Ingår i: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 37:3, s. 635-643
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Tidskriftsartikel (refereegranskat)abstract
- Species differences occur in the brain concentrations of drugs, but the reasons for these differences are not yet apparent. This study was designed to compare brain uptake of three radiolabeled P-glycoprotein (P-gp) substrates across species using positron emission tomography. Brain concentrations and brain-to-plasma ratios were compared; [11C]verapamil in rats, guinea pigs, and monkeys; [11C](S)-(2-methoxy-5-(5-trifluoromethyltetrazol-1-yl)-phenylmethylamino)-2(S)-phenylpiperidine (GR205171) in rats, guinea pigs, monkeys, and humans; and [18F]altanserin in rats, minipigs, and humans. The fraction of the unbound radioligand in plasma was studied along with its metabolism. The effect of P-gp inhibition was investigated by administering cyclosporin A (CsA). Pronounced species differences were found in the brain and brain-to-plasma concentrations of [11C]verapamil, [11C]GR205171, and [18F]altanserin with higher brain distribution in humans, monkeys, and minipigs than in rats and guinea pigs. For example, the brain-to-plasma ratio of [11C]GR205171 was almost 9-fold higher in humans compared with rats. The species differences were still present after P-gp inhibition, although the increase in brain concentrations after P-gp inhibition was somewhat greater in rats than in the other species. Differences in plasma protein binding and metabolism did not explain the species-related differences. The findings are important for interpretation of brain drug delivery when extrapolating preclinical data to humans. Compounds found to be P-gp substrates in rodents are likely to also be substrates in higher species, but sufficient blood-brain barrier permeability may be retained in humans to allow the compound to act at intracerebral targets.
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| 23. |
- Syvänen, Stina, et al.
(författare)
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Synthesis of two potential NK1-receptor ligands using [1-11C]ethyl iodide and [1-11C]propyl iodide and initial PET-imaging
- 2007
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Ingår i: BMC Medical Imaging. - : Springer Science and Business Media LLC. - 1471-2342. ; 7, s. 6-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:The previously validated NK1-receptor ligand [O-methyl-11C]GR205171 binds with a high affinity to the NK1-receptor and displays a slow dissociation from the receptor. Hence, it cannot be used in vivo for detecting concentration changes in substance P, the endogenous ligand for the NK1-receptor. A radioligand used for monitoring these changes has to enable displacement by the endogenous ligand and thus bind reversibly to the receptor. Small changes in the structure of a receptor ligand can lead to changes in binding characteristics and also in the ability to penetrate the blood-brain barrier. The aim of this study was to use carbon-11 labelled ethyl and propyl iodide with high specific radioactivity in the synthesis of two new and potentially reversible NK1-receptor ligands with chemical structures based on [O-methyl-11C]GR205171.METHODS:[1-11C]Ethyl and [1-11C]propyl iodide with specific radioactivities of 90 GBq/μmol and 270 GBq/μmol, respectively, were used in the synthesis of [O-methyl-11C]GR205171 analogues by alkylation of O-desmethyl GR205171. The brain uptake of the obtained (2S,3S)-N-(1-(2- [1-11C]ethoxy-5-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)-2-phenylpiperidin-3-amine (I) and (2S,3S)-2-phenyl-N-(1-(2- [1-11C]propoxy-5-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)piperidin-3-amine (II) was studied with PET in guinea pigs and rhesus monkeys and compared to the uptake of [O-methyl-11C]GR205171.RESULTS:All ligands had similar uptake distribution in the guinea pig brain. The PET-studies in rhesus monkeys showed that (II) had no specific binding in striatum. Ligand (I) had moderate specific binding compared to the [O-methyl-11C]GR205171. The ethyl analogue (I) displayed reversible binding characteristics contrary to the slow dissociation rate shown by [O-methyl-11C]GR205171.CONCLUSION:The propyl-analogue (II) cannot be used for detecting changes in NK1-ligand levels, while further studies should be performed with the ethyl-analogue (I).
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| 24. |
- Sällman Almén, Markus, et al.
(författare)
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Shrunken Pore Syndrome Is Associated With Increased Levels of Atherosclerosis-Promoting Proteins
- 2019
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Ingår i: Kidney International Reports. - : Elsevier BV. - 2468-0249. ; 4:1, s. 67-79
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Shrunken pore syndrome (SPS), originally defined by cystatin C-based estimated glomerular filtration rate (eGFRcystatin C) being less than 60% of creatinine-based estimated glomerular filtration rate (eGFRcreatinine) in the absence of extrarenal influences on the plasma levels of cystatin C or creatinine, is associated with a high increase in mortality, even in the absence of reduced glomerular filtration rate (GFR). The objective of the present study was to determine whether the proteome of patients with SPS shows differences from that of patients with normal or reduced measured GFR (mGFR) without SPS.Methods: Four patient cohorts were included: 1 cohort with normal mGFR without SPS, 1 with normal mGFR with SPS, 1 with reduced mGFR without SPS, and 1 with reduced mGFR with SPS. The plasma levels of 177 selected proteins were analyzed.Results: Differences in the levels of 30 proteins were specific for SPS; 31 differences were specific for patients with both SPS and reduced mGFR; and 27 were specific for reduced mGFR. Eighteen of the differences specific for SPS concerned proteins described as promoting, or being associated with, atherosclerosis. Twelve of the differences specific for patients with both SPS and reduced mGFR and 10 of the differences specific for reduced mGFR also concerned proteins described as promoting, or being associated with, atherosclerosis. Almost all (82 of 88) of the concentration differences represented increased levels. For SPS, but not for reduced mGFR, a correlation between protein size and increase in level was observed, with smaller proteins being associated with higher levels.Conclusion: The high mortality in shrunken pore syndrome might be caused by the accumulation of atherosclerosis-promoting proteins in this condition.
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| 25. |
- Velikyan, Irina, et al.
(författare)
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Preparation and evaluation of (68)Ga-DOTA-hEGF for visualisation of EGFR expression in malignant tumours
- 2005
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Ingår i: Journal of Nuclear Medicine. - 0161-5505 .- 1535-5667. ; 46:11, s. 1881-1888
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Tidskriftsartikel (refereegranskat)abstract
- Detection of epidermal growth factor receptor (EGFR) overexpression in many carcinomas provides important diagnostic information, which can influence patient management. The use of PET may enable such detection in vivo by a noninvasive procedure with high sensitivity. The aim of this study was to develop a method for preparation of a positron-emitting tracer based on a natural ligand to EGFR, the recombinant human epidermal growth factor (hEGF), and to perform a preclinical evaluation of the tracer.METHODS: DOTA-hEGF (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) was prepared by coupling of a N-sulfosuccinimide ester of DOTA to hEGF. The conjugate was labeled with a generator-produced positron-emitting nuclide, (68)Ga (half-life = 68 min), using microwave heating. Binding specificity, affinity, internalization, and retention of (68)Ga-DOTA-hEGF was studied in 2 EGFR-expressing cell lines, U343 glioma cells and A431 cervical carcinoma cells. Biodistribution and microPET visualization studies were performed in BALB/c nu/nu mice bearing A431 carcinoma xenografts.RESULTS: A 1-min-long microwave-assisted labeling provided radioactivity incorporation of 77% +/- 4%. Both cell lines demonstrated receptor-specific uptake of the conjugate, rapid internalization of the tracer, and good retention of radioactivity. Binding to both cell lines occurred with high affinity, approximately 2 nmol/L. The biodistribution study demonstrated accumulation of radioactivity in xenografts and in EGFR-expressing organs. The microPET imaging study enabled visualization of tumors and demonstrated quick--within 5 min--localization of radioactivity in tumors.CONCLUSION: (68)Ga-DOTA-hEGF has potential for imaging EGFR overexpression in tumors.
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| 26. |
- Wallén-Mackenzie, Åsa, et al.
(författare)
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Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function.
- 2009
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401 .- 0270-6474. ; 29:7, s. 2238-51
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in neuroscience is to resolve the connection between gene functionality, neuronal circuits, and behavior. Most, if not all, neuronal circuits of the adult brain contain a glutamatergic component, the nature of which has been difficult to assess because of the vast cellular abundance of glutamate. In this study, we wanted to determine the role of a restricted subpopulation of glutamatergic neurons within the forebrain, the Vglut2-expressing neurons, in neuronal circuitry of higher brain function. Vglut2 expression was selectively deleted in the cortex, hippocampus, and amygdala of preadolescent mice, which resulted in increased locomotor activity, altered social dominance and risk assessment, decreased sensorimotor gating, and impaired long-term spatial memory. Presynaptic VGLUT2-positive terminals were lost in the cortex, striatum, nucleus accumbens, and hippocampus, and a downstream effect on dopamine binding site availability in the striatum was evident. A connection between the induced late-onset, chronic reduction of glutamatergic neurotransmission and dopamine signaling within the circuitry was further substantiated by a partial attenuation of the deficits in sensorimotor gating by the dopamine-stabilizing antipsychotic drug aripiprazole and an increased sensitivity to amphetamine. Somewhat surprisingly, given the restricted expression of Vglut2 in regions responsible for higher brain function, our analyses show that VGLUT2-mediated neurotransmission is required for certain aspects of cognitive, emotional, and social behavior. The present study provides support for the existence of a neurocircuitry that connects changes in VGLUT2-mediated neurotransmission to alterations in the dopaminergic system with schizophrenia-like behavioral deficits as a major outcome.
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| 27. |
- Åberg, Ola, 1978-, et al.
(författare)
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Synthesis and Biological Evaluation of [Carboxyl-11C]eprosartan
- 2009
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Ingår i: Journal of labelled compounds & radiopharmaceuticals. - : Wiley. - 0362-4803 .- 1099-1344. ; 52:8, s. 295-303
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Tidskriftsartikel (refereegranskat)abstract
- Essential hypertension occurs in approximately 25% of the adult population and one cause of hypertension is primary aldosteronism. Targeting the angiotensin II AT1 receptor using PET and an appropriate tracer may offer a diagnostic method for adrenocortical tissue. This report describes the synthesis of the selective AT1 receptor antagonist [carboxyl-11C]eprosartan 10, 4-[2-butyl-5-((E)-2-carboxy-3-thiophen-2-yl-propenyl)-imidazol-1-ylmethyl]-[carboxyl-11C]benzoic acid, and its precursor (E)-3-[2-butyl-3-(4-iodo-benzyl)-3H-imidazol-4-yl]-2-thiophen-2-ylmethyl-acrylic acid 9. 11C-carboxylation of the iodobenzyl moiety was performed using a palladium-mediated reaction with [11C]carbon monoxide in the presence of tetra-n-butyl-ammonium hydroxide in a micro-autoclave using a temperature gradient from 25 to 140°C over 5 min. After purification by semipreparative HPLC, [carboxyl-11C]eprosartan 10 was obtained in 37–54% decay-corrected radiochemical yield (from [11C]carbon monoxide) with a radiochemical purity >95% within 35 min of the end of bombardment (EOB). A 5-µAh bombardment gave 2.04 GBq of 10 (50% rcy from [11C]carbon monoxide) with a specific activity of 160 GBq µmol−1 at 34 min after EOB. Frozen-section autoradiography shows specific binding in kidney, lung and adrenal cortex. In vivo experiments in rats demonstrate a high accumulation in kidney, liver and intestinal wall.
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