153,292 research outputs found
Development of Novel Fluorine-18 Labeled PET Radioligands for Monoamine Oxidase B (MAO-B)
Full text linkMonoamine oxidases (MAO-A and MAO-B) are important enzymes regulating the levels of monoaminergic neurotransmitters. Selective and irreversible MAO-B inhibitors such as L-deprenyl and rasagiline are clinically used for the treatment of psychiatric and neurological disorders. Positron emission tomography (PET) is a noninvasive imaging technique which has been utilized to visualize the localization of MAO-B in monkey and human brain and thereby has potential for studying neurodegenerative diseases and epilepsy. This thesis deals with the synthesis and evaluation of novel fluorine-18 labeled PET radioligands for detection of MAO-B activity.
The present thesis demonstrates that nine fluorinated propargyl amines were synthesized and tested for inhibition of MAO-B. In order to label those compounds with fluorine-18 seven chloro-precursors and two sulphamidate-precursors were also synthesized by multi step organic synthesis. Radiolabeling of six chloro-precursors with fluorine-18 was accomplished by a one-step nucleophilic substitution reaction. Radiolabeling of two sulphamidate-precursors with fluorine-18 was performed in two steps, compromising a nucleophilic substitution followed by the removal of the protecting group. The incorporation yield of the fluorination reactions varied from 40- 70%. The radiochemical purity was >99% and the specific radioactivities were in a range of 190-240 GBq/μmol at the time of administration.
In vitro MAO inhibition and/or autoradiography (ARG) experiments demonstrated a high selectivity for MAO-B over MAO-A for five of the compounds namely [18F]fluorodeprenyl, [18F]fluororasagiline, [18F]fluoro-N,4-dimethyl-N-(prop-2-ynyl) pentan-2-amine, [18F]fluorodeprenyl-D2 and [18F]fluororasagiline-D2. All five compounds were examined by PET and showed a high initial brain uptake in known MAO-B rich regions in cynomolgus monkey. [18F]Fluorodeprenyl showed a kinetic behavior similar to [11C]deprenyl where its fast irreversible binding to the enzyme renders the distribution of this radioligand in tissue limited by blood flow rather than the MAO-B enzyme concentration. [18F]Fluororasagiline and [18F]fluoro-N,4-dimethyl-N-(prop-2-ynyl)pentan-2-amine showed continuous increase of the radioactivity throughout the PET measurement that might be an indication of a blood-brain barrier penetrating radiometabolite which might in turn complicate a reliable quantification. Only [18F]fluorodeprenyl-D2 and [18F]fluororasagiline-D2 showed fast wash-out from the brain and less accumulation in cortical and sub-cortical regions. Radiometabolite studies demonstrated that both deuterated analogues were more stable measured in monkey plasma when compared to the non-deuterated analogues.
These results together suggest that both [18F]fluorodeprenyl-D2 and [18F]fluororasagiline-D2 may be improved PET radioligands and potential molecular imaging biomarker candidates for PET studies in neuroinflammation and neurodegeneration, accompanied with astrocyte activation
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Expression regulation of MAO isoforms in monocytic cells in response to Th2 cytokines
No full textBackground: Th2-cytokines, such as interleukins-4 and –13 (IL-4, IL-13), have been identified as alternative stimuli of monocytes/macrophages. We have recently profiled the gene-expression pattern of IL-4-teated human peripheral monocytes and found that 15-lipoxygenase-1 (15-LOX1) and monoamine oxidase A (MAO-A) are among the five most strongly upregulated gene products in IL-4-treated cells. Transfection of monocytic cells (U937) with 15-LOX1 also induced MAO-A expression. These data suggested that 15-LOX1 products might play a role in the IL4-induced signaling cascade leading to expression of MAO-A in human monocytes. Material/Methods: To test this hypothesis we incubated wild-type and 15-LOX1-transfected U937 cells with different concentrations of either IL-4 or 15-LOX-products [13S-H(p)ODE, 15S-H(p)ETE] and quantified the expression of 15-LOX1, MAO-A, and MAO-B by activity assays and real-time RT-PCR. Results: Wild-type U937 cells express neither MAO-A nor MAO-B, but after three days of IL4 treatment, MAO-A mRNA was detected. A similar isoform-specific expression of MAO-A mRNA was observed when U937 cells were transfected with 15-LOX1 or when the cells were incubated with primary 15-LOX1 products (hydroperoxy fatty acids) or H2O2. In contrast, the corresponding hydroxy fatty acids were ineffective. Conclusions: These data indicate that increased intracellular peroxide concentrations (oxidative stress) induce MAO-A expression in monocytes/macrophages, which normally do not express the enzyme. Our findings also suggest that IL-4-induced upregulation of MAO-A expression in human peripheral monocytes may proceed via 15-LOX1-dependent and 15-LOX1-independent pathways. The biological role of MAO-A expression for monocyte function is discussed
Newly Synthesized Fluorinated Cinnamylpiperazines Possessing Low In Vitro MAO-B Binding
Full text linkHerein, we report on the synthesis and pharmacological evaluation of ten novel fluorinated cinnamylpiperazines as potential monoamine oxidase B (MAO-B) ligands. The designed derivatives consist of either cinnamyl or 2-fluorocinnamyl moieties connected to 2-fluoropyridylpiperazines. The three-step synthesis starting from commercially available piperazine afforded the final products in overall yields between 9% and 29%. An in vitro competitive binding assay using l-[3H]Deprenyl as radioligand was developed and the MAO-B binding affinities of the synthesized derivatives were assessed. Docking studies revealed that the compounds 8–17 were stabilized in both MAO-B entrance and substrate cavities, thus resembling the binding pose of l-Deprenyl. Although our results revealed that the novel fluorinated cinnamylpiperazines 8–17 do not possess sufficient MAO-B binding affinity to be eligible as positron emission tomography (PET) agents, the herein developed binding assay and the insights gained within our docking studies will certainly pave the way for further development of MAO-B ligands
The portrayal of women in Mao Dun's early fiction 1927-1932
Full text linkIt is the prevailing critical assessment of Mao Dun's early creative writing that he displays a singular insight in his portrayal of women. This thesis seeks not only to challenge this assessment by a predominantly male body of criticism but also the assumptions on which it is based, namely that an intellectual sympathy for the women’s cause necessarily implies a transcendence of the patriarchal attitudes with which society is imbued. The major short stories and novellas written between 1927 and 1932 are analysed systematically to identify Mao Dun's underlying attitudes towards women. His portrayal of women is assessed from the following perspectives:~ his autobiographical accounts of his encounters with women in his political and personal life and his deliberate association of his female comrades with his creative inspiration;- traditional Chinese perceptions of women and gender roles as these are manifested in the classical tradition;-- Mao Dun's numerous articles and essays on the women's question written during the nineteen twenties and his work in the women's section of the Party in Shanghai;- Mao Dun's attempt to reconcile his conflicting sympathies for feminism and socialism. This thesis relies for its methodology on Western feminist criticism. While the approach is maintained, in its application to the context of early twentieth century China, its eurocentrism in terms of cultural assumptions and perceptions of gender has been replaced by a definition of Chinese values. Since a fundamental prerequisite, of feminist criticism is the assessment of the writer in his/her own cultural context, a historical survey of the portrayal of women in traditional literature is provided to serve as a standard against which to measure Mao Dun’s portrayal
Platelet MAO-B, personality, and psychopathology
No full textThe article investigates the relationships between platelet monoamine oxidase-B (MAO-B) activity, personality, and psychopathology (Diagnostic and Statistical Manual of Mental Disorders [4th ed.; American Psychiatric Association, 1994] diagnoses. These relationships were assessed in 178 incarcerated male juvenile delinquents. Even after controlling for smoking, the authors found that both Internalizing and Externalizing Psychopathology were negatively related to MAO-B activity. In the final reduced model, novelty seeking fully mediated the relationships between MAO-B and Externalizing Psychopathology but not between MAO-B and Internalizing Psychopathology. It was hypothesized that low platelet MAO-B activity does not directly predispose individuals to psychopathology but is related to specific personality traits, which in turn represent a vulnerability factor for psychopathology. Future studies should help clarify the nature of the relationships between personality, biological markers, and psychopathology.</p
Natural and synthetic geiparvarins are strong and selective MAO-B inhibitors. Synthesis and SAR studies.
No full textNatural geiparvarin 1 and a number of its analogues were prepared and tested as inhibitors of both monoamine oxidase isoforms, MAO-B and MAO-A. The desmethyl congener 6 of geiparvarin, proved potent and selective MAO-B inhibitor (pIC(50)=7.55 vs 4.62). X-ray crystallography and molecular modelling studies helped the understanding of the observed structure-activity relationships
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Monoamine oxidase in neuronal cell death
No full textMonoamine oxidase (MAO) is an oxidative enzyme that deaminates a variety of amine substrates, including the neurotransmitter dopamine. The enzymatic reaction requires molecular oxygen and produces hydrogen peroxide as a by-product. MAO is localised in the outer mitochondrial membrane and exists as two isoforms, MAO-A and MAO-B, which are differentially expressed in the body and differ in their substrate and inhibitor specificities. Previous studies have suggested that MAO-generated reactive oxygen species (ROS) contribute to oxidative stress in the cell and can directly inhibit electron transport, cause damage to mitochondrial DNA and enhance cell death signalling. In this study the role of MAO in cell death was investigated in dopaminergic neuroblastoma (SH-SY5Y) cells, in three diverse models of mitochondrially-mediated apoptosis. The relevance of MAO in cell death signalling was confirmed with the use of two unrelated MAO inhibitors and the creation of stable SH-SY5Y cell lines that either over express MAO-A or have reduced levels of MAO-A. The study is the first to over express MAO-A using recombinant technology and to use miRNA to stably knock-down MAO-A expression in human neuronal cells
Combined treatment with MAO-A inhibitor and MAO-B inhibitor increases extracellular noradrenaline levels more than MAO-A inhibitor alone through increases in β-phenylethylamine
Full text linkMonoamine oxidase inhibitors (MAO inhibitors) have been widely used as antidepressants. However, it remains unclear whether a difference exists between non-selective MAO inhibitors and selective MAO-A inhibitors in terms of their antidepressant effects. Using in vivo microdialysis methods, we measured extracellular noradrenaline and serotonin levels following administration of Ro 41-1049, a reversible MAO-A inhibitor and/or lazabemide, a reversible MAO-B inhibitor in the medial prefrontal cortex (mPFC) of rats. We examined the effect of local infusion of β-phenylethylamine to the mPFC of rats on extracellular noradrenaline and serotonin levels. Furthermore, the concentrations of β-phenylethylamine in the tissue of the mPFC after combined treatment with Ro 41-1049 and lazabemide were measured. The Ro 41-1049 alone and the combined treatment significantly increased extracellular noradrenaline levels compared with vehicle and lazabemide alone. Furthermore, the combined treatment increased noradrenaline levels significantly more than Ro 41-1049 alone did. The Ro 41-1049 alone and the combined treatment significantly increased extracellular serotonin levels compared with vehicle and lazabemide alone, but no difference in serotonin levels was found between the combined treatment group and the Ro 41-1049 group. Local infusion of low-dose β-phenylethylamine increased extracellular noradrenaline levels, but not that of serotonin. Only the combined treatment significantly increased β-phenylethylamine levels in tissues of the mPFC. Our results suggest that the combined treatment with a MAO-A inhibitor and a MAO-B inhibitor strengthens antidepressant effects because the combined treatment increases extracellular noradrenaline levels more than a MAO-A inhibitor alone through increases in β-phenylethylamine
Platelet monoamine oxidase activity in alcoholics with and without a family history of alcoholism
Full text linkA number of studies point at platelet monoamine oxidase (MAO) activity being reduced in alcoholics with a family history of drinking, this being a possible vulnerability marker for alcoholism. To test this hypothesis, we examined a group of recently detoxified alcoholics with high (n = 25) and low genetic loading for alcoholism (n = 28) and a group of healthy controls (n = 21). Clinical assessments were made using the SCID II interview for psychiatric disorders, the Family History Assessment Module and the Semi-Structural Assessment of Genetics in Alcoholism, a questionnaire especially designed for genetic studies. Platelet MAO activity with and without ethanol stimulation and the percentage of MAO activity with ethanol did not differ between groups. The only significant difference was a lower inhibition of MAO activity with ethanol in alcoholics both with and without a family history compared to controls. In patients with antisocial personality traits, platelet MAO activity was also not found to be different from other alcoholics. Our findings question the hypothesis of reduced platelet MAO activity to be a possible vulnerability marker for alcoholism. Copyright (C) 2000 S. Karger AG. Basel
Design, synthesis and biological evaluation of oxygenated chalcones as potent and selective MAO-B inhibitors
No full textThe present study documents the synthesis of oxygenated chalcone (O1-O26) derivatives and their abilities to inhibit monoamine oxidases. All 26 derivatives examined showed potent inhibitory activity against MAO-B. Compound O23 showed the greatest inhibitory activity against MAO-B with an IC50 value of 0.0021 μM, followed by compounds O10 and O17 (IC50 = 0.0030 and 0.0034 μM, respectively). In addition, most of the derivatives potently inhibited MAO-A and O6 was the most potent inhibitor with an IC50 value of 0.029 μM, followed by O3, O4, O9, and O2 (IC50 = 0.035, 0.053, 0.072, and 0.082 μM, respectively). O23 had a high selectivity index (SI) value for MAO-B of 138.1, and O20 (IC50 value for MAO-B = 0.010 μM) had an extremely high SI of >4000. In dialysis experiments, inhibitions of MAO-A and MAO-B by O6 and O23, respectively, were recovered to their respective reversible reference levels, demonstrating both are reversible inhibitors. Kinetic studies revealed that O6 and O23 competitively inhibited MAO-A and MAO-B, respectively, with respective Ki values of 0.016 ± 0.0007 and 0.00050 ± 0.00003 μM. Lead compound are also non-toxic at 200 μg/mL in normal rat spleen cells. Molecular docking simulations and subsequent Molecular Mechanics/Generalized Born Surface Area calculations provided a rationale that explained experimental data
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