10 research outputs found

    Synthesis, radiolabelling and in vitro and in vivo evaluation of a novel fluorinated ABP688 derivative for the PET imaging of metabotropic glutamate receptor subtype 5

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    (E)-3-(Pyridin-2-ylethynyl)cyclohex-2-enone O-(2-(3-18F-fluoropropoxy)ethyl) oxime ([18F]-PSS223) was evaluated in vitro and in vivo to establish its potential as a PET tracer for imaging metabotropic glutamate receptor subtype 5 (mGluR5). [18F]-PSS223 was obtained in 20% decay corrected radiochemical yield whereas the non-radioactive PSS223 was accomplished in 70% chemical yield in a SN2 reaction of common intermediate mesylate 8 with potassium fluoride. The in vitro binding affinity of [18F]-PSS223 was measured directly in a Scatchard assay to give Kd = 3.34 ± 2.05 nM. [18F]-PSS223 was stable in PBS and rat plasma but was significantly metabolized by rat liver microsomal enzymes, but to a lesser extent by human liver microsomes. Within 60 min, 90% and 20% of [18F]-PSS223 was metabolized by rat and human microsome enzymes, respectively. In vitro autoradiography on horizontal rat brain slices showed heterogeneous distribution of [18F]-PSS223 with the highest accumulation in brain regions where mGluR5 is highly expressed (hippocampus, striatum and cortex). Autoradiography in vitro under blockade conditions with ABP688 confirmed the high specificity of [18F]-PSS223 for mGluR5. Under the same blocking conditions but using the mGluR1 antagonist, JNJ16259685, no blockade was observed demonstrating the selectivity of [18F]-PSS223 for mGluR5 over mGluR1. Despite favourable in vitro properties of [18F]-PSS223, a clear-cut visualization of mGluR5- rich brain regions in vivo in rats was not possible mainly due to a fast clearance from the brain and low metabolic stability of [18F]-PSS223

    Positron Emission Tomography in the Neuroimaging of Autism Spectrum Disorder

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    Autism spectrum disorder (ASD) is a pervasive developmental disease characterized by persistent impairment, repetitive and stereotypical behaviors in social interaction, as well as restricted interests and activities. The etiology of ASD is not clear yet, which results in difficulties in clinical diagnosis and treatment, and also brings heavy burden to patients and society. Positron emission tomography (PET) is a frequently used molecular imaging technology in quantitative, dynamic and in vivo research for therapeutic efficacy evaluation, pathophysiological mechanism investigation, thereby promoting development of ASD therapeutic drugs. More and more imaging studies have been reported on ASD recently, and the physiological changes featured by PET have been disclosed. This chapter reviews the specific radioligands for PET imaging of critical biomarkers involved in ASD. Herein, we discuss cerebral blood perfusion, cerebral glucose metabolism, and neurotransmitter system (transporters, precursors and receptors), as well as some other novel targets, including arginine vasopressin receptor targets and neuroinflammation related targets. The status of application and future prospect of the PET technology in research of ASD were discussed. This chapter provides a detailed and comprehensive literature review on ASD PET probe development, thereby can help readers intuitively and conveniently understand the status quo of research on ASD PET, and develop new research directions in this field

    Metabotropic glutamate receptor 5 neuroimaging in schizophrenia

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    The metabotropic glutamate receptor 5 (mGluR5) is a promising drug target for the treatment of schizophrenia. In this study, we compared mGluR5 distribution volume ration (DVR) in subjects with schizophrenia and healthy controls. Given our previous findings, we matched samples for gender, age, and smoking status. Binding to mGluR5 was determined using positron emission tomography and [(11)C]ABP688, which binds to an allosteric site with high selectivity. DVR in the 15 individuals with schizophrenia did not differ from that of the 15 controls. In both groups, smoking was associated with marked global reductions in mGluR5 availability (on average 23.8%). In nonsmoking subjects with schizophrenia, there was a positive correlation between mGluR5 DVR in the medial orbitofrontal cortex and the use of antipsychotic drugs (r=0.9, p=0.019). Because antipsychotic drugs such as clozapine appeared to have indirect effects on mGluR5 signaling, our findings may be clinically relevant. They also provide promising leads for elucidating the high comorbidity between schizophrenia and tobacco addiction. Low mGluR5 DVR in smokers my represent a risk factor for schizophrenia. Alternatively, smoking may counteract the potential upregulation of mGluR5 by antipsychotic drugs

    Neuroimaging - Clinical Applications

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    Modern neuroimaging tools allow unprecedented opportunities for understanding brain neuroanatomy and function in health and disease. Each available technique carries with it a particular balance of strengths and limitations, such that converging evidence based on multiple methods provides the most powerful approach for advancing our knowledge in the fields of clinical and cognitive neuroscience. The scope of this book is not to provide a comprehensive overview of methods and their clinical applications but to provide a "snapshot" of current approaches using well established and newly emerging techniques

    Perspectives on Nuclear Medicine for Molecular Diagnosis and Integrated Therapy

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    nuclear medicine; diagnostic radiolog

    Probes of tocopherol biochemistry: fluorophores, imaging agents, and fake antioxidants

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    The body has many defence systems against reactive radical species, but none are as crucial in the protection of lipid membranes as vitamin E. As a result of a selection process mediated by the α-tocopherol transfer protein (α-TTP), α-tocopherol is the only form of vitamin E retained in the body. This chaperon protein has been well studied because of its role in vitamin E transport. Furthermore, malfunctions of α-TTP cause vitamin E deficiency leading to ataxia and other neurodegenerative disease. Protection of neuronal tissue is critical and is reflected in the high retention of α-tocopherol in the central nervous system. Neuronal tissues receive α tocopherol from astrocytes, cells that are linked to hepatic tissue and able to express α-TTP, however the exact path of delivery between these cells is still unclear. A technique called fluorescent microscopy allows the tracking of fluorescent molecules in cells to find their location and interactions with other parts of the cell. The focus of this study is the synthesis of a fluorescent tocopherol analogue with a long absorption wavelength, high photostability, and that binds selectively to  α-TTP with high affinity. Most health benefits associated with vitamin E consumption are based on its capability to inhibit lipid peroxidation in cell membranes by scavenging reactive oxygen species (ROS). Oxidative damage in membranes puts cells in a “stressful” state, activating signalling events that trigger apoptosis. Vitamin E down-regulates apoptotic functions like inflammation, macrophage activation and cell arrest in a stressed state, returning the cell back to normal functioning. At the same time, vitamin E has a preventive effect for atherosclerosis, Alzheimer’s and cancer. With the deeper understanding of cell signalling processes associated with vitamin E the question arose whether protein interactions or the ROS scavenging is responsible for cell survival. To test this hypothesis, a non-antioxidant but α-TTP binding tocopherol analogue was synthesized and administered into oxidatively stressed, α-TTP deficient cells. If the cells were unable to restore homeostasis and stop apoptosis with the new molecule, this would suggest that the antioxidant function of α-tocopherol is the reason for survival. Cancer is regarded as one of the most detrimental diseases with a high mortality rate. One key aspect in medical research is the increased drug specificity towards targeting cancer. Chemotherapy applies cytotoxic compounds, which weaken the immune system because both malignant and healthy cells are destroyed. The specificity of the anti-cancer drugs are enhanced when encapsulated into liposomes that bear target-directing molecules such as antibodies which recognize cancer cell specific antigens on the cell membrane. The question remains if the encapsulated drug reaches the cancer or not. Magnetic resonance imaging (MRI) and computed tomography (CT) are used to find malignant tissue in the body. CT imaging uses highly charged X-ray particles to scan the patient, possibly having damaging cytotoxic effects. Obtaining MRI results require the use of contrast agents to enhance the quality of images. These agents are based on transition metals, which potentially have chronic toxicity when retained in the body. Alternatively short-lived radiotracers that emit a γ-photon upon positron decay are used through a process called positron emission tomography (PET). Rapid decay times make the use of PET a less toxic alternative, however the decay products might be toxic to the cell. For this reason a vitamin E based PET agent was created, which produces naturally safe decay products based on known metabolites of vitamin E, useful to track liposomal delivery of chemotherapeutic agents. This work describes the non-radioactive synthetic procedures towards a variety of vitamin E PET analogues. The cytotoxicity of the most promising vitamin E PET tracer was evaluated along with its synthetic byproducts

    [<sup>18</sup>F]fluorination of biorelevant arylboronic acid pinacol ester scaffolds synthesized by convergence techniques

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    Aim: The development of small molecules through convergent multicomponent reactions (MCR) has been boosted during the last decade due to the ability to synthesize, virtually without any side-products, numerous small drug-like molecules with several degrees of structural diversity.(1) The association of positron emission tomography (PET) labeling techniques in line with the “one-pot” development of biologically active compounds has the potential to become relevant not only for the evaluation and characterization of those MCR products through molecular imaging, but also to increase the library of radiotracers available. Therefore, since the [18F]fluorination of arylboronic acid pinacol ester derivatives tolerates electron-poor and electro-rich arenes and various functional groups,(2) the main goal of this research work was to achieve the 18F-radiolabeling of several different molecules synthesized through MCR. Materials and Methods: [18F]Fluorination of boronic acid pinacol esters was first extensively optimized using a benzaldehyde derivative in relation to the ideal amount of Cu(II) catalyst and precursor to be used, as well as the reaction solvent. Radiochemical conversion (RCC) yields were assessed by TLC-SG. The optimized radiolabeling conditions were subsequently applied to several structurally different MCR scaffolds comprising biologically relevant pharmacophores (e.g. β-lactam, morpholine, tetrazole, oxazole) that were synthesized to specifically contain a boronic acid pinacol ester group. Results: Radiolabeling with fluorine-18 was achieved with volumes (800 μl) and activities (≤ 2 GBq) compatible with most radiochemistry techniques and modules. In summary, an increase in the quantities of precursor or Cu(II) catalyst lead to higher conversion yields. An optimal amount of precursor (0.06 mmol) and Cu(OTf)2(py)4 (0.04 mmol) was defined for further reactions, with DMA being a preferential solvent over DMF. RCC yields from 15% to 76%, depending on the scaffold, were reproducibly achieved. Interestingly, it was noticed that the structure of the scaffolds, beyond the arylboronic acid, exerts some influence in the final RCC, with electron-withdrawing groups in the para position apparently enhancing the radiolabeling yield. Conclusion: The developed method with high RCC and reproducibility has the potential to be applied in line with MCR and also has a possibility to be incorporated in a later stage of this convergent “one-pot” synthesis strategy. Further studies are currently ongoing to apply this radiolabeling concept to fluorine-containing approved drugs whose boronic acid pinacol ester precursors can be synthesized through MCR (e.g. atorvastatin)
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