Browsing by Author "Ballantyne, P"

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    Assessment of neuroinflammation in transferred EAE via a translocator protein ligand
    (IntechOpen, 2012-02-03) Mattner, F; Staykova, M; Callaghan, PD; Berghofer, PJ; Ballantyne, P; Grégoire, MC; Fordham, S; Pham, TQ; Rahardjo, GL; Jackson, TW; Linares, D; Katsifis, A
    Neuroinflammation is involved in the pathogenesis and progression of neurological disorders such as Alzheimer's disease and multiple sclerosis (MS) (Doorduin et al., 2008). MS has been considered a T cell-mediated autoimmune disorder of the central nervous system (CNS), characterized by inflammatory cell infiltration and myelin destruction (Hauser et al., 1986) and focal demyelinated lesions in the white matter are the traditional hallmarks of MS. However more recent evidence suggests more widespread damage to the brain and spinal cord, to areas of white matter distant from the inflammatory lesions and demyelination of deep and cortical grey matter (McFarland & Martin, 2007). Experimental autoimmune encephalomyelitis (EAE) is an extensively used model of T-cell mediated CNS inflammation; modelling disease processes involved in MS. EAE can be induced in several species by immunization with myelin antigens or via adoptive transfer of myelin-reactive T cells. The models of EAE in rodents [actively induced and transferred] provide information about different phases [inflammation, demyelination and remyelination] and types [monophasic, chronic-relapsing and chronic-progressive] of the human disease multiple sclerosis and a vast amount of clinical and histopathologic data has been accumulated through the decades. A key aim of current investigations is developing the ability to recognise the early symptoms of the disease and to follow its course and response to treatment. Molecular imaging is a rapidly evolving field of research that involves the evaluation of biochemical and physiological processes utilising specific, radioactive, fluorescent and magnetic resonance imaging probes. However, it is positron emission tomography (PET) and single photon emission computer tomography (SPECT) which, due to their exquisite sensitivity involving specifically designed radiolabelled molecules, that is leading the way in molecular imaging and has greatly enabled the non-invasive “visualisation” of many diseases in both animal models and humans. Furthermore, PET and SPECT molecular imaging are providing invaluable imaging data based on a biochemical-molecular biology interaction rather than from the traditional anatomical view. Increasingly, PET and SPECT radiotracers have been exploited to study or identify molecular biomarkers of disease, monitor disease progression, determining the effects of a drug on a particular pathology and assess the pharmacokinetic behaviour of pharmaceuticals in vivo. Significantly, these new imaging systems provide investigators with an unprecedented ability to examine and measure in vivo biological and pharmacological processes over time in the same animals thus reducing experimental variability, time and costs. Molecular imaging based on the radiotracer principle allows chemical processes ranging from cellular events, to cellular communication and interaction in their environment, to the organisation and function of complete tissue and organs to be studied in real time without perturbation. One of the key benefits of molecular imaging is a technique that allows longitudinal studies vital for monitoring intra-individual progression in disease, or regression with supplementary pharmacotherapies. This is key in animal models of diseases such as MS, where there is significant intra-individual variability in the disease course and severity. Recent investigations have proposed the translocator protein (TSPO; 18 kDa), also known as the peripheral benzodiazepine receptor (PBR), as a molecular target for imaging neuroinflammation (Chen & Guilarte, 2008; Doorduin et al., 2008; Papadopoulos et al., 2006). TSPO (18 kDa) is a multimeric protein consisting of five transmembrane helices, which, in association with a 32 kDa subunit that functions as a voltage dependent anion channel and a 30 kDa subunit that functions as an adenine nucleotide carrier forms part of a hetero-oligomeric complex (McEnery et al., 1992) responsible for cholesterol, heme and calcium transport in specific tissue. TSPO is primarily located on the outer mitochondrial membrane and is predominantly expressed in visceral organs (kidney, heart) and the steroid hormone producing cells of the adrenal cortex, testis and ovaries. In the central nervous system (CNS), TSPO is sparsely expressed under normal physiological conditions, however its expression is significantly upregulated following CNS injury (Chen et al., 2004; Papadopoulos et al., 1997; Venneti et al., 2006; Venneti, et al., 2008). Several studies have identified activated glial cells as the cells responsible for TSPO upregulation in inflamed brain tissue, both in humans and in experimental models (Mattner et al., 2011; Myers et al., 1991a; Stephenson et al., 1995; Vowinckel et al., 1997) and the TSPO ligand [11C]-PK11195 was one of the first PET ligands used for imaging activated microglia in various neurodegenerative diseases (Venneti et al., 2006). Although [11C]-(R)-PK11195 is widely used for imaging of microglia, its considerable high plasma protein binding, high levels of nonspecific binding, relatively poor blood–brain barrier permeability and short half-life, limits its use in brain imaging (Chauveau et al., 2008). Recently, alternative PET radioligands for TSPO including the phenoxyarylacetamide derivative [11C]-DAA1106 and its analogues (Gulyas et al., 2009; Takano et al., 2010; Venneti et al., 2008), the imidazopyridines (PBR111) and its analogues (Boutin et al., 2007a; Fookes et al., 2008) and the pyrazolo[1,5-a]pyrimidine derivatives [18F]-DPA-714 and [11C]-DPA-713 (Boutin et al., 2007b; James et al., 2008) have been investigated. In addition to imaging with PET, recent advances in new generation of hybrid SPECT imaging systems enabling increased resolution and morphological documentation with associated computed tomography have been made for use clinically and preclinically. These advances have created a need and an opportunity for SPECT tracers; particularly those incorporating the longer lived radiotracer iodine-123 (t ½ = 13.2 h), to facilitate extended longitudinal imaging studies. In this study the recently developed high-affinity TSPO, SPECT ligand, 6-chloro-2-(4′-iodophenyl)-3-(N,N-diethyl)-imidazo[1,2-a]pyridine-3-acetamide or CLINDE , was used to explore the expression of activated glia in a model of transferred EAE (tEAE). [123I]-CLINDE has demonstrated its potency and specificity for TSPO binding, its ability to penetrate the blood-brain barrier and suitable pharmacokinetics for SPECT imaging studies (Mattner et al., 2008). It has also been shown that [123I]-CLINDE was able to detect in vivo inflammatory processes characterized by increased density of TSPO in several animal models (Arlicot et al., 2008; Arlicot et al., 2010; Mattner et al., 2005; Mattner et al., 2011; Song et al., 2010), thus representing a promising SPECT radiotracer for imaging neuroinflammation. The present study aimed to investigate the effectiveness of [123I]-CLINDE to detect and quantify the activated glia and consequently correlate the intensity of TSPO upregulation with the severity of disease in a model of tEAE. © 2022 IntechOpen (Open Access).
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    Detection of apoptotic cell death in the thymus of dexamethasone treated rats using [123I]Annexin V and in situ oligonucleotide ligation
    (Springer Nature, 2007-06-29) Zavitsanou, K; Nguyen, VH; Greguric, I; Chapman, J; Ballantyne, P; Katsifis, A
    In the present study we aimed to establish an animal model of dexamethasone (DEX)-induced apoptosis in the thymus of rats. The degree of apoptosis was determined in the same animals at 6 and 11 h after a single administration of DEX (5 mg/kg, ip) by (a) in vivo biodistribution of the uptake of [123I]Annexin V, a biomarker of the early stages of apoptosis; (b) in vitro evaluation of the apoptotic index (percentage of number of apoptotic cells versus total number of cells) in the form of DNA fragmentation, on tissue sections using in situ oligo ligation (ISOL). ISOL demonstrated a 62- and 90-fold increase of apoptotic index at 6 and 11 h after DEX administration respectively, in the outer part of the thymic lobule (cortex) and a 25- and 54-fold increases in the inner part of the thymic lobule (medulla) in the corresponding treatment groups. In the biodistribution study, [123I]Annexin V uptake was significantly increased in the thymus of rats 11 h after DEX administration (by 1.3- to 1.4-fold) and significantly decreased at the 6-h time point. We conclude that the specificity of the apoptotic signal provided by isotopic methods in vivo would always require confirmation by complementary in vitro techniques that verify the assessment of ongoing apoptosis accurately. © 2007 Springer Science+Business Media B.V.
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    Discovery of [F-18]N-(2-(Diethylamino)ethyl)-6-fluoronicotinamide: a melanoma positron emission tomography imaging radiotracer with high tumor to body contrast ratio and rapid renal clearance
    (American Chemical Society, 2009-09-10) Greguric, I; Taylor, SR; Denoyer, D; Ballantyne, P; Berghofer, PJ; Roselt, P; Pham, TQ; Mattner, F; Bourdier, T; Neels, OC; Dorow, DS; Loc'h, C; Hicks, RJ; Katsifis, A
    The high melanoma uptake and rapid body clearance displayed by our series of [123I]iodonicotinamides prompted the development of [18F]N-(2-(diethylamino)ethyl)-6-fluoronicotinamide ([18F]2), a novel radiotracer for PET melanoma imaging. Significantly, unlike fluorobenzoates, [18F]fluorine incorporation on the nicotinamide ring is one step, facile, and high yielding. [18F]2 displayed high tumor uptake, rapid body clearance via predominantly renal excretion, and is currently being evaluated in preclinical studies for progression into clinical trials to assess the responsiveness of therapeutic agents. © 2009, American Chemical Society
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    Evaluation of [I-123]-CLINDE as a potent SPECT radiotracer to assess the degree of astroglia activation in cuprizone-induced neuroinflammation
    (Springer, 2011-08-01) Mattner, F; Bandin, DL; Staykova, M; Berghofer, PJ; Grégoire, MC; Ballantyne, P; Quinlivan, M; Fordham, S; Pham, TQ; Willenborg, DO; Katsifis, A
    The purpose of this study was to assess the feasibility and sensitivity of the high-affinity translocator protein (TSPO) ligand [123I]-CLINDE in imaging TSPO changes in vivo and characterise and compare astroglial and TSPO changes in the cuprizone model of demyelination and remyelination in C57BL/6 mice. Methods C57BL/6 mice were fed with cuprizone for 4 weeks to induce demyelination followed by 2–4 weeks of standard diet (remyelination). Groups of mice were followed by in vivo single photon emission computed tomography (SPECT)/CT imaging using [123I]-CLINDE and uptake correlated with biodistribution, autoradiography, immunohistochemistry, immunofluorescence and real-time polymerase chain reaction (RT-PCR). Results The uptake of [123I]-CLINDE in the brain as measured by SPECT imaging over the course of treatment reflects the extent of the physiological response, with significant increases observed during demyelination followed by a decrease in uptake during remyelination. This was confirmed by autoradiography and biodistribution studies. A positive correlation between TSPO expression and astrogliosis was found and both activated astrocytes and microglial cells expressed TSPO. [123I]-CLINDE uptake reflects astrogliosis in brain structures such as corpus callosum, caudate putamen, medium septum and olfactory tubercle as confirmed by both in vitro and in vivo results. Conclusion The dynamics in the cuprizone-induced astroglial and TSPO changes, observed by SPECT imaging, were confirmed by immunofluorescence, RT-PCR and autoradiography. The highly specific TSPO radioiodinated ligand CLINDE can be used as an in vivo marker for early detection and monitoring of a variety of neuropathological conditions using noninvasive brain imaging techniques. © 2011, Springer.
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    Preparation and biologic evaluation of a novel radioiodinated benzylpiperazine, 123I-MEL037, for malignant melanoma
    (Society of Nuclear Medicine and Molecular Imaging, 2007-07-13) Pham, TQ; Berghofer, PJ; Liu, X; Greguric, I; Dikic, B; Ballantyne, P; Mattner, F; Nguyen, VH; Loc'h, C; Katsifis, A
    Radiopharmaceuticals that can target the random metastatic dissemination of melanoma tumors may present opportunities for imaging and staging the disease as well as potential radiotherapeutic applications. A novel molecule, 2-(2-(4-(4-123I-iodobenzyl)piperazin-1-yl)-2-oxoethyl)isoindoline-1,3-dione (MEL037), was synthesized, labeled with 123I, and evaluated for application in melanoma tumor scintigraphy and radiotherapy. Methods: The tumor imaging potential of 123I-MEL037 was studied in vivo in C57BL/6J female mice bearing the B16F0 murine melanoma tumor and in BALB/c nude mice bearing the A375 human amelanotic melanoma tumor by biodistribution, competition studies, and SPECT. Results: 123I-MEL037 exhibited high and rapid uptake in the B16F0 melanoma tumor at 1 h (13 %ID/g [percentage injected dose per gram]), increasing with time to reach 25 %ID/g at 6 h. A significant uptake was also observed in the eyes (2 %ID, at 3–6 h after injection) of black mice. No uptake was observed in the tumor or in the eyes of nude mice bearing the A375 tumor. Because of high uptake and long retention in the tumor and rapid body clearance, the mean contrast ratios (MCR) of 123I-MEL037 were 30 and 60, at 24 and 48 h after injection, respectively. At 24 h after injection of mice bearing the B16 melanoma, SPECT indicated that the radioactivity was located predominately in the tumor followed by the eyes, whereas no specific localization of the radioactivity was noted in mice bearing the A375 human amelanotic tumor. In competition experiments, uptake of 123I-MEL037 in brain, lung, heart, and kidney—organs known to contain σ-receptors—was not significantly different in haloperidol-treated animals compared with control animals. Therefore, reduction of uptake in tumor and eyes of the pigmented mice bearing the B16F0 tumor suggested that the mechanism of tumor uptake was likely due to an interaction with melanin. Conclusion: These findings suggested that 123I-MEL037, which displays a rapid and very high tumor uptake, appeared to be a promising imaging agent for detection of most melanoma tumors with the potential for development as a therapeutic agent in melanoma tumor proliferation. © 2007 by the Society of Nuclear Medicine, Inc.
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    Rapid cortico-limbic alterations in AMPA receptor densities after administration of PCP: implications for schizophrenia
    (Elsevier, 2008-10) Zavitsanou, K; Nguyen, VH; Newell, KA; Ballantyne, P; Huang, XF
    Phencyclidine (PCP), a non-competitive NMDA/glutamate receptor antagonist, is a psychotomimetic drug that produces a syndrome in normal humans that resembles schizophrenia. The present study investigated the mechanisms of PCP actions by examining the density of glutamate and muscarinic receptors in the rat brain 4 h after a single injection of PCP. We used receptor autoradiography and [H-3]MK801, [H-3]AMPA, [H-3]pirenzepine and [H-3]AFDX384 to target glutamate NMDA, glutamate AMPA and muscarinic M1 and M2 receptors, respectively. The major outcome from the present study was an overall decrease in levels of the glutamate AMPA receptor density (F= 14.5, d.f. = 1, p < 0.001) in the PCP treated rats. More specifically, PCP-treated animals displayed decreased AMPA receptor density in hippocampus CA1 (-16%), hippocampus CA2 (-25%), dentate gyrus (-27%), parietal cortex layers III-VI (-19%), central nucleus of the amygdala (-40%), and basolateral amygdala (-19%). Other brain regions examined were unaffected. PCP administration did not significantly affect glutamate NMDA, muscarinic M1 and M2 receptor density. The present study demonstrates the limbic system as the anatomical locus of alterations in AMPA receptor density after acute administration of PCP and may have implications for models of schizophrenia that focus on glutamatergic dysfunction in limbic cortical regions. © 2008, Elsevier Ltd.
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    Synthesis and evaluation of an [18F] labelled imidazopyridine, for the study of the peripheral benzodiazepine binding sites using PET
    (Society of Nuclear Medicine and Molecular Imaging, 2007-05-01) Katsifis, A; Mattner, F; Pham, TQ; Fookes, CJR; Greguric, I; Berghofer, PJ; Ballantyne, P; Shepherd, R; Liu, X
    Objectives: The purpose of this study was to synthesise and evaluate the F-18 imidazopyridine 2-(2-(4-(3-fluoropropoxy)phenyl)-6,8-dichloroimidazo[1,2-a]pyridin-3-yl)-N-methyl-N-phenylacetamide 1 as a potential tracer for the study of PBBS using PET. Methods: [18F]1 has been prepared by nucleophilic substitution of the tosylethyloxy precursor with 18F-fluoride in the presence of K222, K2CO3 in ACN at 100°C for 5 mins followed by RP-HPLC purification. The biodistribution of [18F]1 was performed in SD rats and brain and peripheral tissues were analysised at 15, 30 min, 1, and 4 h p.i. The specificity and selectivity of the tracer was assessed by pre-treatment with the PBBS ligands PK11195 and Ro 5-4864 and with Flumazenil for CBR at 1 mg/kg 5 min prior to injection of [18F]1. Results: In vitro binding of 1 indicated an IC50 of 7.4 nM for PBBS and >4000 nM for the CBR. [18F]1 was synthesised in 40-55 % radiochemical yield non-decay corrected and with > 95 % radiochemical purity. The specific activity ranged from 37-80 GBq/μmol (non optimised). Biodistribution studies indicated uptake of [18F]1 in tissue expressing PBBS. The adrenals showed high uptake, increasing from 9% ID/g at 30 min p.i to 11% at 4 h. In the kidneys the activity peaked at 15 min p.i.(5%) and decreased over time to 3.6% at 4h. In the heart the uptake was maintained at 7% througout the experiment (15 min to 4 h). Bone uptake ranged from 1% (at 15 min) to 2.9% at 4h. [18F]1 readily penetrated the blood-brain barrier with uptake in the olfactory regions ranging from an initial 0.66% at 15 min to 0.26% at 4 h p.i. The concentration in the blood was significantly lower than the brain regions (0.7% at 15 min to 0.15% at 4 h). Pre-treatment with PK 11195, Ro 5-4864 and non radioactive analogue 1 significantly decreased the uptake in the brain and peripheral organs except in the adrenals which showed a modest increase or no change in uptake. Flumazenil had no effect in the uptake of [18F]1 in the brain or peripheral organs. Conclusions: These results demonstrate the specific PBBS uptake of [18F]1 in vivo. Therefore [18F]1 warrants further investigation as a potential PET tracer for the PBBS. Copyright © 2020 Society of Nuclear Medicine and Molecular Imaging
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    Synthesis and evaluation of novel radioiodinated benzamides for malignant melanoma
    (American Chemical Society, 2007-07-26) Pham, TQ; Greguric, I; Liu, X; Berghofer, PJ; Ballantyne, P; Chapman, J; Mattner, F; Dikic, B; Jackson, TW; Loc'h, C; Katsifis, A
    The imaging potential of a series of [123I]benzamides was studied in mice bearing B16F0 melanoma tumors. Compound [123I]25 exhibited tumor uptake >8 %ID/g at 1 h, while that of [123I]14d and [123I]25 reached a maximum of 9−12 %ID/g at 6 h. Standardized uptake values of [123I]14d were higher than 100 between 24 and 72 h after injection. In haloperidol treated animals, the tumor uptake of [123I]14d was not significantly different to controls, while significant reduction of [123I]25 uptake was observed, supporting that [123I]14d uptake relates to melanin interaction, whereas part of the mechanism of [123I]25 uptake is related to its σ1-receptor affinity. Benzamides 14d and 25, which display rapid and high tumor uptake, appear to be promising imaging agents for melanoma detection, while 14d, which displays a long lasting and high melanoma/nontarget ratio, is more suitable for evaluation as a potential radiotherapeutic. © 2007, American Chemical Society.