Browsing by Author "Mardon, K"

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    Pharmacological evaluation of an [123I] labelled imidazopyridine-3-acetamide for the study of benzodiazepine receptors
    (Elsevier Science Ltd, 2006-02-07) Mattner, F; Mardon, K; Loc'h, C; Katsifis, A
    In vitro binding of the iodinated imidazopyridine, N′,N′-dimethyl-6-methyl-(4′-[123I]iodophenyl)imidazo[1,2-a]pyridine-3-acetamide [123I]IZOL to benzodiazepine binding sites on brain cortex, adrenal and kidney membranes is reported. Saturation experiments showed that [123I]IZOL, bound to a single class of binding site (nH = 0.99) on adrenal and kidney mitochondrial membranes with a moderate affinity (Kd = 30 nM). The density of binding sites was 22 ± 6 and 1.2 ± 0.4 pmol/mg protein on adrenal and kidney membranes, respectively. No specific binding was observed in mitochondrial–synaptosomal membranes of brain cortex. In biodistribution studies in rats, the highest uptake of [123I]IZOL was found 30 min post injection in adrenals (7.5% ID/g), followed by heart, kidney, lung (1% ID/g) and brain (0.12% ID/g), consistent with the distribution of peripheral benzodiazepine binding sites. Pre-administration of unlabelled IZOL and the specific PBBS drugs, PK 11195 and Ro 5-4864 significantly reduced the uptake of [123I]IZOL by 30% (p < 0.05) in olfactory bulbs and by 51–86% (p < 0.01) in kidney, lungs, heart and adrenals, while it increased by 30% to 50% (p < 0.01) in the rest of the brain and the blood. Diazepam, a mixed CBR–PBBS drug, inhibited the uptake in kidney, lungs, heart, adrenals and olfactory bulbs by 32% to 44% (p < 0.01) but with no effect on brain uptake and in blood concentration. Flumazenil, a central benzodiazepine drug and haloperidol (dopamine antagonist/sigma receptor drug) displayed no effect in [123I]IZOL in peripheral organs and in the brain. [123I]IZOL may deserve further development for imaging selectively peripheral benzodiazepine binding sites. © 2006, Elsevier Ltd.
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    Synthesis and enantiomeric evaluation of radiolabelled methyl phenidate for the study of dopamine reuptake sites
    (Australasian Environmental Isotope Conference, 2002-04-29) Katsifis, A; Mattner, F; Mardon, K; Dikic, B; Papazian, V; Jackson, T; Greguric, I
    Neurological diseases such as Parkinson's Disease and associated Movement Disorders have been characterised by reductions in the number of dopamine re-uptake sites or dopamine transporters (DAT) on presynaptic neurons in the striatum. Radiolabelled drugs which display specific and selective binding to the DAT has thus found clinical utility in medical imaging. The psychomotor stimulant methyl phenidate (MP) or Ritalin 1 and several derivatives have demonstrated high affinity binding to these DAT where they exert their pharmacological action. MP possesses two chiral centers with its pharmacological activity being attributed to the dl-threo diastereomer, the dl-erythro being inactive. Furthermore, imaging studies using Positron Emission Tomography (PET) with carbon-11 radiolabelled MP confirmed the d-threo enantiomer to be most active. In vitro studies indicate that compounds substituted with either bromine or iodine in the 3 position of the aromatic ring exhibit high affinity and selective binding to DAT and were thus targeted for radiolabelling with both the PET tracer Bromine-76 as well as the SPECT tracer lodione-123. Threo methyl phenidate and its halogenated derivatives were prepared by the condensation of 3-bromophenylacetonitrile and 2-bromopyridine according to modified literature methods. Radiohalogenation with either 76Br or 123I was achieved by halodestannylation reactions of the corresponding tributyl stannane precursor in the presence of chloramine-T as the oxidant. Purification by C-18 reverse phase HPLC gave the dl-threo product in 70-80% radiochemical yield and in greater than 95% radiochemical purity. Separation of the d and / enantiomers was achieved by chiral HPLC. Biodistribution studies in rodents indicated high uptake of radioactivity in tissues with known DAT sites. PET and SPECT imaging studies in primates indicated high uptake in the striatum compared to the cerebellum reference tissue. The synthesis, diastereomeric separation, structure activity studies, radiolabelling and biological studies of these compounds will be presented,
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    Synthesis and evaluation of radioiodinated ligands for the study of peripheral benzodiazepine receptors using SPECT
    (Australian Nuclear Science and Technology Organisation, 2002-04-29) Katsifis, A; Mattner, F; Mardon, K; Dikic, B; Papazian, V; Greguric, I
    The peripheral benzodiazepine receptor (PBR) is a multimeric protein complex located in the outer mitochondrial membrane and predominantly found in steroid producing organs and glial cells in the brain. The PBR have been implicated in the control of cell proliferation and differentiation and shown to display increased levels in a variety of malignant tumours and neurodegenerative disorders. A series of potent imidazo[1,2-a]pyridines have been prepared for development as radiopharmaceuticals to study these disorders in patients using nuclear medicine imaging techniques. In vitro studies indicate that compounds substituted with an electronegative atom in the 6 position of the pyridine ring, a lipophilic group or halogen in the 4'-position of the 2-phenyl ring, and lower alkyl methyl or ethyl substituents on the amide nitrogens of the side chain, exhibit high affinity and selective binding. ' N'N'-dimethyl- and the N'N'-diethyl 6-chloro-(4'-iodophenyl)imidazo[1,2-a]pyridine-3-acetamide 1 and 2 displayed optimum in vitro properties and were thus selected for radiolabelling with the diagnostic radionuclide iodine-123. Radioiodination was achieved by iododestannylation of the corresponding tributyl stannane precursor in the presence of peracetic acid. Purification by C-18 reverse phase HPLC gave the desired products in 70-80% radiochemical yields and in greater than 98% radiochemical purity. Biodistribution studies in normal rodents indicated high uptake of radioactivity in tissues with known PBR sites. Preliminary imaging studies in rodents bearing mammary adenocarcinomas indicated high uptake in the tumour with retention of activity after 24 h. The synthesis, structure activity studies, radiolabelling and biological studies of these compounds will be presented.