Browsing by Author "Dikic, B"
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- ItemDevelopment of PET and SPECT radiopharmaceuticals to study multi-drug resistance (MDR)(Australian Nuclear Science and Technology Organisation, 2002-04-29) Katsifis, A; Guilloteau, D; Dikic, B; Garrigos, M; Emond, P; Greguric, I; Knott, RB; Marvel, S; Mattner, FCellular resistance or Multidrug Resistance (MDR) to cytotoxic agents is the major cause of treatment failure in many human cancers. P-glycoprotein (Pgp), a Mr 17,0000 transmembrane protein and Multi Resistance Protein (MRP) are two proteins that are over expressed and confer resistance to a large number of chemotherapeutic agents by enhancing their extracellular transport. P-glycoprotein is expressed at a relative high level in treated and untreated human malignant tumours, including renal, colonic, adrenal, hepatocellular carcinoma and a considerable percentage of breast carcinomas. 99mTc-Sestamibi, a lipophilic cationic complex is a transport substrate for Pgp. In clinical studies of human neoplasms it was found that tumour uptake and clearance of this tracer correlate with Pgp expression and may be used for the phenotypic assessment of MDR. However, new tracers with better substrate specificity for Pgp and other drug transporters would greatly assist in optimising chemotherapeutic treatment and improving patient management by predicting tumour response to therapy and to assist in the development of antagonists, which may reverse or halt MDR. The aim of this project is therefore to develop PET and SPECT radiopharmaceuticals with improved affinity and selectivity for Pgp and MRP for the clinical evaluation of MDR in cancer patients. To optimise cellular transport characteristics, a number of chemical families that have been found to be substrates of Pgp and other drug efflux pumps, will be investigated. In the first instance, a series of drugs based on the flavonol natural product, Quercetin will be developed, screened for MDR and radiolabelled with PET and SPECT isotopes. Quercetin and related flavonol derivatives have been selected for this project because of their moderate to good affinity for Pgp. With the assistance of molecular modeling and in vitro studies, structural modification will be undertaken to improve the specificity and affinity for PgP. This generic structure also offers the flexibility to prepare a wide range of molecules that are readily suitable for halogenation with either Iodine-123 or F-18 for radiopharmaceutical development. Finally these phenolic type of molecules based on Quercetin are relatively less toxic than equivalent drugs. In this proposal an extensive research program is required to develop specific drugs for the different efflux pumps present in the body, which represent multi drug resistance. A successful outcome is critically dependent on the initial synthesis of a large number of compounds for screening. The combined effort of the three institutions will boost resources significantly to a critical level required to competitively produce successful outcomes in the project. Optimisation studies on derivatives of these flavonols will be made in parallel with the assistance of in vitro studies by measuring the binding of compounds to the ATP sites of Pgp. An extensive in vitro screening program has been established in Paris, prior to radiolabelling and in vivo evaluation. Structural optimisation and attachment of radionuclides to promising molecular targets will be explored using molecular modelling. Initially computational chemistry using Sybyl will be undertaken to develop a pharmacophore and to assist with the incorporation of the radionuclide in the appropriate position. In vivo evaluation will be undertaken in specific animal models both at the University of Tours in France as well as at the Sydney Cancer Centre in Australia. PET functional imaging studies may be undertaken on successful candidates at the SHFJ in Orsay, France whilst SPECT imaging will be undertaken in both Tours and in Sydney. In addition to intellectual property and potential commercial product(s), specific PET or SPECT radiopharmaceuticals can provide valuable information on the assessment of MDR in cancer patients through functional, non-invasive, imaging and therefore make significant contributions to the understanding of MDR. Scientific and clinical researchers from both countries identified the use of PET and SPECT functional imaging of MDR as a priority area of research. Finally the clear benefits to cancer patients include choice of treatment, with minimisation of ineffective drug treatments at an earlier stage, hence reduced drug side effects and discomfort to patients and improvements in their quality of life. There are also reduced health costs by avoiding expensive and ineffective drug treatments,
- ItemPreparation 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, ARadiopharmaceuticals 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.
- ItemRadiosynthesis, in vivo biological evaluation, and imaging of brain lesions with [123I]-CLINME, a new SPECT tracer for the translocator protein(Hindawi Publishing Corporation, 2015-06-25) Mattner, F; Quinlivan, M; Greguric, I; Pham, TQ; Liu, X; Jackson, TW; Berghofer, PJ; Fookes, CJR; Dikic, B; Grégoire, MC; Dollé, F; Katsifis, AThe high affinity translocator protein (TSPO) ligand 6-chloro-2-(4′-iodophenyl)-3-(N,N-methylethyl)imidazo[1,2-a]pyridine-3-acetamide (CLINME) was radiolabelled with iodine-123 and assessed for its sensitivity for the TSPO in rodents. Moreover neuroinflammatory changes on a unilateral excitotoxic lesion rat model were detected using SPECT imaging. [123I]-CLINME was prepared in 70–80% radiochemical yield. The uptake of [123I]-CLINME was evaluated in rats by biodistribution, competition, and metabolite studies. The unilateral excitotoxic lesion was performed by injection of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid unilaterally into the striatum. The striatum lesion was confirmed and correlated with TSPO expression in astrocytes and activated microglia by immunohistochemistry and autoradiography. In vivo studies with [123I]-CLINME indicated a biodistribution pattern consistent with TPSO distribution and the competition studies with PK11195 and Ro 5-4864 showed that [123I]-CLINME is selective for this site. The metabolite study showed that the extractable radioactivity was unchanged [123I]-CLINME in organs which expresses TSPO. SPECT/CT imaging on the unilateral excitotoxic lesion indicated that the mean ratio uptake in striatum (lesion : nonlesion) was 2.2. Moreover, TSPO changes observed by SPECT imaging were confirmed by immunofluorescence, immunochemistry, and autoradiography. These results indicated that [123I]-CLINME is a promising candidate for the quantification and visualization of TPSO expression in activated astroglia using SPECT. © 2015 F. Mattner et al.
- ItemSynthesis 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, INeurological 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,
- ItemSynthesis 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, AThe 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.
- ItemSynthesis 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, IThe 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.