Browsing by Author "Fookes, CJR"

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    In-vivo imaging characteristics of two fluorinated flumazenil radiotracers in the rat
    (Springer, 2009-06) Dedeurwaerdere, S; Grégoire, MC; Vivash, L; Roselt, P; Binns, D; Fookes, CJR; Greguric, I; Pham, TQ; Loc'h, C; Katsifis, A; Hicks, RJ; O'Brien, TJ; Myers, DE
    Purpose: [11C]Flumazenil shows promise as a clinical and research PET radiotracer to image changes in GABAA central benzodiazepine receptor (cBZR), but its widespread use has been limited by practical limitations of [11C]. This study evaluated the imaging characteristics of two fluorinated PET radiotracers in rats in vivo: [18F]fluoroflumazenil ([18F]FFMZ) and [18F]flumazenil ([18F]FMZ). Methods: PET acquisitions were performed on a small-animal scanner following injection of [18F]FFMZ in nine rats and [18F]FMZ in eight rats. The following treatments were investigated: (1) injection of the tracer dose, (2) presaturation then injection of the tracer dose, and (3) injection of the tracer dose followed by a displacement injection. Unchanged tracer was measured in plasma and brain structures in four animals 10 and 30 min after injection, and ex-vivo autoradiography was also performed. Results: For both [18F]FFMZ and [18F]FMZ maximal brain activity peaked rapidly, and was highest in the hippocampus (1.12±0.06 SUV, 1.24±0.10 SUV, respectively), and lowest in the pons (1.00±0.07 SUV, 1.03±0.09 SUV, respectively). By 50 min after injection, maximal uptake for [18F]FFMZ and [18F]FMZ had decreased in the hippocampus to 18±3% and 80±1% (p<0.01), respectively. The presaturation and displacement studies showed a higher nonspecific component for [18F]FFMZ than for [18F]FMZ. Metabolite studies showed that at 30 min only 10% of the signal was from [18F]FFMZ in the brain. This nonspecific binding was apparent on autoradiography. In contrast, [18F]FMZ accounted for >70% of the signal in the brain, which resulted in well-defined regional binding on autoradiography. Conclusion These results demonstrate that [18F]FMZ is a superior radiotracer to [18F]FFMZ for in-vivo PET imaging of the GABAA/cBZR, having slower metabolism and leading to lower concentrations of metabolites in the brain that results in a substantially better signal-to-noise ratio. © 2009, Springer.
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    A new class of fluorinated 5-pyrrolidinylsulfonyl isatin caspase inhibitors for PET imaging of apoptosis
    (Royal Society of Chemistry, 2012-11-12) Krause-Heuer, AM; Howell, NR; Matesic, L; Dhand, G; Young, EL; Burgess, L; Jiang, CD; Lengkeek, NA; Fookes, CJR; Pham, TQ; Sobrio, F; Greguric, I; Fraser, BH
    Thirteen compounds in a new class of fluorinated 5-pyrrolidinylsulfonyl isatin derivatives were synthesised that have potent and selective inhibitory activity against effector caspases-3 and -7. With in vivo animal PET imaging studies of cerebral ischemia being planned, N-benzylation with selected para-substituted benzylic halides allowed systematic variation of lipophilicity (logP 1.94–3.31) without decreasing inhibition potency (IC50). From this series the p-methoxybenzyl analogue was selected for initial ‘proof-of-concept’ [18F]-fluoride radiolabelling which proceeded in good yield and purity with no need for a protection/deprotection strategy. © 2013 Royal Society of Chemistry
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    Radiosynthesis and biological evaluation of L and D S-(3-[18F]Fluoropropyl)-homocysteine for tumor imaging using positron emission tomography
    (Americam Chemical Society, 2011-03-24) Bourdier, T; Shepherd, R; Berghofer, PJ; Jackson, TW; Fookes, CJR; Denoyer, D; Dorow, DS; Greguric, I; Grégoire, MC; Hicks, RJ; Katsifis, A
    Interest in radiolabeled amino acids for metabolic imaging of cancer and limitations with [11C]methionine has prompted the development of a new 18F-labeled methionine derivative S-(3-[18F]fluoropropyl)homocysteine ([18F]FPHCys). The L and D enantiomers of [18F]FPHCys were prepared from their respective protected S-(3-tosyloxypropyl)homocysteine precursors 1 by [18F]fluoride substitution using K2.2.2 and potassium oxalate, followed by acid hydrolysis on a Tracerlab FXFN synthesis module. [18F]-L-FPHCys and [18F]-D-FPHCys were isolated in 20 ( 5% radiochemical yield and >98% radiochemical and enantiomeric purity in 65 min. Competitive uptake studies in A375 and HT29 tumor cells suggest that L- and D-[18F]FPHCys are taken up by the L-transporter system. [18F]-L-FPHCys and [18F]-D-FPHCys displayed good stability In Vivo without incorporation into protein at least 2 h postinjection. Biodistribution studies demonstrate good uptake in A375 tumor-bearing rodents with tumor to blood ratios of 3.5 and 5.0 for [18F]-L-FPHCys and [18F]-D-FPHCys, respectively, at 2 h postinjection. © 2011, American Chemical Society.
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    Radiosynthesis of F-18 PBR111, a selective radioligand for imaging the translocator protein (18 kDa) with PET
    (John Wiley and Sons, 2008-11-04) Dollé, F; Hinnen, F; Damont, A; Kuhnast, B; Fookes, CJR; Pham, TQ; Tavitian, B; Katsifis, A
    PBR111 (2-(6-chloro-2-(4-(3-fluoro-propoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)-N, N-diethylacetamide) is a novel, reported, high-affinity and selective ligand for the translocator protein (18 kDa). PBR111 has been labelled with fluorine-18 (half-life: 109.8 min) using our Zymate-XP robotic system. The process involves (A) a simple one-step to syloxy-for-fluorine nucleophilic aliphatic substitution (performed at 165 degrees C for 5 min in DMSO using K[18F]F-Kryptofix 222 and 6.8-7.6 μ mol of the corresponding tosylate as precursor for labelling) followed by (B) C-18 PrepSep cartridge pre-purification and(C) semi-preparative HPLC purification on a Waters Symmetry C-18. Up to 4.8 GBq (130 mCi) of [18F]PBR111 could be obtained with specific radioactivities ranging from 74 to 148 GBq/μ mol (2-4 Ci/μ mol) in 75-80 min (HPLC purification and SepPak-based formulation included), starting from a 37.0 GBq (1.0 Ci) [18F]fluoride batch. Overall non-decay-corrected isolated yields were 8-13% (13-21% decay-corrected). © 2008 John Wiley & Sons, Ltd.
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    Radiosynthesis, 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, A
    The 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.
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    Synthesis and biological characterisation of 18F-SIG343 and 18F-SIG353, novel and high selectivity σ2 radiotracers, for tumour imaging properties
    (Springer Nature, 2013-12-11) Nguyen, VH; Pham, TQ; Fookes, CJR; Berghofer, PJ; Greguric, I; Arthur, A; Mattner, F; Rahardjo, GL; Davis, E; Howell, NR; Grégoire, MC; Katsifis, A; Shepherd, R
    Sigma2 (σ2) receptors are highly expressed in cancer cell lines and in tumours. Two novel selective 18F-phthalimido σ2 ligands, 18F-SIG343 and 18F-SIG353, were prepared and characterised for their potential tumour imaging properties. © 2013 Nguyen et al.; licensee Springer.
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    Synthesis and biological evaluation of substituted [18F]Imidazo[1,2-a]pyridines and [18F]Pyrazolo[1,5-a]pyrimidines for the study of the peripheral benzodiazepine receptor using positron emission tomography
    (American Chemical Society, 2008-06-17) Fookes, CJR; Pham, TQ; Mattner, F; Greguric, I; Loc'h, C; Liu, X; Berghofer, PJ; Shepherd, R; Grégoire, MC; Katsifis, A
    The fluoroethoxy and fluoropropoxy substituted 2-(6-chloro-2-phenyl)imidazo[1,2- a]pyridin-3-yl)- N, N-diethylacetamides 8 (PBR102) and 12 (PBR111) and 2-phenyl-5,7-dimethylpyrazolo[1,5- a]pyrimidin-3-yl)- N, N-diethylacetamides 15 (PBR099) and 18 (PBR146) were synthesized and found to have high in vitro affinity and selectivity for the peripheral benzodiazepine receptors (PBRs) when compared with the central benzodiazepine receptors (CBRs). The corresponding radiolabeled compounds [ (18)F] 8 [ (18)F] 12, [ (18)F] 15, and [ (18)F] 18 were prepared from their p-toluenesulfonyl precursors in 50-85% radiochemical yield. In biodistribution studies in rats, the distribution of radioactivity of the [ (18)F]PBR compounds paralleled the known localization of PBRs. In the olfactory bulbs, where the uptake of radioactivity was higher than in the rest of the brain, PK11195 and Ro 5-4864 were able to significantly inhibit [ (18)F] 12, while little or no pharmacological action of these established PBR drugs were observed on the uptake of [ (18)F] 8, [ (18)F] 15, and [ (18)F] 18 compared to control animals. Hence, [ (18)F] 12 appeared to be the best candidate for evaluation as an imaging agent for PBR expression in neurodegenerative disorders. © 2008 American Chemical Society
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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 stability of S-(2-[18F]fluoroethyl)-L-homocysteine for potential tumour imaging
    (John Wiley and Sons, 2008-09-25) Bourdier, T; Fookes, CJR; Pham, TQ; Greguric, I; Katsifis, A
    inThe F-18 labelled methionine derivative S-(2-[18F]fluoroethyl)-L-homocysteine ([18F]FEHCys) was prepared by a one-pot two-step synthesis via the protected S-(2-bromoethyl)-L-homocysteine 1 and S-(2-chloroethyl)-L-homocysteine 2 precursors. The bromoethyl derivative 1 gave higher radiochemical yields (40% at 5 min) at 100°C compared with the chloro-analogue (22% at 100°C in 30 min). However, [18F]FEHCys was found to be unstable in aqueous systems being transformed to the corresponding hydroxyl derivative within 20 min. © 2008 John Wiley & Sons, Ltd.