Browsing by Author "Henderson, D"

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    Automated radiosynthesis of [18F]PBR111 and [18F]PBR102 using the TracerLab FXFN and TracerLab MXFDG module for imaging the peripheral benzodiazepine receptor with PET
    (Pergamon-Elsevier Science Ltd, 2012-01-01) Bourdier, T; Pham, TQ; Henderson, D; Jackson, TW; Lam, P; Izard, M; Katsifis, A
    [F-18]PBR111 and [F-18]PBR102 are selective radioligands for imaging of the Peripheral Benzodiazepine Receptor (PBR). We have developed a fully automated method for the radiosynthesis of [F-18]PBR111 and [F-18]PBR102 in the Tracerlab FXFN (30 +/- 2% radiochemical yield non-decay-corrected for both tracers) and Tracerlab MXFDG (25 +/- 2% radiochemical yield non-decay-corrected for both tracers) from the corresponding p-toluenesulfonyl precursors. For all tracers, radiochemical purity was > 99% and specific activity was > 150 GBq/mu mol after less than 60 min of preparation time. © 2012, Elsevier Ltd.
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    Preclinical in vivo and in vitro comparison of the translocator protein PET ligands [18F]PBR102 and [18F]PBR111
    (Springer Link, 2016-10-04) Eberl, S; Katsifis, A; Peyronneau, MA; Wen, LF; Henderson, D; Loc’h, C; Greguric, ID; Verschuer, J; Pham, TQ; Lam, P; Mattner, F; Mohamed, A; Fulham, MJ
    Purpose To determine the metabolic profiles of the translocator protein ligands PBR102 and PBR111 in rat and human microsomes and compare their in vivo binding and metabolite uptake in the brain of non-human primates (Papio hamadryas) using PET-CT. Methods In vitro metabolic profiles of PBR102 and PBR111 in rat and human liver microsomes were assessed by liquid chromatography–tandem mass spectrometry. [18F]PBR102 and [18F]PBR111 were prepared by nucleophilic substitution of their corresponding p-toluenesulfonyl precursors with [18F]fluoride. List mode PET-CT brain imaging with arterial blood sampling was performed in non-human primates. Blood plasma measurements and metabolite analysis, using solid-phase extraction, provided the metabolite profile and metabolite-corrected input functions for kinetic model fitting. Blocking and displacement PET-CT scans, using PK11195, were performed. Results Microsomal analyses identified the O-de-alkylated, hydroxylated and N-de-ethyl derivatives of PBR102 and PBR111 as the main metabolites. The O-de-alkylated compounds were the major metabolites in both species; human liver microsomes were less active than those from rat. Metabolic profiles in vivo in non-human primates and previously published rat experiments were consistent with the microsomal results. PET-CT studies showed that K1 was similar for baseline and blocking studies for both radiotracers; VT was reduced during the blocking study, suggesting low non-specific binding and lack of appreciable metabolite uptake in the brain. Conclusions [18F]PBR102 and [18F]PBR111 have distinct metabolic profiles in rat and non-human primates. Radiometabolites contributed to non-specific binding and confounded in vivo brain analysis of [18F]PBR102 in rodents; the impact in primates was less pronounced. Both [18F]PBR102 and [18F]PBR111 are suitable for PET imaging of TSPO in vivo. In vitro metabolite studies can be used to predict in vivo radioligand metabolism and can assist in the design and development of better radioligands. © 2016 Springer-Verlag
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    The preparation of 32P labelled phosphorous acid
    (Australian Atomic Energy Commission, 1986-11) Henderson, D; Jenkinson, AV; Sorby, PJ
    Phosphorous acid labelled with 32P has been prepared on a small scale starting from neutron-irradiated phosphorus. The compound is intended for tracer studies in the development of novel fungicides.
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    Radiation dosimetry of the translocator protein ligands [18F]PBR111 and [18F]PBR102
    (Elsevier B.V., 2012-07-01) Verschuer, JD; Towson, J; Eberl, S; Katsifis, A; Henderson, D; Lam, P; Wen, LF; Loc'h, C; Mattner, F; Thomson, S; Mohamed, A; Fulham, MJ
    Introduction The translocator protein (TSPO) ligands [18F]PBR111 and [18F]PBR102 show promise for imaging neuroinflammation. Our aim was to estimate the radiation dose to humans from primate positron emission tomography (PET) studies using these ligands and compare the results with those obtained from studies in rodents. Methods [18F]PBR111 and [18F]PBR102 PET–computed tomography studies were carried out in baboons. The cumulated activity in the selected source organs was obtained from the volume of interest time–activity curves drawn on coronal PET slices and adjusted for organ mass relative to humans. Radiation dose estimates were calculated in OLINDA/EXM Version 1.1 from baboon studies and compared with those calculated from Sprague–Dawley rat tissue concentration studies, also adjusted for relative organ mass. Results In baboons, both ligands cleared rapidly from brain, lung, kidney and spleen and more slowly from liver and heart. For [18F]PBR111, the renal excretion fraction was 6.5% and 17% for hepatobiliary excretion; for [18F]PBR102, the renal excretion was 3.0% and 15% for hepatobiliary excretion. The estimated effective dose in humans from baboon data was 0.021 mSv/MBq for each ligand, whilst from rat data, the estimates were 0.029 for [18F]PBR111 and 0.041 mSv/MBq for [18F]PBR102. Conclusion Biodistribution in a nonhuman primate model is better suited than the rat model for the calculation of dosimetry parameters when translating these ligands from preclinical to human clinical studies. Effective dose calculated from rat data was overestimated compared to nonhuman primate data. The effective dose coefficient for both these TSPO ligands determined from PET studies in baboons is similar to that for [18F]FDG. © 2012 Elsevier Inc.
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    A rapid solid-phase extraction method for measurement of non-metabolised peripheral benzodiazepine receptor ligands, [18F]PBR102 and [18F]PBR111, in rat and primate plasma
    (Elsevier, 2011-01) Katsifis, A; Loc'h, C; Henderson, D; Bourdier, T; Pham, TQ; Greguric, ID; Lam, P; Callaghan, PD; Mattner, F; Eberl, S; Fulham, MJ
    To develop a rapid and reliable method for estimating non-metabolised PBR ligands fluoroethoxy ([18F]PBR102)- and fluoropropoxy ([18F]PBR111)-substituted 2-(6-chloro-2-phenyl)imidazo[1,2-a]pyridine-3-yl)-N,N-diethylacetamides in plasma. © 2011 Elsevier Inc.
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    Synthesis and pharmacological evaluation of [ 18 F]PBR316: a novel PET ligand targeting the translocator protein 18 kDa (TSPO) with low binding sensitivity to human single nucleotide polymorphism rs6971
    (Royal Society of Chemistry (RSC), 2021-04-01) Mattner, F; Katsifis, A; Bourdier, T; Loc'h, C; Berghofer, PJ; Fookes, CJR; Hung, TT; Jackson, TW; Henderson, D; Pham, TQ; Lee, BJ; Shepherd, R; Greguric, ID; Wyatt, NA; Le, T; Poon, J; Power, C; Fulham, MJ
    Radiopharmaceuticals that target the translocator protein 18 kDa (TSPO) have been investigated with positron emission tomography (PET) to study neuroinflammation, neurodegeneration and cancer. We have developed the novel, achiral, 2-phenylimidazo[1,2-a]pyridine, PBR316 that targets the translocator protein 18 kDa (TSPO) that addresses some of the limitations inherent in current TSPO ligands; namely specificity in binding, blood brain barrier permeability, metabolism and insensitivity to TSPO binding in subjects as a result of rs6971 polymorphism. PBR316 has high nanomolar affinity (4.7–6.0 nM) for the TSPO, >5000 nM for the central benzodiazepine receptor (CBR) and low sensitivity to rs6971 polymorphism with a low affinity binders (LABs) to high affinity binders (HABs) ratio of 1.5. [18F]PBR316 was prepared in 20 ± 5% radiochemical yield, >99% radiochemical purity and a molar activity of 160–400 GBq μmol−1. Biodistribution in rats showed high uptake of [18F]PBR316 in organs known to express TSPO such as heart (3.9%) and adrenal glands (7.5% ID per g) at 1 h. [18F]PBR316 entered the brain and accumulated in TSPO-expressing regions with an olfactory bulb to brain ratio of 3 at 15 min and 7 at 4 h. Radioactivity was blocked by PK11195 and Ro 5-4864 but not Flumazenil. Metabolite analysis showed that radioactivity in adrenal glands and the brain was predominantly due to the intact radiotracer. PET–CT studies in mouse-bearing prostate tumour xenografts indicated biodistribution similar to rats with radioactivity in the tumour increasing with time. [18F]PBR316 shows in vitro binding that is insensitive to human polymorphism and has specific and selective in vivo binding to the TSPO. [18F]PBR316 is suitable for further biological and clinical studies. © Royal Society of Chemistry 2025.