Browsing by Author "Eberl, S"

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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, I; 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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    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, I; 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.