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Browsing by Author "Loc'h, C"

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Characterisation of peripheral benzodiazepine receptors changes in early phase of epileptogenesis in the rat with PET and [18F]PBR111
(Society of Nuclear Medicine, 2009-05) Grégoire, MC; Dedeurwaerdere, S; Callaghan, PD; Loc'h, C; Pham, TQ; Katsifis, A
The current project aims at investigating the role of microglial activation in epileptogenesis by estimating PBR changes in the rat brain with a new and highly specific PBR ligand, [18F]PBR111, during the early phase, i.e. one week after status epilepticus induced by kainic acid (KA). Methods Four controls and 6 KA rats were scanned for 180 minutes with our small animal PET/CT under a triple-injection protocol. The results presented here cover only the first 60 minutes after injection of 0.06nmoles of [18F]PBR111. Arterial blood samples were withdrawn and metabolite corrected plasma time-activity curves were derived. Each CT and PET data were co-registered to an age and strain matched rat brain atlas containing 25 Regions-Of-Interest (ROIs). The Volume of Distribution (Vd) were calculated for each region. Whole-brain-normalised Vd (nVd) were also calculated to assess local variations. Results Compared to controls, KA-treated rats show a 2 to 3-fold increase of the Vd in all brain areas except the midbrain. No significant asymmetry was detected (< 9%), so the ROIs were grouped. Normalized Vd values (Table 1) show that Amygdala, Striata, Thalamus and Hippocampus are predominantly involved. No significant changes were detected in the midbrain and all cortical areas. Estimates of receptors densitiy (Bmax) and apparent affinity (KdVr) will be calculated from the full kinetics (three phases) and reported later. Conclusions This in vivo imaging study has identified significant microglial activation during early epileptogenesis in several brain regions which are known to play a key role in chronic epilepsy.
Comparison of in vivo binding properties of the 18-kDa translocator protein (TSPO) ligands [18F]PBR102 and [18F]PBR111 in a model of excitotoxin-induced neuroinflammation
(Springer Link, 2015-01) Callaghan, PD; Wimberley, CA; Rahardjo, GL; Berghofer, PJ; Pham, TQ; Jackson, TW; Zahra, D; Bourdier, T; Wyatt, N; Greguric, ID; Howell, NR; Siegele, R; Pastuovic, Z; Mattner, F; Loc'h, C; Grégoire, MC; Katsifis, A
The in vivo binding parameters of the novel imidazopyridine TSPO ligand [18F]PBR102 were assessed and compared with those of [18F]PBR111 in a rodent model of neuroinflammation. The validity of the key assumptions of the simplified reference tissue model (SRTM) for estimation of binding potential (BP) was determined, with validation against a two-tissue compartment model (2TC). Methods Acute neuroinflammation was assessed 7 days after unilateral stereotaxic administration of (R,S)-α-amino-3-hydroxy-5-methyl-4-isoxazolopropionique (AMPA) in anaesthetized adult Wistar rats. Anaesthetized rats were implanted with a femoral arterial cannula then injected with a low mass of [18F]PBR102 or [18F]PBR111 and dynamic images were acquired over 60 min using an INVEON PET/CT camera. Another population of rats underwent the same PET protocol after pretreatment with a presaturating mass of the same unlabelled tracer (1 mg/kg) to assess the validity of the reference region for SRTM analysis. Arterial blood was sampled during imaging, allowing pharmacokinetic determination of radiotracer concentrations. Plasma activity concentration–time curves were corrected for unchanged tracer based on metabolic characterization experiments in a separate cohort of Wistar rats. The stability of neuroinflammation in both imaging cohorts was assessed by [125I] CLINDE TSPO quantitative autoradiography, OX42/GFAP immunohistochemistry, Fluoro-Jade C histology, and elemental mapping using microparticle-induced x-ray emission spectroscopy. The BP of each ligand were assessed in the two cohorts of lesioned animals using both SRTM and a 2TC with arterial parent compound concentration, coupled with the results from the presaturation cohort for comparison and validation of the SRTM. Results The BPs of [18F]PBR102 [18F]PBR111 were equivalent, with improved signal-to-noise ratio and sensitivity compared with [11C]PK11195. The presaturation study showed differences in the volume of distribution between the ipsilateral striatum and the striatum contralateral to the injury (0.7) indicating that an assumption of the SRTM was not met. The modelling indicated that the BPs were consistent for both ligands. Between the SRTM and 2TC model, the BPs were highly correlated, but there was a bias in BP. Conclusion [18F]PBR102 and [18F]PBR111 have equivalent binding properties in vivo, displaying significantly greater BPs with lower signal-to-noise ratio than [11C]PK11195. While an assumption of the SRTM was not met, this modelling approach was validated against 2TC modelling for both ligands, facilitating future use in longitudinal PET imaging of neuroinflammation.© 2014, Springer Nature
Discovery of [F-18]N-(2-(Diethylamino)ethyl)-6-fluoronicotinamide: a melanoma positron emission tomography imaging radiotracer with high tumor to body contrast ratio and rapid renal clearance
(American Chemical Society, 2009-09-10) Greguric, ID; Taylor, SR; Denoyer, D; Ballantyne, P; Berghofer, PJ; Roselt, P; Pham, TQ; Mattner, F; Bourdier, T; Neels, OC; Dorow, DS; Loc'h, C; Hicks, RJ; Katsifis, A
The high melanoma uptake and rapid body clearance displayed by our series of [123I]iodonicotinamides prompted the development of [18F]N-(2-(diethylamino)ethyl)-6-fluoronicotinamide ([18F]2), a novel radiotracer for PET melanoma imaging. Significantly, unlike fluorobenzoates, [18F]fluorine incorporation on the nicotinamide ring is one step, facile, and high yielding. [18F]2 displayed high tumor uptake, rapid body clearance via predominantly renal excretion, and is currently being evaluated in preclinical studies for progression into clinical trials to assess the responsiveness of therapeutic agents. © 2009, American Chemical Society
France Australia collaboration in nuclear medicine and biology: 10 years of success
(Australian Nuclear Science and Technology Organisation, 2002-04-29) Loc'h, C; Katsifis, A; Kassiou, M
In 1992, a collaboration in Nuclear Biomedicine was initiated with the support of the French Embassy in Australia. From a meeting held in Sydney that year, the following 3 objectives were decided: 1. Development of new radiopharmaceuticals. This subject involved the design, synthesis and radiolabelling with positron emitters (carbon-11, fluorine-18, bromine-76) for positron tomography (PET) and with iodine-123 for single photon tomography (SPET) of novel ligands and their radiopharmacological evaluation. 2. Improvement of instrumentation and data processing: measurement of input function, data analysis of medical images, motion detection/correction. 3. Development of clinical investigations in the fields of diagnosis and metabolic radiotherapy of melanoma, assessment of myocardial viability, studies of neurodegenerative and neuropsychiatric disorders. The form of the collaboration took advantage of the expertises and resources in each country. During 1992-2002 period, 11 centers from our 2 countries collaborated: a. from France: CEA-SHFJ (Orsay), INSERM U316 (Tours), CERMEP (Lyon) CEA-LETI (Grenoble), Centre J. PERRIN (Clermont-Ferrand), CHU (Nantes): CHU (Brest). b. from Australia: Radiopharmaceutical Division ANSTO, Menai, Centre for PET Austin Hospital, Melbourne, PET and Nuclear Medicine, RPAH, Sydney, Nuclear Medicine Westmead Hospital, Sydney, This scientific cooperation took the following forms: exchanges of information, visits of scientists, research and publication on joint projects and seminars. Specifically, the Orsay group collaborated with centers from Australia to develop and characterize new radiotracers and radiopharmaceuticals for research or clinical use and to establish protocols to investigate physiological and pathological mechanisms in humans or animals, especially in the area of neurotransmission (neurodegenerative diseases, psychiatric disorders). As main results of these collaborations, 3 main subjects were achieved and followed by articles published in well recognized scientific journals.
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, ID; 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.
Metabolism of CLINDE, a peripheral benzodiazepine receptor SPECT ligand
(Springer, 2010-10-11) Peyronneau, MA; Mattner, F; Howell, NR; Jiang, C; Pelegrini, P; Greguric, ID; Loc'h, C; Katsifis, A
Aim: The iodinated imidazopyridine, N′, N′-diethyl-6-Chloro-(4′-[123I]iodophenyl)imidazo[1,2-a]pyridine-3-acetamide ([123I]CLINDE) has been characterized as a high affinity and selectivity ligand for SPECT imaging the peripheral benzodiazepine receptor (TSPO)1. As part of the development of this probe and for future investigations in humans, the metabolism of CLINDE was investigated in different species. The aim of this study was to identify the main metabolic pathways and the form(s) of cytochrome P450 (CYP) responsible for the biotransformation of this ligand. Materials and Methods: The in vitro metabolism of CLINDE and [123I]-CLINDE was carried out using rat and human liver microsomes as well as human recombinant CYP. Similar studies were performed in rat hepatocytes. Microsomalor hepatocyte incubations were analyzed by LC/MS and the structure of the metabolites characterized by MS-MS experiments. Results: In rat and human liver microsomes, CLINDE was converted to two main polar metabolites identified by LC/MS asN-dealkylated (m/z440)and hydroxylated metabolites (m/z484). In rat liver microsomes, the main metabolite resulted from hydroxylation of the ligand. In human liver microsomes, the metabolism of CLINDE was slower with major formation of anN-dealkyl metabolite. Microsomes from baculovirus-infected insect cells expressing human P450s isoforms (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18,2C19, 2D6, 2E1, 3A4, 3A5, SF9 control) were used to test their ability to catalyse the oxidation of CLINDE. CYP3A4 and CYP3A5 exhibited the highest catalytic activity for N-dealkylation, (3.3 and 3.8 nmol/nmolP450/min), followed byCYP2C19 (0.67 nmol/nmolP450/min) and CYP2D6 0.09 nmol/nmolP450/min). The other CYP isoforms did not form any detectable metabolites. For the hydroxylase activity relative to the formation of the molecular ion at m/z 484, CYP1A1 (4.05nmol/nmolP450/min), CYP1A2 (1.85 nmol/nmolP450/min) appeared to be the morecatalytically active, followed by CYP3A4 (0.95 nmol/nmolP450/min) and CYP2C19(0.42 nmol/nmolP450/min). The iodine atom was conserved in all the identified metabolites during the process of biotransformation. In rat hepatocytes, [123-I]-CLINDE was extensively and rapidly converted to at least five radiometabolites, the major metabolite being issued from methyl-hydroxylation. Conclusion: Cytochrome P450 catalysed in vitro studies of CLINDE, demonstrated the formation of N-dealkylated and hydroxylated metabolites. Species differences were observed in the rate of formation of rat and human metabolites. The above results suggest that CYP3A4 and CYP3A5 most markedly catalysed N-dealkylation of CLINDE while the hydroxylation was likely to depend more strongly on CYP1A isoforms (extrahepatic CYP1A1 and hepaticCYP1A2).
PET imaging of brain inflammation during early epileptogenesis in a rat model of temporal lobe epilepsy
(Springer-Velag, 2012-11-08) Dedeurwaerdere, S; Callaghan, PD; Pham, TQ; Rahardjo, GL; Amhaoul, H; Berghofer, PJ; Quinlivan, M; Mattner, F; Loc'h, C; Katsifis, A; Grégoire, MC
Background Recently, inflammatory cascades have been suggested as a target for epilepsy therapy. Positron emission tomography (PET) imaging offers the unique possibility to evaluate brain inflammation longitudinally in a non-invasive translational manner. This study investigated brain inflammation during early epileptogenesis in the post-kainic acid-induced status epilepticus (KASE) model with post-mortem histology and in vivo with [18F]-PBR111 PET. Methods Status epilepticus (SE) was induced (N = 13) by low-dose injections of KA, while controls (N = 9) received saline. Translocator protein (TSPO) expression and microglia activation were assessed with [125I]-CLINDE autoradiography and OX-42 immunohistochemistry, respectively, 7 days post-SE. In a subgroup of rats, [18F]-PBR111 PET imaging with metabolite-corrected input function was performed before post-mortem evaluation. [18F]-PBR111 volume of distribution (V t) in volume of interests (VOIs) was quantified by means of kinetic modelling and a VOI/metabolite-corrected plasma activity ratio. Results Animals with substantial SE showed huge overexpression of TSPO in vitro in relevant brain regions such as the hippocampus and amygdala (P < 0.001), while animals with mild symptoms displayed a smaller increase in TSPO in amygdala only (P < 0.001). TSPO expression was associated with OX-42 signal but without obvious cell loss. Similar in vivo [18F]-PBR111 increases in V t and the simplified ratio were found in key regions such as the hippocampus (P < 0.05) and amygdala (P < 0.01). Conclusion Both post-mortem and in vivo methods substantiate that the brain regions important in seizure generation display significant brain inflammation during epileptogenesis in the KASE model. This work enables future longitudinal investigation of the role of brain inflammation during epileptogenesis and evaluation of anti-inflammatory treatments. © 2012, Springer.
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.
Preparation 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, ID; Dikic, B; Ballantyne, P; Mattner, F; Nguyen, VH; Loc'h, C; Katsifis, A
Radiopharmaceuticals 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.
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.
Radiosynthesis of 2-[6-chloro-2-(4-iodophenyl)imidazo [1,2-a]pyridin-3-yl]-N-ethyl-N-[C-11]methyl-acetamide, [C-11]CLINME, a novel radioligand for imaging the peripheral benzodiazepine receptors with PET
(Wiley-Blackwell, 2007-03) Thominiaux, CJ; Mattner, F; Greguric, ID; Boutin, H; Chauveau, F; Kuhnast, B; Grégoire, MC; Loc'h, C; Valette, H; Bottlaender, MA; Hantraye, P; Tavitian, B; Katsifis, A; Dollé, F
Recently, a new 2-(iodophenyl)imidazo[1,2-a]pyridineacetamide series has been developed as iodine-123-labelled radioligands for imaging the peripheral benzodiazepine receptors using single photon emission tomography. Within this series, 2-[6-chloro-2-(4-iodophenyl)-imidazo[1,2-alpyridin-3-yl]-N-ethyl-N-methyl-acetamide (CLINME) was considered as an appropriate candidate for positron emission tomography imaging and was isotopically labelled with carbon-11 (T-1/2: 20.38 min) at the methylacetamide side chain from the corresponding nor-analogue using [C-11]methyl iodide and the following experimental conditions: (1) trapping at -10 degrees C of [C-11]methyl iodide in a 1/2 (v:v) mixture of DMSO/DMF (300 mu l) containing 0.7-1.0 mg of the precursor for labelling and 3-5 mg of powdered potassium hydroxide (excess); (2) heating the reaction mixture at 110 degrees C for 3 min under a nitrogen stream; (3) diluting the residue with 0.6 ml of the HPLC mobile phase; and (4) purification using semi-preparative HPLC (Zorbax(R) SB18, Hewlett Packard, 250 x 9.4 mm). Typically, starting from a 1.5Ci (55.5 GBq) [C-11]CO2 production batch, 120-150 mCi (4.44-5.55 GBq) of [C-11]CLINME were obtained (16-23% decay-corrected radiochemical yield, n = 12) within a total synthesis time of 24-27 min (Sep-pak(R)Plus-based formulation included). Specific radio-activities ranged from 0.9 to 2.7 Ci/mu mol (33.3-99.9 GBq/mu mol) at the end of radiosynthesis. © 2007, Wiley-Blackwell.
Radiosynthesis of a novel PET fluoronicotinamide for melanoma tumour PET imaging [18F]MEL050
(CSIRO Publishing, 2011-01-01) Greguric, ID; Taylor, S; Pham, TQ; Wyatt, NA; Jiang, CD; Bourdier, T; Loc'h, C; Roselt, P; Neels, OC; Katsifis, A
[18F]6-Fluoro-N-[2-(diethylamino)ethyl]nicotinamide [18F]MEL050 is a novel nicotinamide-based radiotracer, designed to target random metastatic dissemination of melanoma tumours by targeting melanin. Preclinical studies suggest that [18F]MEL050 has an excellent potential to improve diagnosis and staging of melanoma. Here we report the radiochemical optimization conditions of [18F]MEL050 and its large scale automated synthesis using a GE FXFN automated radiosynthesis module for clinical, phase-1 investigation. [18F]MEL050 was prepared via a one-step synthesis using no-carrier added K[18F]F-Krytpofix® 222 (DMSO, 170°C, 5 min) followed by HPLC purification. Using 6-chloro-N-[2-(diethylamino)ethyl]nicotinamide as precursor, [18F]MEL050 was obtained in 40–46% radiochemical yield (non-decay corrected), in greater than 99.9% radiochemical purity and specific activity ranging from 240 to 325 GBq μmol–1. Total synthesis time including formulation was 40 min and [18F]MEL050 was stable (99.8%) in PBS for 6 h. © 2011, CSIRO Publishing
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.
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, ID; 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
Synthesis and evaluation of novel radioiodinated benzamides for malignant melanoma
(American Chemical Society, 2007-07-26) Pham, TQ; Greguric, ID; Liu, X; Berghofer, PJ; Ballantyne, P; Chapman, J; Mattner, F; Dikic, B; Jackson, TW; Loc'h, C; Katsifis, A
The 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.
Synthesis and evaluation of novel radioiodinated nicotinamides for malignant melanoma
(Elsevier B.V., 2008-10-01) Liu, X; Pham, TQ; Berghofer, PJ; Chapman, J; Greguric, ID; Mitchell, P; Mattner, F; Loc'h, C; Katsifis, A
Introduction A series of iodonicotinamides based on the melanin-binding iodobenzamide compound N-2-diethylaminoethyl-4-iodobenzamide was prepared and evaluated for the potential imaging and staging of disseminated metastatic melanoma. Methods [123I]Iodonicotinamides were prepared by iododestannylation reactions using no-carrier-added iodine-123 and evaluated in vivo by biodistribution and competition studies and by single photon emission computed tomography (SPECT) imaging in black and albino nude mice bearing B16F0 murine melanotic and A375 human amelanotic melanoma tumours, respectively. Results The iodonicotinamides displayed low-affinity binding for σ1–σ2 receptors (Ki>300 nM). In biodistribution studies in mice, N-(2-(diethylamino)ethyl)-5-[123I]iodonicotinamide ([123I]1) exhibited the fastest and highest uptake of the nicotinamide series in the B16F0 tumour at 1 h (∼8% ID/g), decreasing slowly over time. No uptake was observed in the A375 tumour. Clearance from the animals by urinary excretion was more rapid for N-alkyl-nicotinamides than for piperazinyl derivatives. At 1 h postinjection, the urinary excretion was 66% ID for [123I]1, while the gastrointestinal tract amounted to 17% ID. Haloperidol was unable to reduce the uptake of [123I]1 in pigmented mice, indicating that this uptake was likely due to an interaction with melanin. SPECT imaging of [123I]1 in black mice bearing the B16F0 melanoma indicated that the radioactivity was predominately located in the tumour and eyes. No specific localisation was observed in nude mice bearing A375 amelanotic tumours. Conclusion These findings suggest that [123I]1, which displays high tumour uptake with rapid clearance from the body, could be a promising imaging agent for the detection of melanotic tumours. © 2008 Elsevier Inc.
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.

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