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Saint Beauzire, France

Laboratoires Cyclopharma | Date: 2014-05-23

Medicines; pharmaceutical products for veterinary or medical use; radio-pharmaceutical preparations for medical or veterinary use.

French Institute of Health, Medical Research, Laboratoires Cyclopharma, University Dauvergne Clermont 1 and French Atomic Energy Commission | Date: 2013-09-19

The present invention relates to the compound of formula (I): in which R1 represents a hydrogen atom, an optionally labelled halogen, a radionuclide or a Sn[(C1-C4)alkyl]3 group, Ar represents an aryl group or a heteroaryl group, R9 represents a hydrogen atom, a (C1-C4)alkyl group or forms together with the group R1Ar a ring fused with the Ar group, A represents a group of formula () or (): R3 and R4 independently represent a hydrogen atom, a (C1-C6)alkyl group, a (C1-C6)alkenyl group or a group of formula (): The present invention also relates to pharmaceutical compositions comprising them and to their use in diagnosis, in particular with SPECT or PET imaging and in therapy of melanoma via targeted radionuclide therapy.

Serriere S.,University of Tours | Tauber C.,University of Tours | Vercouillie J.,University of Tours | Mothes C.,Laboratoires Cyclopharma | And 7 more authors.
Neurobiology of Aging | Year: 2015

We studied concomitantly the level of neuroinflammation and β-amyloid (Aβ) load in the APPswePS1dE9 transgenic mouse model of Alzheimer's disease using positron emission tomography. The translocator protein 18kDa (TSPO) tracer [18F]DPA-714 was used to measure neuroinflammation and [18F]AV-45 for Aβ load in mice at 6, 9, 12, 15, and 19months of age. At 19months, we also analyzed the neuroinflammatory and neuroanatomic status of mice brains. The main affected brain areas were the cortex and hippocampus, with a concomitant progression of neuroinflammation with increased amyloid burden. At 19months, no increase in TSPO binding was observed in the cerebellum; immunostaining revealed W0-2-positive plaques, indicating that the amyloid deposits seemed not stimulate inflammation. This finding was in agreement with the observed level of microglia and astrocytes staining. Our findings provide a better understanding of the relationships between neuroinflammation and plaque accumulation in the course of the disease in this mouse model. The monitoring of both processes should be of value to validate potential therapeutic approaches. © 2015 Elsevier Inc.

Varrone A.,Center for Psychiatry Research | Stepanov V.,Center for Psychiatry Research | Nakao R.,Center for Psychiatry Research | Toth M.,Center for Psychiatry Research | And 8 more authors.
Journal of Nuclear Medicine | Year: 2011

The aim of this study was to evaluate the quantification, biodistribution, and radiation dosimetry of the novel dopamine transporter (DAT) radioligand 18F-(2S,3S)-methyl 8-((E)-4-fluorobut-2-en-1-yl)-3-(p-tolyl)-8- azabicyclo[3.2.1]octane-2-carboxylate (18F-LBT-999) in nonhuman primates. Methods: The brain study was conducted in 4 female rhesus monkeys. PET measurements were conducted for 243 min using the high-resolution research tomograph (HRRT) with the measurement of the metabolite-corrected arterial input function and protein binding. Quantification was performed with kinetic analysis using 2-tissue- and 1-tissue-compartment models, with Logan graphical analysis and with different reference tissue models. The outcome measures were total distribution volume (VT), nondisplaceable distribution volume (VND), binding potential relative to the free concentration of radioligand in plasma (BPF), and binding potential relative to the concentration of nondisplaceable radioligand in tissue (BPND) = VT - VND/VND using the cerebellum as a reference region. For the biodistribution and radiation dosimetry, 2 female cynomolgus monkeys were studied.Whole-body PET scans were obtained using a PET/CT system for approximately 250 min. Estimates of the absorbed radiation dose in humans were calculated using OLINDA/EXM software. Results: 18F-LBT-999 showed good brain uptake (300% standardized uptake value) and regional distribution according to known DAT density. The 2-tissuecompartment model was the preferred model for the quantification. Late peak equilibrium (120-140 min) and slow washout were observed in the striatum, with high variability of VT, BPF, and BPND. When the different models were compared with the 2-tissuecompartment model, the underestimation of VT or BPND was larger in the caudate and putamen than in the midbrain and thalamus. The reference tissue models were suitable for the quantification. The whole-body distribution study showed that the main routes of excretion of 18F-LBT-999 were the urinary and gastrointestinal systems, with the bladder being the critical organ. Accumulation of 18F-LBT-999 was found in the bone and skull, with a relatively high dose estimated for the osteogenic cells. The range of calculated effective dose was 0.021-0.022 mSv/MBq. Conclusion: 18F-LBT-999 seemed to be a suitable PET radioligand for the DAT quantification, particularly for extrastriatal regions. The skull uptake did not seem to be a limitation for brain imaging. The calculated dosimetry estimates based on data in nonhuman primates seemed comparable with those of other clinically used 18F-labeled radioligands, for example, 18F-FDG (0.024-0.027 mSv/MBq). Copyright © 2011 by the Society of Nuclear Medicine, Inc.

Vercouillie J.,University of Tours | Vercouillie J.,French Institute of Health and Medical Research | Prenant C.,Laboratoires Cyclopharma | Maia S.,University of Tours | And 8 more authors.
Journal of Labelled Compounds and Radiopharmaceuticals | Year: 2010

[18F]FDDNP has been recently described as a potent tracer to image amyloid plaques in vivo by positron emission tomography. Such a tool will be advisable to diagnose patient with mild cognitive impairment, to follow the disease progression and to evaluate new therapies. To make this radiopharmacetical affordable for the clinicians, we developed an automated method for [18F]FDDNP radiosynthesis using a commercial [ 18F]FDG unit. Radiolabeling with fluorine-18 was carried out by a [18F]fluoro-detosylation reaction on the precursor 2-(1-{6-[(2-tosyloxyoethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile. The reaction was performed in acetonitrile for 15 min at 90°C, and then the reaction mixture was injected into a semi-preparative high-pressure liquid chromatography. The desire [18F]FDDNP fraction was collected, and an SPE was performed. The [18F]FDDNP was formulated in a sodium chloride/ethanol solution followed by a sterile filtration. Stability of [ 18F]FDDNP was studied after 4 h and radiochemical purity of [ 18F]FDDNP remained >98%. The overall decay-corrected radiochemical yield was 15±3% (n = 8). Radiochemical purity was >98% and the specific activity was 164±25GBq/μmol at EOS. Pharmaceutical controls, bioburden, sterility, bacterial endotoxin and residual solvent tests were performed. The results were in accordance with the European Pharmacopoeia and demonstrated our ability to produce [18F]FDDNP with a pharmaceutical grade and a high reproducibility. Copyright © 2010 John Wiley & Sons, Ltd.

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