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ABSTRACT: Diastereoisomeric compounds [(18)F]cis- and [(18)F]trans-4-methylbenzyl 4-[(pyrimidin-2-ylamino)methyl]-3-fluoro-piperidine-1-carboxylates were successfully synthesized as new subtype-selective PET radiotracers for imaging the NR2B subunit containing NMDA receptors. Rat brain section autoradiographies demonstrated a high specific binding in NR2B/NMDA receptor rich regions for both radioligands. The measured logD(7.4) values as well as B(max)/K(d) ratios indicated that both radiotracers possess the adequate properties required for PET radiotracers.
European journal of medicinal chemistry 04/2012; 53:408-15. · 3.27 Impact Factor
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Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis. 07/2011; 31(4):492-5.
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Romain Labas,
Gwénaëlle Gilbert,
Olivier Nicole,
Martine Dhilly,
Ahmed Abbas,
Olivier Tirel,
Alain Buisson,
Joël Henry,
Louisa Barré, Danièle Debruyne,
Franck Sobrio
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ABSTRACT: In this study, novel specific PET radioligands containing the 4-(4-fluorobenzyl)piperidine moiety and selectively antagonistic for the NR2B subunit containing NMDA receptors were developed. Two antagonists, RGH-896 (1a) and 4-(4-fluorobenzyl)piperidinyl-1-methyl-2-benzimidazol-5-ol (2a), belonging to two different structural families, were radiolabeled by an aromatic nucleophilic radiofluorination followed by a reduction of the para-position carbonyl function. Radiotracers [18F]1a, [18F]2a or the pattern 4-(4-[18F]-fluorobenzyl)piperidine ([18F]6) demonstrated an identical in vivo behavior with high accumulation of radioactivity in bone and cartilage which would suggest a radiodefluorination of the radiotracers. The identification of metabolites from 6 by LC-MS-MS confirmed the significant degree of defluorination as a result of the in vivo hydroxylation in the benzyl ring. In conclusion, [18F]1a or [18F]2a are not suitable for imaging the NR2B NMDA receptors due to their poor brain penetration. We also argue for a cautious use of the radiolabeled pattern, 4-(4-[18F]-fluorobenzyl)piperidine, to develop PET radiotracers.
European journal of medicinal chemistry 03/2011; 46(6):2295-309. · 3.27 Impact Factor
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ABSTRACT: This study evaluates the in vitro stability and sterility of fortified ophthalmic antibiotic preparations of 5% solutions (50 mg/mL) made from commercially available powders of amikacin, ceftazidime, and vancomycin stored at -20 degrees C for 6 months.
Antibiotic solutions were prepared with aseptic techniques by reconstitution and dilution of the commercially available powders (amikacin, ceftazidime, and vancomycin) and stored at -20 degrees C. After various durations of storage, the stability of various physical and chemical properties was determined by a pH meter, an osmometer, and high-performance liquid chromatography. Microbiological activity was assayed according to the European Pharmacopoeia.
Solutions of 5% amikacin or ceftazidime in 0.9% sodium chloride and vancomycin in 5% dextrose were found to be physically, chemically, and microbiologically stable after storage at -20 degrees C for 190 days. A time limitation of 6 months is proposed.
Fortified ophthalmic antibiotic solutions prepared and supplied by a pharmacy can be stored in freezers at -20 degrees C for later use.
Cornea 05/2010; 29(7):807-11. · 1.73 Impact Factor
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ABSTRACT: In this study, we compared the effects of five short-, medium-, or long-acting benzodiazepine-receptor agonists (BZDs) [alprazolam (APZ), clonazepam (CLZ), flunitrazepam (FLZ), loprazolam (LPZ), zolpidem (ZLP)], at two distinct doses, 0.2 and 2 mg/kg, on the cell surface regulation of mu-opioid receptor induced by 0.15 mg/kg buprenorphine (BPN) in specific regions of the rat brain. Using 0.312 - 5 nM [(3)H]-DAMGO concentrations and Scatchard plot analysis, B(max) (maximal receptor density) and K(d) (dissociation constant) were determined at different brain regions of interest (amygdala, cortex, hippocampus, hypothalamus, thalamus). Acute BPN induced an expected down-regulation and addition of each of the BZDs to BPN induced less down-regulation than did BPN alone, sometimes while altering affinity. Some significant differences in the intensity of these effects were observed between BZDs. FLZ that is widely abused and enlarges BPN toxicity appeared the most potent to increase mu-cell surface receptor density at the lowest dose of 0.2 mg/kg. Besides, LPZ for which the effect on mu-opioid-receptor regulation appeared lower is considered to have a low risk of dependence in the epidemiological data banks. CLZ and ZLP (2 mg/kg) induced the strongest modification on mu-opioid-receptor density, but a substantial decrease in affinity could minimize the functional consequences. The reported changes were maximal in the amygdala, hippocampus, and thalamus. Among people using BPN and BZDs, the effects described here are likely to influence addictive behaviors and induce toxic effects that could be quantitatively different due to the quality of the BZD.
Journal of Pharmacological Sciences 06/2009; 110(1):36-46. · 2.08 Impact Factor
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ABSTRACT: Radiopharmaceuticals that can bind selectively the kappa-opioid receptor may present opportunities for staging clinical brain disorders and evaluating the efficiency of new therapies related to stroke, neurodegenerative diseases or opiate addiction. The N-methylated derivative of JDTic (named MeJDTic), which has been recently described as a potent and selective antagonist of kappa-opioid receptor in vitro, was labeled with carbon-11 and evaluated for in vivo imaging the kappa-opioid receptor in mice.
[(11)C]-MeJDTic was prepared by methylation of JDTic with [(11)C]-methyl triflate. The binding of [(11)C]-MeJDTic to kappa-opioid receptor was investigated ex vivo by biodistribution and competition studies using nonfasted male CD1 mice.
[(11)C]-MeJDTic exhibited a high and rapid distribution in peripheral organs. The uptake was maximal in lung where the kappa receptor is largely expressed. [(11)C]-MeJDTic rapidly crossed the blood-brain barrier and accumulated in the brain regions of interest (hypothalamus). The parent ligand remained the major radioactive compound in brain during the experiment. Chase studies with U50,488 (a kappa referring agonist), morphine (a mu agonist) and naltrindole (a delta antagonist) demonstrated that this uptake was the result of specific binding to the kappa-opioid receptor.
These findings suggested that [(11)C]-MeJDTic appeared to be a promising selective "lead" radioligand for kappa-opioid receptor PET imaging.
Nuclear Medicine and Biology 08/2008; 35(5):561-9. · 3.02 Impact Factor
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ABSTRACT: [11C]-SIB-1553A ((+/-)-4-[2-((N-[11C]-methyl)-2-pyrrolidinyl)ethyl]thiophenol) was labelled with carbon-11 (t1/2=20.4 min) and evaluated in vivo as potential radiotracer for noninvasive assessment of the beta4 subunit nicotinic acetylcholine neurotransmission system with positron emission tomography (PET). The labelling precursor was obtained within five steps from N-Boc-prolinal in 45-56% overall yields. The radiosynthesis of [11C]-SIB-1553A was achieved by a selective N-[11C]-methylation in 32 min with a radiochemical purity greater than 97%, 7.5-30 GBq/micromol of specific radioactivity and 55-65% radiochemical yield (decay corrected, based on [11C]methyl iodide). The ex vivo pharmacological profile of [11C]-SIB-1553A was evaluated in rats with biodistribution studies in organs and in brain structures by autoradiography. The radiotracer uptake in the brain reached 0.49 %ID/g at 10 min and no brain radiometabolite was detected 40 min after intravenous injection. The quantification of radioactivity in various cerebral structures indicated a significantly higher radioactivity level at 15 min than at 30 min. Among the beta4 nAChR subunit-rich structures studied in the rat brain, only the thalamus at 15 and 30 min and the hippocampus at 30 min showed significantly higher uptake. Moreover, competition studies performed with SIB-1553A (15 min before the radiotracer injection) revealed only a low specific binding estimated to 7% of the total binding at 15 min and 13% at 30 min.
Nuclear Medicine and Biology 05/2008; 35(3):377-85. · 3.02 Impact Factor
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ABSTRACT: Buprenorphine, a partial mu-receptor agonist widely substituted for heroin in the treatment of addiction, is often misused in combination with benzodiazepines. Improved hedonic properties may result, but only at the cost of increased buprenorphine toxicity. In order to elucidate the appeal of the benzodiazepine-buprenorphine combination, the present study looked at its neuropsycho-pharmacological effects on various emotional and cognitive parameters in the mouse. On the basis of previous dose-response studies, the regimen used was buprenorphine 0.3mg/kg, s.c. plus dipotassium clorazepate 1, 4 and 16 mg/kg, i.p. Anxiety-like behaviour was assessed using the black and white test box, and memory processes were examined via the spontaneous alternation paradigm in the Y-maze, and passive avoidance tests. Spontaneous locomotor activity was also evaluated. High doses of clorazepate impaired buprenorphine-induced hyperactivity and anxiogenic-like effects. They also increased buprenorphine-induced spontaneous alternation impairment, but did not modify its impact on long-term memory processes. These results suggest that the positive reinforcement experienced with the buprenorphine-benzodiazepine combination may be attributable, at least in part, to an increase in buprenorphine's sedative effect associated with a decrease in anxiogenicity.
Drug and Alcohol Dependence 12/2006; 85(2):103-13. · 3.38 Impact Factor
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ABSTRACT: A new approach of competitive displacement binding assay using brain sections and a beta-imager is presented to estimate binding parameters such as affinity and selectivity of new compounds or to characterize receptor families or subtypes of receptors in small brain regions. This method includes a preliminary saturation assay intended to define the optimal concentration of displaceable radio-labeled ligand followed by the determination of displacement constants (IC(50) and K(i)) in cerebral regions rich in studied receptor. The technique application was demonstrated in seven rat brain structures, using displacement of the selective tritiated mu-opioid ligand [(3)H]-DAMGO by six opioid ligands: a specific agonist (DAMGO), less specific agonists (morphine, remifentanil), a non-specific antagonist with good affinity for mu receptors (naloxone) and ligands specific of other opioid subtypes (naltrindole, U50.488). Radioactivity counts were collected during 48 h. The assay-validation was performed by measuring intra- and inter-assay variation on determinations and by comparing presently obtained K(i) values with data from recognised methodologies. Both prove the accuracy of the proposed method.
Journal of Neuroscience Methods 07/2006; 154(1-2):60-7. · 1.98 Impact Factor
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ABSTRACT: The aim of the present study was to investigate the acute and chronic effects of clorazepate (CRZ) alone or in combination with buprenorphine (BPN) on binding of the selective mu opiate tritiated ligand [3H]-DAMGO in the rat brain. Using 0.1 to 5 nM [3H]-DAMGO concentrations and a beta-imager, Bmax (maximal receptor density) and K(D) (the dissociation constant) were directly determined at different regions of interest (ROI) in the brains of rats treated with BPN and/or CRZ administered either once or over 21 consecutive days. Differences in Bmax and K(D) were related to both treatment and location. Acute BPN induced a down-regulation (62% mean decrease in Bmax observed on the whole brain) of mu opiate receptors. CRZ induced a mean 39% decrease in Bmax associated with substantially decreased affinity, particularly after acute administration (136% mean K(D) increase). Addition of CRZ to BPN [mean Bmax decreases of 34% (acute) and 29% (chronic)] induced significantly less down-regulation than did BPN alone, while altering affinity. These changes were maximal in the amygdaloid nucleus. Significant and persistent decreases in Bmax and affinity were also detected in the hippocampus, hypothalamus and thalamus. In the thalamus, an opposite regulation of Bmax was observed that was maximal with the combination. As the regions where changes were greatest have been specifically implicated in memory and socio-emotional functions and/or vegetative and endocrine adaptations, there is reason to suspect that the addition of CRZ to BPN may have clinical consequences. On the one hand, it may have some impact on drug abuse and misuse behaviors towards treatments including heroin substitute and BZD, and on the other, amplify the BPN effect-particularly hedonic or toxic-mainly after sporadic BPN-BZD abuses. These pharmacodynamic findings may explain, at least in part, the well-established preference of patients for the BPN-benzodiazepine combination and the toxicity with which it is associated.
Brain Research 09/2005; 1052(2):222-31. · 2.73 Impact Factor
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ABSTRACT: Mecamylamine is a well-described non specific antagonist of nicotinic acetylcholine receptors (nAChRs), used in therapy and in psychopharmacological studies. [(11)C]-Mecamylamine was prepared and evaluated as a putative radioligand for positron emission tomography to study nicotinic acetylcholine receptors. The radiosynthesis consisted in the [(11)C]-methylation of the desmethyl precursor within 40 min with 30-40% radiochemical yield decay corrected. Biodistribution studies in rats showed that radioligand crossed the blood-brain barrier (0.39% ID at 30 min) and only unmetabolized tracer was recovered from brain at 45 min. Ex vivo autoradiography studies in rats did not indicate preferential uptake, and pre-treatment mecamylamine or with chlorisondamine, an nicotinic receptor inhibitor, did not demonstrate a significant specific binding. To investigate possible specie differences and effects of anesthesia, in vivo positron emission tomography (PET) studies were carried out on anaesthetized baboons and conscious macaques. The regional brain distribution of [(11)C]-mecamylamine in the two species of primates exhibited similar kinetics as did the rat with steady state reached about 45-50 min after radiotracer administration. Uptake values were two-fold higher in brain of conscious macaque than in anaesthetized baboon (thalamus: 0.258% ID/(kg mL) in conscious macaques and 0.129% ID/(kg mL) in baboons). PET images showed a radioactivity distribution which was quite homogeneous throughout the brain but with somewhat higher uptake in grey matter than in white. Brain distribution was unaltered by saturation or displacement studies. Possible explanation for the failure to establish specific binding in vivo could be long-lived structural modifications of the ionotropic channel by the unlabeled ligand administered before the tracer. In conclusion, [(11)C]-mecamylamine did not satisfy the requirements for a PET tracer of nicotinic acetylcholine receptors.
Neurochemistry International 06/2005; 46(6):479-88. · 2.86 Impact Factor
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ABSTRACT: We report here the syntheses of N-substituted quinolinimide derivatives displaying sufficient affinity and high selectivity for delta-opioid receptors. Among 9-subsituted derivatives, one showed much higher selectivity for the delta receptor in binding assays than the delta antagonist methylnaltrindole (6: Ki = 42 nM; micro/delta and kappa/delta > 238 on rat brain membranes) and antagonist properties. This compound was labeled with carbon-11 (t1/2 = 20.4 min) as a potential radioligand for the noninvasive assessment of delta opioid receptors in vivo with positron emission tomography (PET). A high yielding radiosynthesis of [11C]-6, based on the [11C]methyl introduction on the pyridine moiety by a Stille reaction, was described (radiochemical yield = 60 +/- 10%, specific activities = 0.8 to 1.5 Ci/micromol). The in vivo pharmacological profile in rats indicated that the radiotracer crossed the blood-brain barrier but was not stable and underwent rapid degradation in both plasma and brain. No specific binding was consequently revealed.
Bioconjugate Chemistry 18(2):538-48. · 4.93 Impact Factor
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Thérapie 59(5):555-8. · 0.30 Impact Factor
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Thérapie 59(2):267-9. · 0.30 Impact Factor
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Thérapie 66(2):175-7. · 0.30 Impact Factor
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http://dx.doi.org/10.2515/therapie/2010028.
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http://dx.doi.org/10.1051/ata/2004009.
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http://dx.doi.org/10.2515/therapie/2010027.
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http://dx.doi.org/10.2515/therapie:2004094.
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http://dx.doi.org/10.2515/therapie:2004052.
