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Michel Bottlaender

Publications and source records attributed to Michel Bottlaender.

26 records · Page 2Linked to original sources
PubMed2003

Long-lasting occupancy of central nicotinic acetylcholine receptors after smoking: a PET study in monkeys.

The aim of this study was to compare the degree of occupancy of central nicotinic acetylcholine receptors (nAChR) in isoflurane anaesthetized baboon brain following inhalation of tobacco smoke (one cigarette containing 0.9 mg nicotine) or i.v. nicotine (0.6 mg i.v.). [18F]Fluoro-A-85380 and positron emission tomography (PET) were used to assess the distribution volumes (DV) of the radiotracer in selected brain areas using a one-compartment model. Eighty minutes after nicotine i.v., DV was reduced by 50 and 66% in the thalamus and putamen, respectively. Six hours after nicotine, a reduction in DV (27% in the thalamus) was still observed. Eighty minutes after inhalation of tobacco smoke, DV was decreased by 52 and 65% in the thalamus and putamen, respectively. Previous PET experiments have demonstrated a short-lasting interaction of [11C]nicotine with nAChRs. Thus, we hypothesized that a metabolite of nicotine with high affinity and long half-live (several hours) could bind at nAChRs. Eighty minutes after a high dose of nornicotine (0.5 mg i.v.), DV was reduced by 53 and 31% in thalamus and putamen, respectively. No significant effect was observed following 0.15 mg nornicotine. Therefore, nornicotine could contribute to the long-lasting occupancy of central nAChRs after smoking.

Animals↗
PubMed2003

Biodistribution and radiation dosimetry of 18F-fluoro-A-85380 in healthy volunteers.

UNLABELLED: This study reports on the biodistribution and radiation dosimetry of 2-(18)F-Fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine ((18)F-fluoro-A-85380), a promising radioligand for the imaging of central nicotinic acetylcholine receptors (nAChRs). METHODS: Whole-body scans were performed in 3 healthy male volunteers up to 2 h after intravenous injection of 137-238 MBq (18)F-fluoro-A-85380. Transmission scans (3 min per step, 8 or 9 steps according to the height of the subject) in 2-dimensional mode were used for subsequent correction of attenuation of emission scans. Emission scans (1 min per step) were acquired over 2 h. Venous blood samples were taken up to 2 h after injection of the radiotracer. Urine was freely collected up to 2 h after injection of the radiotracer. For each subject, the percentage of injected activity measured in regions of interest over brain, intestine, stomach, bladder, kidneys, and liver were fitted to a monoexponential model, as an uptake phase followed by a monoexponential washout, or to a biexponential model to generate time-activity curves. Using the MIRD method, ten source organs were considered in estimating radiation absorbed doses for organs of the body. RESULTS: Injection of (18)F-fluoro-A-85380 was clinically well tolerated and blood and urine pharmacologic parameters did not change significantly. The primary routes of clearance were renal and intestinal. Ten minutes after injection, high activities were observed in the bladder, kidneys, and liver. Slow uptake was seen in the brain. The liver received the highest absorbed dose. The average effective dose of (18)F-fluoro-A-85380 was estimated to be 0.0194 mSv/MBq. CONCLUSION: The amount of (18)F-fluoro-A-85380 required for adequate nAChR imaging results in an acceptable effective dose equivalent to the patient.

Absorption↗
PubMed2002

Pharmacological evaluation of a Br-76 analog of epibatidine: a potent ligand for studying brain nicotinic acetylcholine receptors.

[(76)Br]-Norchlorobromoepibatidine ([(76)Br]BrPH) is a specific and high affinity radioligand for the nicotinic acetylcholine receptors (nAChRs). In vitro, on rat thalamus membranes [(76)Br]BrPH bound to two sites with apparent affinities of 8 pM and 3 nM. The density of binding sites were 1.9 and 70 fmol/mg protein, respectively. In vivo, in biodistribution and autoradiographic studies in rats the regional distribution of [(76)Br]BrPH paralleled the neuroanatomical localization of nAChRs. Two hours postinjection, the highest concentration in the brain was found in thalamus and colliculi (4% ID/g). Competition experiments with specific nicotinic, muscarinic, dopaminergic, and serotoninergic drugs confirmed that the in vivo binding of [(76)Br]BrPH was consistent with neuronal nicotinic receptors. PET imaging of [(76)Br]BrPH in baboon demonstrated a rapid and high uptake in the brain. Peak uptake occurred at 30-40 min for the thalamus. Due to the constant washout in the cerebellum, the thalamus to cerebellum ratio was 5 at 2 h postinjection. Subcutaneous injection of cytisine (1 mg/kg), 3 h postinjection of [(76)Br]BrPH reduced the radioactivity concentration in thalamus and cortex by 58 and 50%, respectively, as observed 1 h later. Cytisine pretreatment (5 mg/kg s.c.) inhibited completely the radioligand accumulation in the thalamus. Chronic MPTP pretreatment resulted in reduction of [(76)Br]BrPH uptake in all brain regions except in cerebellum. These preliminary results suggest that [(76)Br]BrPH has the potential to be a useful radioligand for studying the pharmacology of nicotinic acetylcholine receptors in preclinical experiments.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

Synthesis of a fluorine-18-labelled derivative of 6-nitroquipazine, as a radioligand for the in vivo serotonin transporter imaging with PET.

Considerable efforts have been engaged in the design, synthesis and pharmacological characterization of radioligands for imaging the serotonin transporter, based on its implication in several neuropsychiatric diseases, such as depression, anxiety and schizophrenia. In the 5-halo-6-nitroquipazine series, the fluoro derivative has been designed for positron emission tomography (PET). The corresponding 5-iodo-, 5-bromo- and 5-chloro N-Boc-protected quipazines as labelling precursors, as well as 5-fluoro-6-nitroquipazine as a reference compound have been synthesized. 5-[(18)F]Fluoro-6-nitroquipazine has been radiolabelled with fluorine-18 (positron-emitting isotope, 109.8 min half-life) by nucleophilic aromatic substitution from the corresponding N-Boc protected 5-bromo- and 5-chloro-precursors using K[(18)F]F-K(222) complex in DMSO by conventional heating (145 degrees C, 2 min) or microwave activation (50 W, 30-45 s), followed by removal of the protective group with TFA. Typically, 15-25 mCi (5.5-9.2 GBq) of 5-[(18)F]fluoro-6-nitroquipazine (1-2 Ci/micromol or 37-72 GBq/micromol) could be obtained in 70-80 min starting from a 550-650 mCi (20.3-24.0 GBq) aliquot of a cyclotron [(18)F]F(-) production batch (2.7-3.8% non decay-corrected yield based on the starting [(18)F]fluoride). Ex vivo studies (biodistribution in rat), as well as PET imaging (in monkey) demonstrated that 5-[(18)F]fluoro-6-nitroquipazine ([(18)F]-1d) readily crossed the blood brain barrier and accumulated in the regions rich in 5-HT transporter (frontal- and posterial cortex, striata). However, the low accumulation of the tracer in the thalamus (rat and monkey) as well as the comparable displacement of the tracer observed with both citalopram, a -HT re-uptake inhibitor and maprotiline, a norepinephrine re-uptake inhibitor (rat), indicate that 5-[(18)F]fluoro-6-nitroquipazine ([(18)F]-1d) does not have the suggested potential for PET imaging of the serotin transporter (SERT).

Animals↗
PubMed2002

(+)-[76Br]A-69024: a non-benzazepine radioligand for studies of dopamine D1 receptors using PET.

(+)-[76Br]A-69024 is a specific and enantioselective dopamine D1 receptor radioligand. The Bmax of (+)-[76Br]A-69024 measured in vitro on rat striatum membranes was 320 +/- 25 fmoles/mg protein with an apparent dissociation constant of Kd = 0.6 +/- 0.1 nM. The inactive enantiomer, (-)-[76Br]A-69024, displayed no affinity in the same assay. In vivo, the biodistribution (+)-[76Br]A-69024 in rats showed a rapid and high uptake in the striatum (1% ID/g), followed by a slow wash out. The striatum/cerebellum concentration ratio (index of specific binding) reached a maximum value of 10 at 60 minutes post injection. A tissue to cerebellum ratio of 2.8 and 1.5 was also observed for frontal and posterior cortex respectively. With the pharmacologically inactive enantiomer, (-)-[76Br]A-69024, the brain uptake was determined to be non specific since a striatum/cerebellum ratio of approximately 1 was observed throughout the time course of the experiment. The selectivity of (+)-[76Br]A-69024 uptake was demonstrated in competition experiments. The specific uptake in the striatum and cortical regions was completely prevented after administration of the D1 antagonist SCH 23390. Pre-treatment of rats with unlabelled (+)A-69024 also displayed the same regional inhibition of (+)-[76Br]A-69024 uptake. Pre-administration of rats with spiperone (D2) and ketanserin (5-HT2/5-HT2C) showed no inhibitory effect on (+)-[76Br]A-69024 uptake in any brain region. Using (+)-[76Br]A-69024, PET study in baboon demonstrated a preferential accumulation of the radioactivity in the striatum, frontal and posterior cortex which was displaced to the level of the cerebellum by SCH 23390. These results suggest that (+)-[76Br]A-69024 may deserve further investigation as a potential radioligand for studying striatal and cortical dopamine D1 receptors using PET.

Animals↗
PubMed2002

Fluoro-A-85380 demonstrated no mutagenic properties in in vivo rat micronucleus and Ames tests.

The potential mutagenic properties (micronucleus and the Ames tests) of fluoro-A-85380 (2-fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine) were evaluated as a mandatory pre-clinical step. No statistically significant increase in the frequency of micronucleated polychromatic erythrocytes was found in animals treated at any dose tested. No biologically significant increase in the mean number of revertants was noted in all the Salmonella typhimurium strains tested with fluoro-A-85380. Therefore, fluoro-A-85380 demonstrated no mutagenic properties using these two tests.

Animals↗
PubMed2002

In vivo quantification and parametric images of the cardiac beta-adrenergic receptor density.

UNLABELLED: Previous studies showed that the in vivo concentration of beta-adrenergic receptor sites can be estimated by PET using (-)-4-((S)-3-tert-butylamino-2-hydroxypropoxy)-1,3-dihydrobenzoimidazol-2-one (CGP 12177), a hydrophilic ligand. A graphic method was previously proposed and used by several groups. However, this approach was not completely validated. The purpose of this study was to improve and confirm the validity of this approach through a better knowledge of the associated ligand-receptor model, estimated for the first time using the multiinjection approach. METHODS: The concentration of beta-adrenergic receptor sites was estimated for mini pigs using 2 methods. The first was the usual multiinjection approach, which permits estimation of all model parameters, including receptor concentration. However, this approach needs a complex protocol, including blood sampling, thereby making it difficult to use for studies on patients. The second method was the CGP 12177 graphic method. This approach permits the estimation of only receptor concentration but has the advantage of not requiring blood sampling. Another advantage is the ability to generate parametric images easily. RESULTS: Using the multiinjection approach, we obtained for the first time a complete model describing interactions between CGP 12177 and beta-adrenergic receptors. Knowledge of all parameters of this model permitted good validation of the assumptions included in the graphic method. The concentration of beta-adrenergic receptor sites in mini pigs was estimated at 15.2 +/- 3.4 pmol/mL. CONCLUSION: The graphic method has been improved by taking into account various phenomena, such as protein binding and the nonlinearity between plasma concentration and injected dose. This method is now usable for patient studies and offers the ability to estimate the beta-adrenergic receptor concentration from a single PET experiment without blood sampling. Parametric imaging will enable screening of the receptor site location and observation of potential anomalies in patients.

Adrenergic Agents↗