Browsing by Author "Bottlaender, MA"

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    Cerebral monoamine oxidase a inhibition in tobacco smokers confirmed with PET and [c-11]befloxatone
    (Lippincott, Williams & Wilkins, 2009-02) Leroy, C; Bragulat, V; Berlin, I; Grégoire, MC; Bottlaender, MA; Roumenov, D; Dollé, F; Bourgeois, S; Penttilae, J; Artiges, E; Martinot, JL; Trichard, C
    The inhibition of cerebral monoamine oxidases (MAOs) by cigarette smoke components could participate to the tobacco addiction. However, the actual extent of this inhibition in vivo in smokers is still poorly known. We investigated cerebral MAO-A availability in 7 tobacco-dependent subjects and 6 healthy nonsmokers, using positron emission tomography (PET) and the MAO-A selective radioligand [11C]befloxatone. In comparison to nonsmokers, smokers showed a significant overall reduction of [11C]befloxatone binding potential (BP) in cortical areas (average reduction, -60%) and a similar trend in caudate and thalamus (-40%). Our findings confirm a widespread inhibition of cerebral MAO-A in smokers. This mechanism may contribute to tobacco addiction and for a possible mood-modulating effect of tobacco. © 2009, Lippincott, Williams & Wilkins
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    Decrease of nicotinic receptors in the nigrostriatal system in Parkinson's disease
    (Nature Publishing Group, 2009-09) Kas, A; Bottlaender, MA; Gallezot, JD; Vidailhet, M; Villafane, G; Grégoire, MC; Coulon, CM; Valette, H; Dollé, F; Ribeiro, MJ; Hantraye, P; Remy, P
    Smoking is associated with a lower incidence of Parkinson's disease (PD), which might be related to a neuroprotective action of nicotine. Postmortem studies have shown a decrease of cerebral nicotinic acetylcholine receptors (nAChRs) in PD. In this study, we evaluated the decrease of nAChRs in PD in vivo using positron emission tomography (PET), and we explored the relationship between nAChRs density and PD severity using both clinical scores and the measurement of striatal dopaminergic function. Thirteen nondemented patients with PD underwent two PET scans, one with 6-[18F]fluoro-3,4-dihydroxy-L-phenylalanine (6-[18F]fluoro-L-DOPA) to measure the dopaminergic function and another with 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine (2-[18F]fluoro-A-85380), a radiotracer with high affinity for the nAChRs. Distribution volumes (DVs) of 2-[18F]fluoro-A-85380 measured in the PD group were compared with those obtained from six nonsmoking healthy controls, with regions-of-interest and voxel-based approaches. Both analyses showed a significant (P <0.05) decrease of 2-[18F]fluoro-A-85380 DV in the striatum (−10%) and substantia nigra (−14.9%) in PD patients. Despite the wide range of PD stages, no correlation was found between DV and the clinical and PET markers of PD severity. © 2009, Nature Publishing Group.
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    In vivo quantification of monoamine oxidase A in baboon brain: a PET study using [C-11]befloxatone and the multi-injection approach.
    (Nature Publishing Group, 2010-04-01) Bottlaender, MA; Valette, H; Delforge, J; Saba, W; Guenther, I; Curet, O; George, P; Dollé, F; Grégoire, MC
    [C-11]befloxatone is a high-affinity, reversible, and selective radioligand for the in vivo visualization of the monoamine oxidase A (MAO-A) binding sites using positron emission tomography (PET). The multi-injection approach was used to study in baboons the interactions between the MAO-A binding sites and [C-11] befloxatone. The model included four compartments and seven parameters. The arterial plasma concentration, corrected for metabolites, was used as input function. The experimental protocol-three injections of labeled and/or unlabeled befloxatone-allowed the evaluation of all the model parameters from a single PET experiment. In particular, the brain regional concentrations of the MAO-A binding sites (B-max(')) and the apparent in vivo befloxatone affinity (K-d) were estimated in vivo for the first time. A high binding site density was found in almost all the brain structures (170 +/- 39 and 194 +/- 26 pmol/mL in the frontal cortex and striata, respectively, n = 5). The cerebellum presented the lowest binding site density (66 +/- 13 pmol/mL). Apparent affinity was found to be similar in all structures (KdVR = 6.4 +/- 1.5 nmol/L). This study is the first PET-based estimation of the B-max of an enzyme. © 2010, Nature Publishing Group.
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    Quantification of cerebral nicotinic acetylcholine receptors by PET using 2-[18F]fluoro-A-85380 and the multiinjection approach
    (Nature Publishing Group, 2008-01-01) Gallezot, JD; Bottlaender, MA; Delforge, J; Valette, H; Saba, W; Dollé, F; Coulon, CM; Ottaviani, MP; Hinnen, F; Syrota, A; Grégoire, MC
    The multiinjection approach was used to study in vivo interactions between α4β2* nicotinic acetylcholine receptors and 2-[18F]fluoro-A-85380 in baboons. The ligand kinetics was modeled by the usual nonlinear compartment model composed of three compartments (arterial plasma, free and specifically bound ligand in tissue). Arterial blood samples were collected to generate a metabolite-corrected plasma input function. The experimental protocol, which consisted of three injections of labeled or unlabeled ligand, was aiming at identifying all parameters in one experiment. Various parameters, including B′max (the binding sites density) and KdVR (the apparent in vivo affinity of 2-[18F]fluoro-A-85380) could then be estimated in thalamus and in several receptor-poor regions. B′max estimate was 3.0±0.3 pmol/mL in thalamus, and ranged from 0.25 to 1.58 pmol/mL in extrathalamic regions. Although KdVR could be precisely estimated, the association and dissociation rate constants kon/VR and koff could not be identified separately. A second protocol was then used to estimate koff more precisely in the thalamus. Having estimated all model parameters, we performed simulations of 2-[18F]fluoro-A-85380 kinetics to test equilibrium hypotheses underlying simplified approaches. These showed that a pseudo-equilibrium is quickly reached between the free and bound compartments, a favorable situation to apply Logan graphical analysis. In contrast, the pseudo-equilibrium between the plasma and free compartments is only reached after several hours. The ratio of radioligand concentration in these two compartments then overestimates the true equilibrium value, an unfavorable situation to estimate distribution volumes from late images after a bolus injection. © 2008, Nature Publishing Group.
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    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, I; 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.