Browsing by Author "Delforge, J"

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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.