Michel Monclus

Sex difference in 5HT2 receptor in the living human brain

Serotonergic mechanisms are involved in gender-related behaviors and psychiatric conditions like aggression, eating disorders, depression, impulsivity or suicide. We studied gender differences in the living human brain type-2 serotonin receptor (5HT2r). Twenty-two healthy age-matched men and women were investigated using positron emission tomography and the selective radiotracer, 18F-labeled altanserin. Binding was quantified using a non-linear least-squares minimization procedure. We found significantly higher 5HT2r binding capacity in men than in women, especially in the frontal and cingulate cortices. Distinct liability for men and women to suffer from some psychiatric disorders responding to serotonergic agents may be related to differences in brain serotonin receptors.

Multicompartmental study of fluorine-18 altanserin binding to brain 5HT2 receptors in humans using positron emission tomography

Serotoninergic type 2 (5HT2) receptors have been implicated in the regulation of many brain functions in humans and may play a role in several neurological and psychiatric diseases. Fluorine-18 altanserin has been proposed as a new radiotracer for the study of 5HT2 receptors by PET because of its high affinity for 5HT2 receptors (Ki: 0.13 nM) and its good specificity in in vitro studies. Dynamic PET studies were carried out in 12 healthy volunteers after intravenous injection of 0.1 mCi/kg [18F]altanserin. Ninety minutes after injection, we observed mainly cortical binding. Basal ganglia and cerebellum showed very low uptake and the frontal cortex to cerebellum ratio was about 3. To evaluate the quantitative distribution of this ligand in the brain, we used two different methods of data analysis: a four-compartment model was used to achieve quantitative evaluation of rate constants (K1 and k2 through k6) by non-linear regression, and a multiple-time graphical analysis technique for reversible binding was employed for the measurement of k1/k2 and k3/k4 ratios. Using both methods, we found significant differences in binding capacity (estimated by k3/k4 = Bmax/Kd) between regions, the values increasing as follows: occipital, limbic, parietal, frontal and temporal cortex. After correction of values obtained by the graphical method for the existence of non-specific binding, results generated by the two methods were consistent.

External globus pallidus stimulation modulates brain connectivity in Huntington's disease.

Positron emission tomography with O-15-labeled water was used to study at rest the neurophysiological effects of bilateral external globus pallidus (GPe) deep brain stimulation in patients with Huntingtons disease (HD). Five patients were compared with a control group in the on and off states of the stimulator. External globus pallidus stimulation decreased neuronal activity and modulated cerebral connectivity within the basal ganglia-thalamocortical circuitry, the sensorimotor, and the default-mode networks. These data indicate that GPe stimulation modulates functional integration in HD patients in accordance with the basal ganglia-thalamocortical circuit model.

Development of a positron emission tomography radiopharmaceutical for imaging thymidine kinase gene expression: Synthesis and in vitro evaluation of 9-{3-[18F] Fluoro-1-hydroxy-2-propoxymethyl guanine

9-[(3-fluoro-1-hydroxy-2-propoxy)methyl]guanine (FHPG) 2 has been labeled with fluorine-18 and evaluated in vitro as a potential radiotracer for mapping gene expression in vivo with positron emission tomography (PET).

In vivo binding of [18F]altanserin to rat brain 5HT2 receptors: A film and electronic autoradiographic study

To further validate its use in positron emission tomography (PET), we studied the binding of [18F]altanserin, a specific 5HT2 radioligand, in the rat brain using in vivo autoradiography. Distribution of [18F]altanserin binding was comparable to the in vitro mapping of 5HT2 receptors reported in the literature. Selective displacers were used to test the reversibility and the selectivity of this radioligand. Specific binding of [18F]altanserin in the rat frontal cortex was quantified by direct counting with an electronic imaging system and by quantification on digitalized autoradiograms. Close results of about 30 pmol/g were obtained with both methods. Our data confirmed that [18F]altanserin is a valid tracer for 5HT2 receptors binding studies.

Effect of catechol-O-methyl transferase inhibition on peripheral and central metabolism of 6-[18F]fluoro-L-DOPA

In the presence of carbidopa, L-3,4-dihydroxy-6-[18F]fluorophenylalanine ([18F]fluoro-DOPA) is mainly metabolized by catechol-O-methyl transferase. We studied the effects of entacapone, a peripheral catechol-O-methyl transferase inhibitor, on striatal [18F]fluoro-DOPA uptake in rats. Rats were pretreated with carbidopa, entacapone or both before high specific activity (> 2 Ci/mmol) [18F]fluoro-DOPA administration. Entacapone alone antagonized the appearance of methylated metabolites in plasma, striatum and cerebellum but did not increase striatal [18F]fluoro-DOPA availability. Entacapone added to carbidopa significantly increased the striatum/cerebellum total radioactivity ratio (1.4 versus 1.2 in rats with carbidopa, 1.0 in controls) but significant levels of methylated metabolites were found in the brain. Entacapone added to carbidopa might increase the striatum/cerebellum total radioactivity ratio in humans undergoing [18F]fluoro-DOPA positron emission tomography (PET) studies. However, the appearance of methylated metabolites in the brain could hamper quantification of the PET data.

Production, automatic delivery and bolus injection of [15O]water for positron emission tomography studies

An automatic system allowing repetitive bolus injection of oxygen-15-labeled water for PET studies is described in this report. The production of this radiopharmaceutical by the 16O(p,pn)15O nuclear reaction on H2(16O), its purification and delivery nearby the PET camera, the injection system, and the quality controls are presented.

Asymmetric synthesis of fluorinated l-tyrosine and meta-l-tyrosines

Abstract A convenient asymmetric synthesis of (2S)-2-amino-3-(2-fluoro-5-hydroxyphenyl) propanoic acid, (2S)-2-amino-3-(4-fluoro-3-hydroxyphenyl) propanoic acid and (2S)-2-amino-3-(2-fluoro-4-hydroxyphenyl) propanoic acid is described. Key steps include the synthesis of the benzyl bromides, the alkylation of the glycine enolate derivative ((S)-Boc-BMI) and the hydrolysis of the alkylated Boc-BMI.

Automatic Synthesis of [18F]Altanserin, a Radiopharmaceutical for Positron Emission Tomographic Studies of the Serotonergic Type-2 Receptors

[(18)F]Altanserin is routinely used in several centers to study the serotonergic type-2 receptors (5HT(2)) with positron emission tomography (PET). An automatic production system allowing the preparation of multimillicurie amounts [>1.5 GBq (40 mCi) EOS, mean radiochemical yield 20 +/- 6% EOB, specific activity >1 Ci/μmol, n = 50] of this radiopharmaceutical within a synthesis time of 90 minutes (quality controls included) is described in this paper. The apparatus includes the recovery of the activity from the target, the preparation of the dried [(18)F]KF/kryptofix 2.2.2 complex, the labeling reaction using a microwave cavity, the Sep Pak and HPLC purification. A sterile, pyrogen-free and single use unit was also developed for the formulation of the injectable solution. This last part could be used for the formulation of many other radiopharmaceuticals.

[18F]-FBEM, a tracer targeting cell-surface protein thiols for cell trafficking imaging.

We used [(18)F]-4-fluorobenzamido-N-ethylamino-maleimide ([(18)F]-FBEM) to radiolabel cells ex vivo for in vivo positron emission tomography (PET) in order to assess cell trafficking in mice. In contrast to commonly used imaging agents, [(18)F]-FBEM forms a covalent bond with thiol groups present on the cells surface. The stability of the probe in aqueous medium was tested at different pH values and cross-experiment showed that thiol-labeling efficiency was retained (at least) up to pH 9. The labeling procedure did not affect significantly the cell viability. To illustrate the procedure, PET images of living mice injected intravenously with labeled T lymphocytes were obtained. They showed the expected cell homing in the spleen that was absent in mice injected with free label.