D. Comar

Neuroanatomical Correlates of Visually Evoked Sexual Arousal in Human Males

Brain areas activated in human male sexualbehavior have not been characterized precisely. For thefirst time, positron emission tomography (PET) was usedto identify the brain areas activated in healthy males experiencing visually evoked sexualarousal. Eight male subjects underwent six measurementsof regional brain activity following the administrationof [15O]H2O as they viewedthree categories of film clips: sexually explicit clips,emotionally neutral control clips, and humorous controlclips inducing positive but nonsexual emotions.Statistical Parametric Mapping was used to identifybrain regions demonstrating an increased activity associatedwith the sexual response to the visual stimulus.Visually evoked sexual arousal was characterized by athreefold pattern of activation: the bilateralactivation of the inferior temporal cortex, a visualassociation area; the activation of the right insula andright inferior frontal cortex, which are two paralimbicareas relating highly processed sensory information with motivational states; and the activation ofthe left anterior cingulate cortex, another paralimbicarea known to control autonomic and neuroendocrinefunctions. Activation of some of these areas was positively correlated with plasma testosteronelevels. Although this study should be consideredpreliminary, it identified brain regions whoseactivation was correlated with visually evoked sexualarousal in males.

Functional Anatomy of Perceptual and Semantic Processing for Odors

The functional anatomy of perceptual and semantic processings for odors was studied using positron emission tomography (PET). The first experiment was a pretest in which 71 normal subjects were asked to rate 185 odorants in terms of intensity, familiarity, hedonicity, and comestibility and to name the odorants. This pretest was necessary to select the most appropriate stimuli for the different cognitive tasks of the second experiment. The second one was a PET experiment in which 15 normal subjects were scanned using the water bolus method to measure regional cerebral blood flow (rCBF) during the performance in three conditions. In the first (perceptual) condition, subjects were asked to judge whether an odor was familiar or not. In the second (semantic) condition, subjects had to decide whether an odor corresponded to a comestible item or not. In the third (detection) condition, subjects had to judge whether the perceived stimulus was made of an odor or was just air. It was hypothetized that the three tasks were hierarchically organized from a superficial detection level to a deep semantic level. Odorants were presented with an air-flow olfactometer, which allowed the stimulations to be synchronized with breathing. Subtraction of activation images obtained between familiarity and control judgments revealed that familiarity judgments were mainly associated with the activity of the right orbito-frontal area, the subcallosal gyrus, the left inferior frontal gyrus, the left superior frontal gyrus, and the anterior cingulate (Brodmanns areas 11, 25, 47, 9, and 32, respectively). The comestibility minus familiarity comparison showed that comestibility judgments selectively activated the primary visual areas. In contrast, a decrease in rCBF was observed in these same visual areas for familiarity judgments and in the orbitofrontal area for comestibility judgments. These results suggest that orbito-frontal and visual regions interact in odor processing in a complementary way, depending on the task requirements.

Labelling and metabolism of methionine-methyl-11C

Carbon 11 which is a 20.4 minutes half life isotope emitting positrons was used for methionine labelling on the methyl group by action of 11C-methyl-iodide on DL or L homocysteine. With the method described, 20 to 30 mCi of 11C-methyl-methionine (Specific activity 50 mCi/μM) may be obtained within 25 minutes. The 20 Mev proton beam used for 11C production was 10 μA. The metabolism of 11C methionine studied on mice shows a high uptake in pancreas and to a smaller extent in brain. On humans sequential images were obtained at the head level which allowed measurement of the uptake of the radio-labelled compound in the brain so as to study the radioactivity curve in different parts of the organ.

Synthesis of ethyl 8-fluoro-5,6-dihydro5- [11C]methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylate (RO 15.1788-11C): A specific radioligand for the in vivo study of central benzodiazepine receptors by positron emission tomography

A method of labelling ethyl 8-fluoro-5,6-dihydro-5-[11C]methyl-6-oxo-4H-imidazo[1,5-a][1,4] benzodiazepine-3-carboxylate (RO 15.1788 11C), a benzodiazepine antagonist with carbon-11 has been developed. RO 15.1788-11C was prepared by methylation of the nor derivative by I11CH3. About 100 mCi (maximum 153 mCi, 5.66 GBq) of the chemically and radiochemically pure labelled product were obtained within 25 min with a specific activity on average of 1100 mCi/mumol (maximum 1740 mCi/mu mol--64.4 GBq/mu mol). Preliminary results obtained after i.v. administration in the baboon have shown RO 15.1788-11C to be of interest as a benzodiazepine radioligand for the in vivo study of benzodiazepine receptors by positron emission tomography.

Kinetics and displacements of [11C]RO 15-1788, a benzodiazepine antagonist, studied in human brain in vivo by positron tomography

The brain regional distribution and kinetics of RO 15-1788, a benzodiazepine (BZD) antagonist labeled with 11C was studied by time-of-flight positron tomography after intravenous injection in four normal human volunteers. In two control studies, there was a high uptake of [11C]RO 15-1788 in gray matter structures initially (brain/blood ratio approximately 3), and subsequent retention that was highest in cerebral cortex, a structure known to have a high density of BZD receptors in vitro. Variation in tissue kinetics of [11C]RO among different gray matter structures may, however, suggest regional differences in binding characteristics or environment of BZD receptors. In two displacement studies, unlabeled RO 15-1788 was injected ten minutes after the radioligand: there was an immediate and marked washout of [11C]brain radioactivity that reached 70% in the occipital cortex with a 0.05 mg/kg dose (indicating a high specific to non-specific binding ratio) but was less prominent with a 0.01 mg/kg dose. These data suggest that [11C]RO 15-1788 may be useful for in vivo mapping of human brain BZD receptors using positron tomography.

Automated synthesis of 11C-labelled radiopharmaceuticals: imipramine, chlorpromazine, nicotine and methionine.

Abstract This article describes a method by which about a hundred mCi of different radiopharmaceuticals (imipramine, chlorpromazine, nicotine or methionine) may be prepared in 30–35 min with no irradiation risk to the operators. All operations (preparation of precursor, methylation of the monodesmethyl derivative, purification and sterilisation of the end product) are carried out in a closed shielded hood. The passage of fluids from one reaction tube to another through flexible teflon capillaries is controlled by electrovalves and purification is achieved by HPLC. The end products are chromatographically pure, sterile and apyrogenic. Their specific radioactivity at the time of use averages 500 mCi/μmol (maximum 1.0 Ci/μmol).

Synthesis of methyl iodide-11C and formaldehyde-11C

Abstract A fast 2-stage method of preparing formaldehyde-11C and methyl iodide-11C is described. 11CO2 is reduced to methanol-11C by LiAlH4 in THF, this product leading to formaldehyde-11C by oxidation on a silver catalyst, or to methyl iodine-11C by reaction with hydriodic acid. By means of these two molecules it is easy to methylate certain chemical groups and the method has been used to label substances of biological interest for research in vivo. The specific activity at the moment of use is 20 to 30 mCi/μmole, which indicates a high isotopic dilution.

Central type benzodiazepine binding sites: A positron emission tomography study in the baboon's brain

An in vivo characterization of specific central type benzodiazepine (BZD) binding sites, labelled with [11C]Ro 15-1788 was performed, using positron emission tomography. After i.v. injection of 10 mCi [11C]Ro 15-1788 (corresponding to 1 nmol/kg), sequential quantitative tomographic slices of the brain were obtained during 80 min. In some experiments various doses of different cold drugs (BZD agonist or antagonist) were injected i.v. subsequently in order to explore the specificity of the binding of the radioligand in brain structures. The main criteria usually utilized in vitro to demonstrate a specific binding to receptors, such as regional distribution, stereospecificity and saturability of the binding and pharmacological effect linked to the receptors occupancy, were demonstrated in the brain of a living baboon.

Nicotine-11C: Synthesis and distribution kinetics in animals

In order to study “in vivo” the distribution kinetics of (-)-nicotine in animals, this molecule was labeled with carbon-11. Two synthesis methods are described. Immediately after intravenous administration of (-)-nicotine-methyl-11C in rabbits the gamma-camera shows a strong radioactivity build-up in the brain and kidneys. The biological interest of this carbon-11 labeled molecule is discussed.

High specific activity carbon-11 labelling of benzodiazepines: Diazepam and flunitrazepam

In order to study “in vivo” the brain specific receptor sites of benzodiazepines, a method for carbon-11 labelling of diazepam and flunitrazepam without irradiation risk to personnel is described. 70 mCi (max. 140 mCi) of injectable labelled product, chemically and radiochemically pure, are obtained in 45 minutes with a specific activity of 810 Ci/m mole.