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Previous [(11)C]WAY100-635 PET studies have demonstrated that the short (S) and long (L) alleles of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) were associated with distinct patterns of 5-HT(1A) receptor distribution in human. However, these studies reported discordant findings and did not take into account the recent description of two functional variants of the L allele (L(A)/L(G)). To further explore this issue, we investigated the triallelic functional polymorphism of the 5-HTTLPR in 38 healthy volunteers who underwent a [(18)F]MPPF PET study of 5-HT1A receptors. We used a simplified reference tissue model to generate parametric images of [(18)F]MPPF binding potential (BP(ND)), and compared these data among the different genotypes using statistical parametric mapping and region of interest of the raphe nuclei. Homozygote carriers of the S allele demonstrated greater [(18)F]MPPF BP(ND) than carriers of the L(A) allele, but this association was only found in women. Differences in [(18)F]MPPF BP(ND) between women with and without L(A) allele were observed over large clusters encompassing the right and left temporal lobes, cingulate and perisylvian regions, as well as the right precuneus and frontal dorso-lateral cortex, and the left orbitofrontal cortex. In contrast, no difference was found between groups in the raphe nuclei. The greater [(18)F]MPPF BP(ND) observed in women homozygote carriers of the S allele could either reflect a greater 5-HT1A receptor density or a lower extracellular concentration of 5-HT. Our data suggest that any future PET studies of 5-HT1A receptors should incorporate the 5-HTTLPR polymorphism status of the population studied.

Introduction 5-hydroxytryptamine (5-HT) 6 receptors represent one of the more recently discovered serotoninergic receptor family. However, no 5-HT 6 positron emission tomography (PET) radiotracer is currently used in clinical imaging studies. The purpose of this study was to propose the first fluorinated PET radiotracer for this brain receptor. Methods A new compound presenting in vitro high affinity towards the serotoninergic 5-HT 6 receptor, N -[2-(1-[(4-fluorophenyl)sulfonyl]-1 H -indol-4-yloxy)ethyl] -N , N -dimethylamine, was labelled with fluorine 18 via a nitro-/fluoronucleophilic substitution. Biological evaluations included (i) in vitro and ex vivo autoradiographies in rat brain and (ii) a PET scan on anaesthetized cat. Results and Conclusion Although the radioligand showed excellent brain penetration, it did not reveal any specific binding to the 5-HT 6 receptors indicating that this radiotracer is not suitable for mapping 5-HT 6 receptors using PET.

3'-Deoxy-3'-[18F]fluorothymidine ([18F]-FLT) has recently been described as a positron emission tomography (PET) radiopharmaceutical for visualizing cellular proliferation in vivo. All published radiosyntheses of [18F]-FLT provide crude products that must be purified before injection to human. This study describes a reliable purification procedure for [18F]-FLT. It is based on HPLC. In 17.9+/-0.5 min, pure [18F]-FLT is obtained that could be injected to human after a passage through a sterile 0.22 microm filter.

Resume Le [18F]MPPF est un traceur antagoniste des recepteurs 5-HT1A de la serotonine marque par le fluor 18 qui permet d’obtenir par tomographie par emission de positons une imagerie moleculaire et fonctionnelle des recepteurs 5-HT1A.

The aim of this study was to assess the reliability of 2′-methoxyphenyl-(N-2′-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine (18F-MPPF) PET binding parameter9s quantification via a test–retest study over a long-term period. Methods: Ten healthy volunteers underwent 2 dynamic 18F-MPPF PET scans in an interval of 6 mo. As a methodologic control, 10 simulated datasets, including interindividual functional and anatomic variabilities, were also used to assess the measurement variations in the absence of intraindividual variability. Indices of tracer binding were computed using 2 different models: (a) the simplified reference tissue model (SRTM) and (b) the Logan graphical model. The SRTM allows computing the binding potential (BP) index and plasma-to-brain transport constants (R1, k2). The Logan model evaluates the distribution volume (DV). For both methods, cerebellum was taken as the reference region. From both models, binding indices were calculated with time–activity curves extracted from regions of interest, on one hand, and for each voxel to perform parametric images on the other hand. Results: Reliability indices—that is, bias, variability, and intraclass correlation (ICC)—indicated a good reproducibility: the BP percentage change in mean between test and retest is close to 1% in rich regions and 2% in poor regions. The typical error is around 7%. Mean ICC is over 0.70. The DV percentage change in the mean is ±2.5%, with a typical error close to 6% and an ICC over 0.60. Conclusion: Our results show a good reliability, with a reasonable level of intraindividual biologic variability that allows crossover studies with 18F-MPPF in which small percentage changes are expected between test and retest measurements, in group studies and for single subject assessment.

The α-trifluoromethylthiolation of carbonyl compounds in soft acidic conditions has been developed. With this method only mono-trifluoromethylthiolation was selectively observed. Base-sensitive ketones can then be trifluoromethylthiolated. More sensitive aldehydes are also trifluoromethylthiolated under these conditions with good yields. This work provides a new route towards the synthesis of various valuable trifluoromethylthiolated molecules.

International audience; Serotonergic (5-HT) neurons degenerate in Parkinson's disease. To determine the role of this 5-HT injury-besides the dopaminergic one in the parkinsonian symptomatology-we developed a new monkey model exhibiting a double dopaminergic/ serotonergic lesion by sequentially using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3,4-methylenedioxy-N-methamphetamine (MDMA, better known as ecstasy). By positron emission tomography imaging and immunohistochemistry, we demonstrated that MDMA injured 5-HT nerve terminals in the brain of MPTP monkeys. Unexpectedly, this injury had no impact on tremor or on bradykinesia, but altered rigidity. It abolished the L-DOPA-induced dyskinesia and neuropsychiatric-like behaviours, without altering the anti-parkinsonian response. These data demonstrate that 5-HT fibres play a critical role in the expression of both motor and non-motor symptoms in Parkinson's disease, and highlight that an imbalance between the 5-HT and dopaminergic innervating systems is involved in specific basal ganglia territories for different symptoms.

Experimental data in animals show that 5-HT(1A) receptors are predominantly located in limbic areas and suggest that serotonin, via these receptors, mediates an antiepileptic and anticonvulsant effect. In this PET study, we used an antagonist of the 5-HT(1A) receptor, [(18)F]MPPF, to assess the extent of 5-HT(1A) receptor binding changes in a group of seven temporal lobe epilepsy (TLE) patients with hippocampal ictal onset demonstrated by intracerebral EEG recording. On the basis of MRI-measured hippocampal volumes (HV), patients were classified into "normal HV" or "hippocampal atrophy" (HA). Voxel-based analyses (SPM99) were performed to objectively assess the differences in [(18)F]MPPF binding potential (BP) between patients (taken as a group or as individuals) and a database of 48 controls subjects. In the full group of patients, a significant decreased BP was detected ipsilateral to the epileptogenic zone in the hippocampus, temporal pole, insula, and temporal neocortex. This result was confirmed in the subgroup of patients with HA. In patients with normal HV, the BP decrease was restricted to the temporal pole. TLE patients also demonstrated an increased BP in various regions contralateral to the epileptogenic zone. These data suggest that in TLE patients with hippocampal seizure onset, the decrease in 5-HT(1A) receptor binding partly reflects hippocampal neuronal loss, but is also observed in various regions involved in temporo-limbic epileptogenic networks that appeared normal on MRI. Further studies are warranted to evaluate the clinical usefulness of [(18)F]MPPF-PET as compared to other established PET tracers in drug resistant TLE.

International audience; In Parkinson's disease, functional imaging studies during limb motor tasks reveal cerebral activation abnormalities that can be reversed by subthalamic nucleus (STN) stimulation. The effect of STN stimulation on parkinsonian dysarthria has not, however, been investigated using PET. The aim of the present study was to evaluate the effect of STN stimulation on regional cerebral blood flow (rCBF) during speech production and silent articulation in patients with Parkinson's disease. Ten Parkinson's disease patients surgically implanted bilaterally in the STN and with significant improvement of their dysarthria induced by STN stimulation were included. Ten healthy control subjects also participated in this study. Control subjects performed six sessions of [15O]H2O±PET scanning corresponding to three duplicated conditions externally cued by an auditory signal. The conditions were: (i) rest; (ii) production of a short, simple sentence; and (iii) silent articulation of the same sentence. Parkinson's disease patients carried out the six PET sessions twice, i.e., in the ON and OFF STN stimulation states. PET data analysis was performed using statistical parametric mapping (SPM99). In control subjects, speech production (SP) compared with rest was associated with increased rCBF bilaterally in the primary motor cortex (M1) corresponding to the orofacial somatotopy, the supplementary motor area (SMA), the associative auditory cortex and the cerebellar hemispheres. Silent articulation (SA) compared with rest induced a bilateral rCBF increase restricted to the orofacial M1 and cerebellar hemispheres. In Parkinson's disease patients in the OFF stimulation condition, during both SP and SA there was a lack of activation in the right orofacial M1 and in the cerebellum, abnormal increased rCBF in the right superior premotor cortex, and overactivation of the SMA. There was also an abnormal, increased rCBF in the dorsolateral prefrontal cortex (DLPFC) only during SP and increased rCBF in the left insula only during SA. In Parkinson's disease patients ON stimulation, for both SP and SA the activation pattern appeared similar to that in control subjects. In conclusion, our results suggest that parkinsonian dysarthria is associated with altered recruitment of the main motor cerebral regions (orofacial M1, cerebellum), and increased involvement of the premotor and prefrontal cortices (DLPFC, SMA, superior premotor cortex). These abnormal activations are different from those reported during hand motor tasks. They could be a compensatory mechanism, but might also arise directly as part of the pathophysiology of Parkinson's disease. STN stimulation tends to reverse these abnormal activations, which is consistent with the observed improvement of Parkinson's disease dysarthria.

The aim of our study was to assess abnormalities in 5-hydroxytryptamine-1A (5-HT1A) receptor density in patients suffering from refractory temporal lobe epilepsy (TLE). Experimental data in animals show that 5-HT1A receptors are predominantly located in limbic areas, and that serotonin, via these receptors, mediates an antiepileptic and anticonvulsant effect. In TLE patients, we quantified 5-HT1A receptor density in epileptogenic and non-epileptogenic areas, as defined by intracranial recordings with stereo-electroencephalography (SEEG). Nine TLE patients and 53 control subjects were studied by PET using a 5-HT1A receptor antagonist ([18F]MPPF). Anatomical regions of interest (ROIs) were drawn on patient and control MRIs co-registered with PET. PET data were quantified using a simplified model to assess binding potential (BP) values in each ROI, with cerebellum as reference. For each patient, a normalized percentage BP change was calculated as the relative variation of BP in each ROI compared with the corresponding ROI in control subjects. In patients, ROIs explored by SEEG were categorized according to their degree of epileptic activity (ictal onset, ictal spreading, interictal spikes, no epileptic activity) and according to their lesional aspect and volume (lesional with volume loss, lesional without volume loss, non-lesional). Compared with control values, the binding to 5-HT1A receptors in TLE patients was decreased in the epileptogenic temporal lobe. BP decrease was significantly greater in: (i) regions involved in the seizure onset than regions where only interictal paroxysms or no epileptic activity was recorded; and (ii) regions where the discharge propagated than regions where only interictal paroxysms or no epileptic activity was recorded. BP decrease was shown to be significantly influenced by the existence of a lesion on MRI. However, in the group of ROIs with normal quantitative and qualitative MRI aspect, BP decrease remained strongly correlated to the degree of epileptic activity. This study shows that in vivo availability of 5-HT1A receptors is decreased in epileptic patients compared with normal subjects. This decrease is highly correlated to the degree of epileptogenicity of cortical areas explored by intracerebral recordings, and does not reflect only pathological changes or neuronal loss in the epileptic focus.

Although hypoactive sexual desire disorder (HSDD) is a common condition and has long been hypothesized to result from malfunctions of the cerebral control mechanisms that adjust the level of sexual motivation, very little is known about the pathophysiology of this disorder. The primary objective was to identify in patients with HSDD brain regions where functional perturbations disrupt the regulation of sexual motivation. We used positron emission tomography to compare seven male patients with HSDD with eight healthy men on their regional cerebral blood flow responses to visual sexual stimuli (VSS) of graded intensity. Statistical Parametric Mapping was used to locate brain regions that demonstrated a differential activation (or deactivation) across the groups. Whereas in control subjects the medial orbitofrontal cortex showed a deactivation in response to VSS, in HSDD patients there was an abnormally maintained activity of this region, which has been implicated in the inhibitory control of motivated behavior. By contrast, the reverse pattern-activation in control subjects, deactivation or unchanged activity in patients-was found in the secondary somatosensory cortex and inferior parietal lobules, regions mediating emotional and motor imagery processes, as well as in those areas of the anterior cingulate gyrus and of the frontal lobes that are involved in premotor processes.

The selectivity of [18F]MPPF (fluorine-18-labeled 4-(2' -methoxyphenyl)-1-[2' -(N-2“-pirydynyl)-p-fluorobenzamido]ethylpiperazine) for serotonergic 5-hydroxytryptamine(1A) (5-HT1A) receptors has been established in animals and humans. The authors quantified the parameters of ligand-receptor exchanges using a double-injection protocol. After injection of a tracer and a coinjection dose of [18F]MPPF, dynamic positron emission tomography (PET) data were acquired during a 160-minute session in five healthy males. These PET and magnetic resonance imaging data were coregistered for anatomical identification. A three-compartment model was used to determine six parameters: Fv (vascular fraction), K1, k2 (plasma/free compartment exchange rate), koff, kon/Vr (association and dissociation rate), Bmax (receptor concentration), and to deduce Kd (apparent equilibrium dissociation rate). The model was fitted with regional PET kinetics and arterial input function corrected for metabolites. Analytical distribution volume and binding potential were compared with indices generated by Logan-Patlak graphical analysis. The 5HT1A specificity for MPPF was evidenced. A Bmax of 2.9 pmol/mL and a Kd of 2.8 nmol/L were found in hippocampal regions, Kd and distribution volume in the free compartment were regionally stable, and the Logan binding potential was linearly correlated to Bmax. This study confirms the value of MPPF in the investigation of normal and pathologic systems involving the limbic network and 5-HT1A receptors. Standard values can be used for the simulation of simplified protocols.

International audience; Background Dysembryoplastic neuroepithelial tumors (DNTs) represent a prevalent cause of epileptogenic brain tumors, the natural evolution of which is much more benign than that of most gliomas. Previous studies have suggested that [11C]methionine positron emission tomography (MET-PET) could help to distinguish DNTs from other epileptogenic brain tumors, and hence optimize the management of patients. Here, we reassessed the diagnostic accuracy of MET-PET for the differentiation between DNT and other epileptogenic brain neoplasms in a larger population. Methods We conducted a retrospective study of 77 patients with focal epilepsy related to a nonrapidly progressing brain tumor on MRI who underwent MET-PET, including 52 with a definite histopathology. MET-PET data were assessed by a structured visual analysis that distinguished normal, moderately abnormal, and markedly abnormal tumor methionine uptake and by semiquantitative ratio measurements. Results Pathology showed 21 DNTs (40%), 10 gangliogliomas (19%), 19 low-grade gliomas (37%), and 2 high-grade gliomas (4%). MET-PET visual findings significantly differed among the various tumor types (P < .001), as confirmed by semiquantitative analyses (P < .001 for all calculated ratios), regardless of gadolinium enhancement on MRI. All gliomas and gangliogliomas were associated with moderately or markedly increased tumor methionine uptake, whereas 9/21 DNTs had normal methionine uptake. Receiver operating characteristics analysis of the semiquantitative ratios showed an optimal cutoff threshold that distinguished DNTs from other tumor types with 90% specificity and 89% sensitivity. Conclusions Normal MET-PET findings in patients with an epileptogenic nonrapidly progressing brain tumor are highly suggestive of DNT, whereas a markedly increased tumor methionine uptake makes this diagnosis unlikely.

We propose here a new methodology to prepare 3-fluoro-α-methylphenylalanine in which fluorine is introduced at the end of the synthesis, on an elaborated substrate bearing a triazeno substituent which is decomposed by triflic acid in the presence of fluoride anions (yield=31% versus 19 F − ). As 18 F − cannot be available free of other basic anions, this technique has been modified and adapted with some success to the radiosynthesis of [ 18 F ]-3-fluoro-α-methylphenylalanine.

Renal blood flow measurement by positron emission tomography using 15O-labeled water.BackgroundOnly few noninvasive methods have the potential to quantitate renal blood flow (RBF) in humans. Positron emission tomography (PET) is a clinical imaging method that can be used to measure the tissue blood flow noninvasively. The purpose of this study was to validate PET measurement of RBF using 15O-labeled water (H215O), a tracer that allows repeated measurements at short time intervals.MethodsRBF was measured in six pigs by PET and by radioactive microspheres (MS). Three measurements were performed in each pig at baseline (BL), during vascular expansion and dopamine infusion (DA; 20 μg · kg-1 · min-1 intravenously), and during angiotensin II (Ang II) infusion (50 ng · kg-1 · min-1 intravenously). RBF was estimated from aortic and renal tracer kinetics using a model adapted from the blood flow model described by Kety and Smith.ResultsPET and MS values correlated strongly (y = 0.79x + 42, r = 0.93, P < 0.0001) over the RBF range from 100 to 500 mL · min-1 · 100 g-1. Pharmacologically induced changes were significant and were measured equally well by PET and MS: 38 and 39%, respectively, below BL (P < 0.005 and P < 0.05) under Ang II, and 47 and 48%, respectively, above BL (P < 0.005 and P < 0.01) under DA. A Bland and Altman representation showed a low average difference of -17 ± 45 mL · min-1 · 100 g-1 (mean ± SD).ConclusionTo our knowledge, this study provides the first validation of RBF measurement by PET using H215O over a large range of RBF values (100 to 500 mL · min-1 · 100 g-1), which correspond to RBF values in both healthy subjects and in patients suffering from chronic renal failure.

International audience; Template Brain PET MRI MRI templates and digital atlases are needed for automated and reproducible quantitative analysis of non-human primate PET studies. Segmenting brain images via multiple atlases outperforms single-atlas labelling in humans. We present a set of atlases manually delineated on brain MRI scans of the monkey Macaca fascicularis. We use this multi-atlas dataset to evaluate two automated methods in terms of accuracy, robustness and reliability in segmenting brain structures on MRI and extracting regional PET measures. Methods: Twelve individual Macaca fascicularis high-resolution 3DT1 MR images were acquired. Four individual atlases were created by manually drawing 42 anatomical structures, including cortical and sub-cortical structures, white matter regions, and ventricles. To create the MRI template, we first chose one MRI to define a reference space, and then performed a two-step iterative procedure: affine registration of individual MRIs to the reference MRI, followed by averaging of the twelve resampled MRIs. Automated segmentation in native space was obtained in two ways: 1) Maximum probability atlases were created by decision fusion of two to four individual atlases in the reference space, and transformation back into the individual native space (MAXPROB). 2) One to four individual atlases were registered directly to the individual native space, and combined by decision fusion (PROPAG). Accuracy was evaluated by computing the Dice similarity index and the volume difference. The robustness and reproducibility of PET regional measurements obtained via automated segmentation was evaluated on four co-registered MRI/PET datasets, which included test-retest data. Results: Dice indices were always over 0.7 and reached maximal values of 0.9 for PROPAG with all four individual atlases. There was no significant mean volume bias. The standard deviation of the bias decreased significantly when increasing the number of individual atlases. MAXPROB performed better when increasing the number of atlases used. When all four atlases were used for the MAXPROB creation, the accuracy of morphometric segmen-tation approached that of the PROPAG method. PET measures extracted either via automatic methods or via the manually defined regions were strongly correlated, with no significant regional differences between methods. Intra-class correlation coefficients for test-retest data were over 0.87. Conclusions: Compared to single atlas extractions, multi-atlas methods improve the accuracy of region definition. They also perform comparably to manually defined regions for PET quantification. Multiple atlases of Macaca fascicularis brains are now available and allow reproducible and simplified analyses.

Vagal innervation modulates the electrical stability of the left ventricle (LV) during ischemia. Thus, abnormal parasympathetic activity in myocardial infarction (MI) patients with primary ventricular fibrillation (FV) can account for their arrhythmic disorders. We evaluated LV muscarinic receptor density (B max) after MI in patients with (FVG, n = 11) or without (nFVG, n = 12) primary FV. The B max was measured by positron emission tomography and the specific antagonist [11C]methylquinuclidinyl benzilate ([11C]MQNB) in 23 patients 39 ± 19 days post-MI, and 10 volunteers. Myocardial damage was quantified by delayed contrast-enhanced magnetic resonance imaging. Three short-axis slices per subject were analyzed and six time-activity curves per slice were fitted to a 3-compartment ligand-receptor model. The B max in remote regions of the 23 patients (67 ± 36 pmol/mL · tissue; n = 139) was higher than in normal regions of volunteers (33 ± 16 pmol/mL · tissue; n = 171; P = .01). Receptor density in remote regions was similarly upregulated in nFVG (69 ± 31 pmol/mL · tissue, n = 73) and FVG (66 ± 40 pmol/mL · tissue, n = 66; P = .72). In damaged regions, the B max was reduced in both patient groups (44 pmol/mL · tissue). Chronically infarcted patients with or without primary FV share similar patterns of ventricular muscarinic receptor remodeling, characterized by receptor upregulation, in remote non-damaged territories.

Serotonin (5-HT) neurotransmission plays a key modulatory role in the brain. This system is critical for pathophysiological processes and many drug treatments for brain disorders interact with its 14 subtypes of receptors. Positron emission tomography (PET) is a unique tool for the study of the living brain in translational studies from animal models to patients in neurology or psychiatry. This short review is intended to cover the current status of PET radioligands used for imaging human brain 5-HT receptors. Here, we describe the available PET radioligands for the 5-HT1A , 5-HT1B , 5-HT2A , 5-HT4 and 5-HT6 receptors. Finally, we highlight the future challenges for a functional PET imaging of serotonin receptors, including the research towards specific PET radiotracers for yet unexplored serotonin receptors, the need of radiotracers for endogenous serotonin level measurement and the contribution of agonist radiotracers for functional imaging of 5-HT neurotransmission.

International audience; Depression is frequent in Parkinson's disease, but its pathophysiology remains unclear. Two recent studies have investigated the role of serotonergic system at the presynaptic level. The objective of the present study was to use positron emission tomography and [18F]MPPF to investigate the role of postsynaptic serotonergic system dysfunction in the pathophysiology of depression in Parkinson's disease. Four parkinsonian patients with depression and 8 parkinsonian patients without depression were enrolled. Each patient underwent a scan using [18F]MPPF, a selective serotonin 1A receptor antagonist. Voxel‐by‐voxel statistical comparison of [18F]MPPF uptake of the 2 groups of parkinsonian patients and with 7 matched normal subjects was made using statistical parametric mapping (P uncorrected < .001). Compared with nondepressed parkinsonian patients, depressed patients exhibited reduced tracer uptake in the left hippocampus, the right insula, the left superior temporal cortex, and the orbitofrontal cortex. Compared with controls, nondepressed parkinsonian patients presented reduced [18F]MPPF uptake bilaterally in the inferior frontal cortex as well as in the right ventral striatum and insula. Compared with controls, [18F]MPPF uptake was decreased in depressed parkinsonian patients in the left dorsal anterior cingulate and orbitofrontal cortices, in the right hippocampic region, and in the temporal cortex. The present imaging study suggests that abnormalities in serotonin 1A receptor neurotransmission in the limbic system may be involved in the neural mechanisms underlying depression in patients with Parkinson's disease.

Brain serotonin 7 (5-hydroxytryptamine 7, or 5-HT(7)) is the most recently identified serotonin receptor. It is involved in mood disorders and is studied as a target for antidepressants. Because no radioligand has yet been successfully used to study this receptor by PET neuroimaging, the objective of the present study was to develop a 5-HT(7) (18)F-labeled radiotracer.Four structural analogs of SB269970, a specific 5-HT(7) receptor antagonist, were synthesized. The nitro precursors of these analogs were radiolabeled by (18)F nucleophilic substitution. Analog antagonist effects were investigated by cellular functional assay. The cerebral distribution of radiolabeled molecules was studied by in vitro autoradiography in rats, and respective selectivity was determined by competition with the 5-HT(7) receptor antagonist SB269970 at different concentrations. Ex vivo small-animal PET studies in rats and in vivo PET studies in cats focused on the 1-(2-{(2R)-1-[(fluorophenyl)sulfonyl]pyrrolidin-2-yl}ethyl)-4-methylpiperidine (FP3) series.Four analogs were synthesized from the SB269970 pharmacophore and divided into an FP3 ((18)F-4FP3 and (18)F-2FP3) and an 1-(2-{(2R)-1-[(fluorophenyl)sulfonyl]pyrrolidin-2-yl}ethyl)-4-(2-methoxyphenyl)piperazine (FPMP) ((18)F-2FPMP and (18)F-4FPMP) series. The chemical and radiochemical purities of the 4 radiolabeled molecules were greater than 98%. All presented suitable affinity for 5-HT(7) (apparent dissociation constant [K(D)] between 1.6 and 14 nM), although the FPMP series showed moderate agonist activity for 5-HT(1A) receptors. Lipophilicity values were predictive of good radiotracer blood-brain barrier penetration (logD from 1.4 to 3.9). In vitro competition with a 5-HT(7) antagonist, SB269970, revealed that only radioligands from the FP3 series were displaced by the 5-HT(7)-specific antagonist: subsequent in vivo study, therefore, focused on this series. Ex vivo (18)F-4FP3 and (18)F-2FP3 autoradiography was in accordance with the 5-HT(7) brain distribution, with few brain radioactive metabolites. PET scans in cats showed that pretreatment with a 5-HT(7) antagonist significantly reduced (18)F-2FP3 but not (18)F-4FP3 binding.The 4 PET radiotracers had suitable characteristics for 5-HT(7) receptor probing in vitro, although the FP3 series seemed to be more specific for in vivo imaging of 5-HT(7) receptors. In particular, on the basis of the in vivo results, (18)F-2FP3 appears to be the first PET radiotracer to enable in vivo imaging of 5-HT(7) receptors in animal models, possibly leading to neuroimaging studies in humans.

International audience; Neuroimaging studies are increasingly performed on non-human primates, including Macaca fascicularis. The analysis of functional imaging studies requires a corresponding anatomical image in order to identify brain structures. In the specific case of positron emission tomography (PET), anatomical correspondence is also required for quantification and modeling of interactions between the PET ligand and its pharmacological receptors. For voxel-based statistical parametric mapping, a reference frame (template) is needed to perform spatial normalization of individual brains. In this work we introduce a specific brain template and its associated atlas, with the purpose of enabling accurate, robust and reliable normalization and anatomical labeling of Macaca fascicularis brain images. Methods: Seven animals were included for template creation. For each, three high-resolution (0.6 mm 3) 3D T1 MRI scans were acquired and averaged for noise reduction. The atlas was created from the MRI of one subject by labeling 38 brain structures in three dimensions, following a precise manual delineation protocol. Regions included cortex, sub-cortical nuclei, brainstem, white matter and cerebrospinal fluid. The chosen MRI was then used as the target for an automatic iterative procedure of template creation: each MRI was subjected to automatic brain extraction, coregistered to the target with rigid-body transformations and resampled. Coregistered MRIs were averaged. The average brain was then coregistered to the original brain target to compensate for misalignment bias. The resulting image constituted the first template, and was used as the target for the next iteration. Iterations continued until each parameter of the coregistration of the ith template to the original target was below 0.3 mm and 1 arc degree. The final template was tested for accuracy, robustness and reproducibility as follows: accuracy was assessed by visually inspecting the normalized brain on the template, with positioning inspection of the brain structures of the atlas projected on individual MRI with the reverse normalization transform. Robustness was tested by normalizing a new set of MRIs coming from other individuals to the template. Reproducibility was tested on four of the seven monkeys which were also submitted to PET acquisitions with various tracers ([ 11 C] raclopride, [ 18 F]-dopa, [ 18 F]MPPF, [ 11 C]pe2i, and [ 11 C]DASB), with test-retest scans. Time-activity curves were extracted from manually delineated regions of interest (ROI), from automated delineated ROIs of the atlas on normalized data, and from atlases propagated to S174 NRM2010 abstracts-Poster presentations

In search of a serotonin 5-HT(7) radiotracer for positron emission tomography, we developed 1-[2-[(2S)-1-(phenylsulfonyl)pyrrolidin-2-yl]ethyl]piperidin-4-yl 4-fluorobenzoate. After labeling in good yield with fluorine-18 via nitro for fluorine exchange, preliminary biological experiments with autoradiographies failed to evidence any specific 5-HT(7) receptor delineation.

International audience; PURPOSE: The serotonin-1A (5-HT(1A)) receptor is implicated in the pathophysiology of major neuropsychiatric disorders. Thus, the functional imaging of 5-HT(1A) receptors by positron emission tomography (PET) may contribute to the understanding of its role in those pathologies and their therapeutics. These receptors exist in high- and low-affinity states and it is proposed that agonists bind preferentially to the high-affinity state of the receptor and therefore could provide a measure of the functional 5-HT(1A) receptors. Since all clinical PET 5-HT(1A) radiopharmaceuticals are antagonists, it is of great interest to develop a( 18)F labelled agonist. METHODS: F15599 (3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-methyl-pyrimidin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl)-methanone) is a novel ligand with high affinity and selectivity for 5-HT(1A) receptors and is currently tested as an antidepressant. In pharmacological tests in rat, it exhibits preferential agonist activity at post-synaptic 5-HT(1A) receptors in cortical brain regions. Here, its nitro-precursor was synthesised and radiolabelled via a fluoronucleophilic substitution. Radiopharmacological evaluations included in vitro and ex vivo autoradiography in rat brain and PET scans on rats and cats. Results were compared with simultaneous studies using [(18)F]MPPF, a validated 5-HT(1A) antagonist radiopharmaceutical. RESULTS: The chemical and radiochemical purities of [(18)F]F15599 were >98%. In vitro [(18)F]F15599 binding was consistent with the known 5-HT(1A) receptors distribution (hippocampus, dorsal raphe nucleus, and notably cortical areas) and addition of Gpp(NH)p inhibited [(18)F]F15599 binding, consistent with a specific binding to G protein-coupled receptors. In vitro binding of [(18)F]F15599 was blocked by WAY100635 and 8-OH-DPAT, respectively, prototypical 5-HT(1A) antagonist and agonist. The ex vivo and in vivo studies demonstrated that the radiotracer readily entered the rat and the cat brain and generated few brain radioactive metabolites. Remarkably, in microPET studies, [(18)F]F15599 notably displayed a pattern of brain labelling that did not correlate with in vitro observations. Thus, in cat, the highest binding was observed in dorsal raphe and cingulate cortex with little binding in other cortical regions and none in hippocampus. In vivo binding was abolished by WAY100635, indicating specific labelling of 5-HT(1A) receptors. CONCLUSION: [(18)F]F15599 is a radiofluorinated agonist presenting interesting characteristics for probing in vitro and in vivo the high-affinity states of the 5-HT(1A) receptors. Its differential labelling of 5-HT(1A) receptors in vitro and in vivo may result from its reported preferential interaction with receptors coupled to specific G-protein subtypes.

We performed 99mTc-hexamethylpropyleneamineoxime-single-photon emission computed tomography (SPECT) and 18F-fluorodeoxyglucose-positron emission tomography (PET) in 20 epileptic patients with well-lateralized temporal electroencephalographic focus, normal computed tomographic scan, and brain magnetic resonance imaging (MRI) either normal (n = 10) or showing nonspecific changes in the epileptogenic temporal lobe (n = 10). In patients with a normal MRI, PET exhibited focal hypometabolism in 80%, whereas SPECT showed corresponding hypoperfusion in only 20%. In patients with an abnormal MRI, PET and SPECT yielded 100% and 90% sensitivity, respectively. The metabolic and regional cerebral blood flow disturbances were topographically concordant with electroencephalographic and MRI findings in all these patients. Only patients with a large and pronounced hypometabolism on PET images exhibited hypoperfusion on SPECT. Spatial resolution appeared to be the critical factor responsible for the higher sensitivity of PET. However, this superiority of PET did not prove clinically useful in patients whose SPECT was abnormal, particularly when brain MRI showed nonspecific changes in the epileptogenic temporal lobe.

International audience; A recent [(18)F]MPPF-positron emission tomography study has highlighted an overexpression of 5-HT(1A) receptors in the hippocampus of patients with mild cognitive impairment compared to a decrease in those with Alzheimer's disease (AD) [Truchot, L., Costes, S.N., Zimmer, L., Laurent, B., Le Bars, D., Thomas-Antérion, C., Croisile, B., Mercier, B., Hermier, M., Vighetto, A., Krolak-Salmon, P., 2007. Up-regulation of hippocampal serotonin metabolism in mild cognitive impairment. Neurology 69 (10), 1012-1017]. We used in vivo and in vitro neuroimaging to evaluate the longitudinal effects of injecting amyloid-beta (Abeta) peptides (1-40) into the dorsal hippocampus of rats. In vivo microPET imaging showed no significant change in [(18)F]MPPF binding in the dorsal hippocampus over time, perhaps due to spatial resolution. However, in vitro autoradiography with [(18)F]MPPF (which is antagonist) displayed a transient increase in 5-HT(1A) receptor density 7 days after Abeta injection, whereas [(18)F]F15599 (a radiolabelled 5-HT(1A) agonist) binding was unchanged suggesting that the overexpressed 5-HT(1A) receptors were in a non-functional state. Complementary histology revealed a loss of glutamatergic neurons and an intense astroglial reaction at the injection site. Although a neurogenesis process cannot be excluded, we propose that Abeta injection leads to a transient astroglial overexpression of 5-HT(1A) receptors in compensation for the local neuronal loss. Exploration of the functional consequences of these serotoninergic modifications during the neurodegenerative process may have an impact on therapeutics targeting 5-HT(1A) receptors in AD.

Background The Pittsburgh compound-B ([11C]PIB) is a highly interesting radiotracer for imaging amyloid plaques in Alzheimer's disease by positron emission tomography (PET). An increasing number of PET centres schedule its transfer for clinical studies and therefore are interested in its automated synthesis. Method With the aim of flexibility, we reported the first fully automated synthesis of [11C]PIB with the coupling of two commercial synthesizers. Results [11C]PIB was prepared from 2-(4'-aminophenyl)-6-hydroxybenzothiazole by [11C]methyl triflate methylation reacting in an high-performance liquid chromatography loop and resulting in a total radiochemical yield of 13+/-15% after a synthesis time of 25 min. The specific activity of [11C]PIB was 20-60 GBq/micromol and its radiochemical purity is more than 99%. Conclusion The rapid synthesis and the automatic auto-cleaning procedure allow convenient and reproducible [11C]PIB synthesis to be performed during the same day for preclinical or clinical PET scans.

Background Serotonin (5-HT) pathway abnormalities were demonstrated in anorexia nervosa (AN). Brain imaging studies on 5-HT receptors support this evidence. 4-(2-methoxyphenyl)-1-[2-(N-2-pyridinyl)-p-fluorobenzamido]-ethylpiperazine ([ 18 F]MPPF) is a selective 5-HT 1A receptor antagonist with an affinity close to that of endogenous 5-HT. Methods In 24 subjects including 8 lean restrictive-type AN patients, 9 recovered from restrictive-type AN subjects and 7 age-matched control subjects, we assessed in vivo brain [ 18 F]MPPF binding by positron emission tomography and eating-related psychopathological traits. Inter-groups differences in [ 18 F]MPPF binding were evaluated by voxel-based analyses. Results Restrictive AN patients presented increased [ 18 F]MPPF binding in a selective area of the right cortex including part of the superior temporal gyrus, inferior frontal gyrus, parietal operculum, and temporoparietal junction. Striking regional similarities of increased [ 18 F]MPPF binding were found in recovered from AN subjects. Most of the psychiatric scores were increased in restrictive AN patients, and elevated perfectionism and interpersonal distrust scores were noticed in subjects recovered from AN. Conclusions The persistent increased 5-HT 1A receptor binding in frontotemporal region of recovered AN concomitantly with specific psychopathological traits support the hypothesis of an organic dysfunction of this area and corroborates with previous literature reports of AN cases induced by temporal lesions.

Tardive dystonia (TD) is a disabling disorder induced by neuroleptics. Internal globus pallidus (GPi) stimulation can dramatically improve TD. The present positron emission tomography and H215O study aimed to characterize the abnormalities of brain activation of TD and the impact of GPi stimulation on these abnormalities in five TD patients treated with GPi stimulation and eight controls. Changes of regional cerebral blood flow (rCBF) were determined: (i) at rest; (ii) when moving a joystick with the right hand in three freely chosen directions in on and off bilateral GPi stimulation. A significant increase of rCBF was found in TD patients in off-stimulation condition compared to controls: (1) during motor execution in the prefrontal, premotor lateral, and anterior cingulate cortex; (2) at rest, in the prefrontal and anterior cingulate cortex and the cerebellum. Internal globus pallidus stimulation led to a reduction of rCBF (1) during motor execution, in the primary motor and prefrontal cortex and the cerebellum; (2) at rest, in the primary motor and anterior cingulate cortex and supplementary motor area. The results are as follows: (1) TD is related to an excess of brain activity notably in the prefrontal and premotor areas; (2) GPi stimulation reduces the activation of motor, premotor, and prefrontal cortex as well as cerebellum.

Prone positioning is frequently used during acute respiratory distress syndrome. However, mechanisms by which it improves oxygenation are poorly understood, as well as its interaction with positive end-expiratory pressure. This study was conducted to decipher the respective effects of positive end-expiratory pressure and posture during lung injury on regional lung ventilation, perfusion and recruitment assessed by positron emission tomography.Experimental study.Research laboratory of a university hospital.Six female piglets.After oleic acid-induced lung injury, all animals were studied in supine and prone position at both positive end-expiratory pressure 0 and positive end-expiratory pressure 10 cm H2O.In each experimental condition, regional lung perfusion and ventilation were assessed with positron emission tomograph using intravenous 15O-labeled water and inhaled nitrogen-13. Nonaerated lung weight was assessed with positron emission tomograph, and alveolar recruitment was defined as the difference of nonaerated lung weight between conditions. Positive end-expiratory pressure was associated with significant alveolar recruitment (130 +/- 85 and 65 +/- 29 g of lung in supine and prone position, respectively [p0.05 vs. 0]), whereas recruitment induced by posture was not statistically significant (77 +/- 97 g with positive end-expiratory pressure 0 and 13 +/- 19 g with positive end-expiratory pressure 10 [p0.05 vs. 0]). Regardless the posture, positive end-expiratory pressure redistributed both perfusion and ventilation toward dependent regions. Recruitment by positive end-expiratory pressure was restricted to dorsal regions in supine position, but extended diffusely along the ventral-to-dorsal dimension in prone position. Prone position was associated with recruitment in dorsal regions with concomitant derecruitment in ventral regions, magnitude of this being reduced by positive end-expiratory pressure. Prone position redistributed ventilation toward dorsal and ventral regions at positive end-expiratory pressure 0 and positive end-expiratory pressure, respectively. Finally, prone position redistributed perfusion toward ventral regions, to an extent amplified by positive end-expiratory pressure.Positive end-expiratory pressure and posture act synergistically by redistributing lung regional perfusion toward ventral regions, but have antagonistic effects on regional ventilation.

International audience; PURPOSE: The aim of this study was to investigate (a) in vitro the relationship between [(18)F]fluorocholine ([(18)F]FCH) uptake and cell growth in endocrine cell lines and (b) in vivo the uptake of [(18)F]FCH by tumoral sites in an animal model of metastasized endocrine tumor. METHODS: In vitro studies were conducted on three endocrine and two nonendocrine digestive tumoral cell lines. The proliferative ratio was estimated using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. The uptake of [(18)F]FCH and that of [(18)F]fluorodeoxyglucose ([(18)F]FDG) were measured before and after cytotoxic therapy. [(18)F]FCH biodistribution was studied in nude mice and in an endocrine xenografted mice model. RESULTS: The [(18)F]FCH uptake in tumoral cell lines was related to their proliferative capacities as measured by the MTT assay in basal conditions. After cytotoxic therapy, the IC(50) values calculated with the [(18)F]FCH incorporation test were very close to those determined with the MTT assay. Biodistribution studies showed that [(18)F]FCH was predominantly concentrated in the liver and kidney of nude mice. In the STC-1 xenografted animal model, the uptake of [(18)F]FCH in the primary tumor was only 1.1%. On autoradiography and micro-positron emission tomography, there was no uptake of [(18)F]FCH in liver metastases but there was a significant uptake of [(18)F]FDG. CONCLUSIONS: In vitro studies suggested that the incorporation of [(18)F]FCH in endocrine tumor cell lines was related to their growth capacities; however, in vivo studies conducted in an endocrine xenografted animal model showed an uptake of [(18)F]FCH in hepatic metastases lower than that in normal liver cells. An influence of the microenvironment or a competition phenomenon for [(18)F]FCH uptake between normal liver and endocrine tumor cells cannot be excluded.

In acute lung injury (ALI) activated protein C (APC) may reopen occluded lung vessels and minimize lung inflammation. We aimed at assessing the effect of APC on regional lung perfusion, aerated lung volume, cytokine production and oxygenation in experimental ALI.Prospective, controlled study in an imaging facility.Pigs tracheotomized and mechanically ventilated.Pigs were randomly given intravenously APC (n = 8) or saline (n = 8). Thirty minutes later, ALI was induced by injecting oleic acid.Lung perfusion and aerated lung volume measured with positron emission tomography, plasma cytokines and arterial blood gas were determined just before ALI and 110 and 290 min thereafter. Lung cytokines were measured at the end of the experiment. PaO2 under F I O2 1 was significantly lower in the APC group before lung injury (473+/-129 vs. 578+/-54 mmHg) and 110 min (342+/-138 vs. 446+/-103 mmHg) and 290 min (303+/-171 vs. 547+/-54 mmHg) thereafter (p0.05). Lung perfusion nonsignificantly tended to redistribute towards dorsal lung regions with APC. Total aerated lung volume was not different between APC and control before ALI (10.0+/-1.5 vs. 11.0+/-2.5 ml/kg) (p0.05) or thereafter. Plasma IL-6 and IL-8 at 110 min were greater with APC (p0.05).In contrast to studies using other models, pretreatment with APC was associated with worsening oxygenation in the present investigation. This might be due to ventilation-perfusion mismatch, with more perfusion to dependent nonaerated areas.

International audience; This PET H 2 15 O study uses a reaching task to determine the neural basis of the unconscious motor speed up observed in the context of urgency in healthy subjects. Three conditions were considered: self-initiated (produce the fastest possible movement toward a large plate, when ready), externally-cued (same as self-initiated but in response to an acoustic cue) and temporally-pressing (same as externally-cued with the plate controlling an electromagnet that prevented a rolling ball from falling at the bottom of a tilted ramp). Results show that: (1) Urgent responses (Temporally-pressing versus Externally-cued) engage the left parasagittal and lateral cerebellar hemisphere and the sensorimotor cortex (SMC) bilaterally; (2) Externally-driven responses (Externally-cued versus Self-initiated) recruit executive areas within the contralateral SMC; (3) Volitional responses (Self-initiated versus Externally-cued) involve prefrontal cortical areas. These observations are discussed with respect to the idea that neuromuscular energy is set to a submaximal threshold in self-determined situations. In more challenging tasks, this threshold is raised and the first answer of the nervous system is to optimize the response of the lateral (i.e. crossed) corticospinal tract (contralateral SMC) and ipsilateral cerebellum. In a second step, the anterior (i.e. uncrossed) corticospinal tract (ipsilateral SMC) and the contralateral cerebellum are recruited. This recruitment is akin to the strategy observed during recovery in patients with brain lesions.

To compare changes in aerated lung volumes measured by positron emission tomography (PET) and inflation volume-pressure curve (V – P) of the respiratory system, and to evaluate the reliability of PET to assess alveolar recruitment. Experimental study in six anesthetized and mechanically ventilated pigs in a PET facility in an experimental university laboratory. Lung injury was induced by oleic acid. Animals were randomly studied in four conditions: PEEP 0 cmH2O (ZEEP) in supine position (SP), PEEP 10 cmH2O in SP, ZEEP in prone position (PP) and PEEP in PP, each applied for 30 min. With PET aerated lung volume was obtained from pulmonary density analysis using transmission scan (VAtrans) and from nitrogen-13 kinetics on emission scan (VAem). Changes in VAtrans and VAem were computed as the difference in aerated volume between conditions. VAtrans and VAem did not differ between SP and PP, on either ZEEP or PEEP, suggesting no modification in relaxation volume of the respiratory system induced by posture. Changes in VAtrans or VAem were significantly correlated with changes in aerated volume assessed from superimposed V – P curves (R 2 = 0.74 and 0.75, respectively). Alveolar recruitment assessed by PET was significantly correlated with both PaO2 (R 2 = 0.61) and PaCO2 (R 2 = 0.40) variations induced by PEEP. PET is a new reliable tool of scientific interest to image lung volume and alveolar recruitment during acute lung injury.

Neurotransmission imaging studies require normative data for the statistical assessment of neurophysiologic dysfunctions. 2'-Methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine (18F-MPPF) is a specific serotonin 5-HT1A antagonist PET tracer recently characterized, modeled, and used for clinical research to explore abnormalities in the serotoninergic system. Our study reports, to our knowledge, the first large normative imaging database of 18F-MPPF binding potential (BP) over aging, for both males and females.Fifty-three healthy volunteers (27 females, 26 males; age, 20-70 y) were selected to undergo structural MRI and single-injection 18F-MPPF multiframe dynamic PET. 18F-MPPF BP values were computed using a nonlinear modeling method with tissue reference. The statistical assessment of the effect of age and sex was performed both at the anatomic structure level, using regions of interest drawn manually on individual MR images, and at the voxel level, using normalized BP parametric images in different statistical parametric mapping designs.A negative linear correlation between age and 18F-MPPF binding (3.6% decrease by decade) was found in females but not in males and involved most of the limbic and paralimbic regions; on the other hand, males in their 30s showed decreased binding in most cerebral regions.A comparison of males and females revealed higher BP values independent of age in females in the right hemisphere and a different evolution of BP over aging. These results confirm the necessity of a database for further statistical analysis in individuals or groups with pathology.

Data from animal studies suggest that serotonin release promotes wakefulness and suppresses REM sleep, but there are dangers in extrapolating these findings to humans. Binding of the radioligand [18F]MPPF to 5HT1A receptors is sensitive to levels of endogenous serotonin. In this study, we aimed to demonstrate changes in serotonin receptor availability in the human brain in wakefulness and sleep using [18F]MPPF and positron emission tomography. 14 subjects with narcolepsy cataplexy underwent [18F]MPPF PET scans in wakefulness and in sleep. Subjects who used the stimulant methylphenidate took their normal medication for the wake scan but omitted it prior to the sleep scan. The change in binding potential (BP) between the sleep and wake scans was examined using paired t test. Methylphenidate is thought to have little or no effect on serotonergic neurotransmission, and in order to confirm the absence of an effect on [18F]MPPF binding, a concurrent study was performed using a β-microprobe technique to examine the effect of methylphenidate administration on [18F]MPPF binding in Sprague–Dawley rats. The human study showed a significant increase in [18F]MPPF binding in sleep compared to wakefulness in the whole brain and all regions of interest examined (temporal cortex, mesial temporal region and cingulate cortex). The β-microprobe study confirmed that methylphenidate administration had no effect on [18F]MPPF binding. These findings indicate that serotonin receptor availability is increased in sleep compared to wakefulness in narcoleptic humans.

Although hypoactive sexual desire disorder (HSDD) is a common condition and has long been hypothesized to result from malfunctions of the cerebral control mechanisms that adjust the level of sexual motivation, very little is known about the pathophysiology of this disorder. The primary objective was to identify in patients with HSDD brain regions where functional perturbations disrupt the regulation of sexual motivation. We used positron emission tomography to compare seven male patients with HSDD with eight healthy men on their regional cerebral blood flow responses to visual sexual stimuli (VSS) of graded intensity. Statistical Parametric Mapping was used to locate brain regions that demonstrated a differential activation (or deactivation) across the groups. Whereas in control subjects the medial orbitofrontal cortex showed a deactivation in response to VSS, in HSDD patients there was an abnormally maintained activity of this region, which has been implicated in the inhibitory control of motivated behavior. By contrast, the reverse pattern-activation in control subjects, deactivation or unchanged activity in patients-was found in the secondary somatosensory cortex and inferior parietal lobules, regions mediating emotional and motor imagery processes, as well as in those areas of the anterior cingulate gyrus and of the frontal lobes that are involved in premotor processes.

A new compound, 8[[3-[4-(2-[(11)C]methoxyphenyl)piperazin-1-yl]-2-hydroxypropyl]oxy]thiochroman was labeled via O-methylation with [(11)C]methyl iodide in good yield and specific activity. Original biological evaluations included (i) the study in anesthetized rat with a beta-sensitive intracerebral probe (beta-Microprobe), allowing to measure locally the kinetic of the new PET ligand, and (ii) a PET-scan on a conditioned cat maintained awake during the acquisition. In both in vivo techniques, the new ligand did not reveal any specific binding in hippocampus indicating that this radiotracer is not suitable for mapping 5HT(1A) receptors using positron emission tomography.

Background: Positron emission tomography (PET) is a functional imaging device that allows dynamic regional blood flow measurements. We performed a study to test whether PET could detect acute changes in renal blood flow (RBF) in patients with chronic renal failure (CRF). Methods: RBF was measured by means of PET (PET-RBF) using oxygen 15-labeled water (H 2 15 O) in eight men with hypertension and moderate CRF before and 5, 40, 80, and 120 minutes after the injection of quinaprilat (10 mg intravenously). Effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were measured simultaneously by para-aminohippuric acid (PAH-ERPF) and inulin clearances before and 20, 60, 100, and 140 minutes after quinaprilat injection. Results: Baseline RBF and ERPF were decreased in all patients (221 ± 20 mL/min/100 g and 225 ± 38 mL/min/1.73 m 2 , respectively). PET-RBF increased significantly after quinaprilat injection (+15%, +26%, +19%, and +23% versus baseline; P P = 0.15). GFR (50.1 ± 8.9 mL/min/1.73 m 2 at baseline) did not change significantly after quinaprilat injection; however, filtration fraction (GFR-ERPF ratio) decreased significantly from 0.23% ± 0.02% to 0.20% ± 0.02% ( P = 0.0004). Mean arterial pressure decreased significantly after quinaprilat injection ( P Conclusion: This study dynamically measured RBF by means of PET in patients with CRF for the first time. It showed that RBF rapidly increased after quinaprilat injection. PET using H 2 15 O is a powerful method for the noninvasive measurement of dynamic changes in RBF that remain undetected by PAH clearance. Am J Kidney Dis 40:947-954. © 2002 by the National Kidney Foundation, Inc.

Microsphere technique is the reference for assessment of pulmonary blood flow (PBF) but is destructive; PET, however, can determine PBF noninvasively. Comparisons of these 2 methods are scanty. Our study aimed at comparing these 2 techniques using a mathematic model taking into account the right ventricle in determining the transit time of a tracer through lung tissue.Ten normal pigs were investigated at baseline, during dobutamine infusion, and during 10 cm H(2)O of positive end-expiratory pressure. Under each condition, PBF was successively measured with PET (PET-PBF) and radioactive microspheres (MS-PBF). For PET-PBF, 2 mCi (74 MBq) (15)O-labeled water were injected intravenously over 20 s and PET scanning was performed for 10 min. The input function was determined noninvasively from PET and invasively from mixed venous blood withdrawals. PET-PBF was computed using a mathematic model taking into account the right ventricle in determining the transit time of the tracer through lung tissue. For MS-PBF, 1 given isotope was injected under a given condition. PET-PBF and MS-PBF for 5 lung regions were compared.PET-PBF significantly correlated with MS-PBF both over all experimental points (PET-PBF = 0.79. MS-PBF + 1,538; r = 0.79; P0.001) and in separate lung regions. Invasive and noninvasive input functions also correlated significantly (r = 0.90; P0.001). Simulations stressed the crucial role of the right ventricle to the transit time of tracer through lung tissue in the determination of PET-PBF.PBF can accurately be assessed using PET and a mathematic model taking into account the right ventricle in determining the transit time of a tracer through lung tissue. Noninvasive determination of the input function of the right ventricle is accurate and can readily be used for clinical applications.

By using a combination of an original beta+-sensitive intracerebral probe and microdialysis, the effect of increased endogenous serotonin on specific binding of 18F-MPPF [4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-fluorobenzamido]ethyl]piperazine] to the serotonin-1A (5-HT1A) receptors was investigated in the hippocampus of the anaesthetized rat. Our beta-sensitive probe prototype was sensitive enough to obtain specific 18F-MPPF time-activity curves in the rodent (hippocampus/cerebellum ratio approximately 2). The serotonin neuronal release was pharmacologically enhanced using fenfluramine at three different doses (1, 2 and 10 mg/kg intravenous) multiplying by 2-15 the extracellular serotonin in the hippocampus. These extracellular variations of extracellular serotonin resulted in dose-ranging decreases in 18F-MPPF-specific binding in the same rat. Our results showed for the first time that 18F-MPPF binding could be modulated by modifications of extracellular serotonin in the rat hippocampus. These results were confirmed by the enhancement of extracellular radioactivity collected in dialysates after the displacement of 18F-MPPF by fenfluramine. After modelization, 18F-MPPF binding could constitute an interesting radiotracer for positron emission tomography in evaluating the serotonin endogenous levels in limbic areas of the human brain.

Despite its critical sociobiological importance, the brain processing of visual sexual stimuli has not been characterized precisely in human beings. We used Positron Emission Tomography (PET) to investigate responses of regional cerebral blood flow (rCBF) in nine healthy males presented with visual sexual stimuli of graded intensity. Statistical Parametric Mapping was used to locate brain regions whose activation was associated with the presentation of the sexual stimuli and was correlated with markers of sexual arousal. The claustrum, a region whose function had been unclear, displayed one of the highest activations. Additionally, activations were recorded in paralimbic areas (anterior cingulate gyrus, orbitofrontal cortex), in the striatum (head of caudate nucleus, putamen), and in the posterior hypothalamus. By contrast, decreased rCBF was observed in several temporal areas. Based on these results, we propose a model of the brain processes mediating the cognitive, emotional, motivational, and autonomic components of human male sexual arousal. Hum. Brain Mapping 11:162–177, 2000. © 2000 Wiley‐Liss, Inc.

The in vivo and ex vivo distributions and the pharmacological profile of the fluorinated phenylpiperazine derivative p-[(18)F]MPPF (4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-fluorobenzamido]-et hyl piperazine) were evaluated in the cat brain as a potential selective antagonist for 5-HT(1A) receptors using PET. After intravenous injection of p-[(18)F]MPPF in cats, there was a rapid accumulation of radioactivity in the brain, with 4% of the total radioactivity injected present in the brain at 4 minutes postinjection. The highest uptakes of radioactivity were observed in the hippocampus and cingulate cortex, regions known to be rich in 5-HT(1A) receptors, whereas lower levels of radioactivity were observed in the cerebellum. The mean ratio of radioactivity in the hippocampus to the cerebellum was 4.29 (SD = 0.21; n = 5) from 40 to 90 minutes postinjection of p-[(18)F]MPPF. The corresponding ratio for the cingulate cortex was 3.01 (SD = 0.16; n = 5). Specific binding in the hippocampus and the cingulate cortex was markedly reduced following injection of unlabeled WAY-100635 and pindolol but was unaffected by treatment with alpha1, 5-HT(2), or reuptake inhibitor agents indicating reversibility and selectivity of p-[(18)F]MPPF binding to 5-HT(1A) receptors. Ex vivo autoradiographic study with p-[(18)F]MPPF in cat brain sections showed labeling of areas rich in 5-HT(1A) receptors with a regional brain distribution that closely matched that observed using PET. These results indicate that p-[(18)F]MPPF may be a useful candidate for noninvasive PET imaging of 5-HT(1A) receptors in the living human brain.

We investigated the cerebral metabolic patterns associated with non-specific hyperintense T2-weighted image on Magnetic Resonance Imaging (MRI) in Temporal Lobe Epilepsy (TLE). Nineteen patients suffering from TLE with a normal CT scan underwent Positron Emission Tomography (PET) using 18F-fluorodeoxyglucose; 8 had hyperintense T2-weighted image on MRI in the epileptogenic temporal lobe and 11 had a normal MRI. Interictally, PET exhibited focal hypometabolism in all the patients with hyperintense T2-weighted image and in 8 of the 11 whose MRI was normal. The hypometabolic area was significantly more extensive in patients with hyperintense T2-weighted image in whom it always encompasses the site of the MRI abnormality. Moreover, these patients had higher metabolic asymmetry index in the temporal and parietal lobes than patients with a normal MRI. One patient with mesial temporal hyperintense T2-weighted image underwent an ictal PET, which showed that the focal hypermetabolism fitted remarkably with the site and size of the abnormal MR signal. Thus, non-specific hyperintense T2-weighted images are associated with particular interictal and ictal metabolic patterns which might suggest that these MRI abnormalities reflect an epileptogenic lesion.