Processing of voices in deafness rehabilitation by auditory brainstem implant.

The superior temporal sulcus (STS) is specifically involved in processing the human voice. Profound acquired deafness by post-meningitis ossified cochlea and by bilateral vestibular schwannoma in neurofibromatosis type 2 patients are two indications for auditory brainstem implantation (ABI). In order to objectively measure the cortical voice processing of a group of ABI patients, we studied the activation of the human temporal voice areas (TVA) by PET H(2)(15)O, performed in a group of implanted deaf adults (n=7) with more than two years of auditory brainstem implant experience, with an intelligibility score average of 17%+/-17 [mean+/-SD]. Relative cerebral blood flow (rCBF) was measured in the three following conditions: during silence, while passive listening to human voice, and to non-voice stimuli. Compared to silence, the activations induced by voice and non-voice stimuli were bilaterally located in the superior temporal regions. However, compared to non-voice stimuli, the voice stimuli did not induce specific supplementary activation of the TVA along the STS. The comparison of ABI group with a normal-hearing controls group (n=7) showed that TVA activations were significantly enhanced among controls group. ABI allowed the transmission of sound stimuli to temporal brain regions but lacked transmitting the specific cues of the human voice to the TVA. Moreover, among groups, during silent condition, brain visual regions showed higher rCBF in ABI group, although temporal brain regions had higher rCBF in the controls group. ABI patients had consequently developed enhanced visual strategies to keep interacting with their environment.

Quantification of cerebral nicotinic acetylcholine receptors by PET using 2-[18F]fluoro-A-85380 and the multiinjection approach.

The multiinjection approach was used to study in vivo interactions between alpha4beta2(*) nicotinic acetylcholine receptors and 2-[(18)F]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 K(d)V(R) (the apparent in vivo affinity of 2-[(18)F]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 K(d)V(R) could be precisely estimated, the association and dissociation rate constants k(on)/V(R) and k(off) could not be identified separately. A second protocol was then used to estimate k(off) more precisely in the thalamus. Having estimated all model parameters, we performed simulations of 2-[(18)F]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.

Cochlear implant benefits in deafness rehabilitation: PET study of temporal voice activations.

UNLABELLED: Cochlear implants may improve the medical and social prognosis of profound deafness. Nevertheless, some patients have experienced poor results without any clear explanations. One correlate may be an alteration in cortical voice processing. To test this hypothesis, we studied the activation of human temporal voice areas (TVA) using a well-standardized PET paradigm adapted from previous functional MRI (fMRI) studies. METHODS: A PET H(2)(15)O activation study was performed on 3 groups of adult volunteers: normal-hearing control subjects (n = 6) and cochlear-implanted postlingually deaf patients with >2 y of cochlear implant experience, with intelligibility scores in the "Lafon monosyllabic task" >80% (GOOD group; n = 6) or <20% (POOR group; n = 6). Relative cerebral blood flow was measured in 3 conditions: rest, passive listening to human voice, and nonvoice stimuli. RESULTS: Compared with silence, the activations induced by nonvoice stimuli were bilaterally located in the superior temporal regions in all groups. However these activations were significantly and similarly reduced in both cochlear implant groups, whereas control subjects showed supplementary activations. Compared with nonvoice, the voice stimuli induced bilateral activation of the TVA along the superior temporal sulcus (STS) in both the control and the GOOD groups. In contrast, these activations were not detected in the POOR group, which showed only left unilateral middle STS activation. CONCLUSION: These results suggest that PET is an adequate method to explore cochlear implant benefits and that this benefit could be linked to the activation of the TVA.

Assessment of 11C-PE2I binding to the neuronal dopamine transporter in humans with the high-spatial-resolution PET scanner HRRT.

UNLABELLED: The high-resolution research tomograph (HRRT), dedicated to brain imaging, may offer new perspectives for identifying small brain nuclei that remain neglected by the spatial resolution of conventional scanners. However, the use of HRRT for neuroimaging applications still needs to be fully assessed. The present study aimed at evaluating the HRRT for measurement of the dopamine transporter (DAT) binding to validate its quantification and explore the gain induced by the increased spatial resolution in comparison with conventional PET scanners. METHODS: Fifteen and 11 healthy subjects were examined using the selective DAT radioligand (11)C-PE2I with HRRT and HR+ scanners, respectively. Quantification of the DAT binding was assessed by the calculation of binding potential (BP) values using the simplified reference tissue model in anatomic regions of interest (ROIs) defined on the dorsal striatum and in a standardized ROI defined on the midbrain. RESULTS: Quantification of (11)C-PE2I binding to the DAT measured in the midbrain and striatum with both scanners at the same spatial resolution (smoothed HRRT images) exhibited similar BP values and intersubject variability, thus validating the quantification of DAT binding on the HRRT. For age-paired comparison, BP values of subjects examined with HRRT were significantly higher than those of the subjects examined with HR+. The increase ranged from 29% in the caudate and 35% in the putamen to 92% in the midbrain. The decline in DAT binding with age in the striatum was in good agreement between both scanners and literature, whereas no significant decrease in DAT binding with age was observed in the midbrain with either HRRT or HR+. CONCLUSION: HRRT allows quantitative measurements of neurotransmission processes in small brain nuclei and allows recovering higher values as compared with coarser spatial resolution PET scanners. High-spatial-resolution PET appears promising for a more accurate detection of neurobiologic modifications and also for the exploration of subtle modifications in small and complex brain structures largely affected by the partial-volume effect.

Whole-body distribution and radiation dosimetry of the dopamine transporter radioligand [(11)C]PE2I in healthy volunteers.

INTRODUCTION: This study reports on the biodistribution and radiation dosimetry of a cocaine analog, the (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4'-tolyl)nortropane (PE2I), labeled with carbon 11 ([(11)C]PE2I). [(11)C]PE2I is used in positron emission tomography (PET) for examination of the dopamine neuronal transporter (DAT). DAT radioligands are often used to evaluate the progression of Parkinson's disease or the efficiency of neuroprotective therapeutics, and, typically, these studies required several successive PET scans. METHODS: In three healthy male volunteers, whole-body scans were performed up to 2 h following intravenous injection of 321+/-6 MBq of [(11)C]PE2I. For each subject, regions of interest were defined over all visible organs to generate time-activity curves and calculate the percentage of injected activity. Time-activity data were fitted to a monoexponential model, as an uptake phase followed by a mono-exponential washout, or bi-exponential model to obtain residence times. With the use of the MIRD method, several source organs were considered in estimating residence time and mean effective radiation absorbed doses. RESULTS: Blood pressure and ECG findings remained unchanged after radioligand injection. The primary route of clearance was renal. Ten minutes after injection, high activities were observed in the kidneys, urinary-bladder, stomach, liver, salivary glands and brain. The urine bladder wall, stomach and liver received the highest absorbed doses. The average effective dose of [(11)C]PE2I was estimated to be 6.4+/-0.6 microSv/MBq. CONCLUSION: The amount of [(11)C]PE2I required for adequate DAT PET imaging results in an acceptable effective dose equivalent permitting two or three repeated cerebral PET studies, with the injection of 222 MBq for each study.

Congenital hyperinsulinism: pancreatic [18F]fluoro-L-dihydroxyphenylalanine (DOPA) positron emission tomography and immunohistochemistry study of DOPA decarboxylase and insulin secretion.

CONTEXT: Congenital hyperinsulinism (HI) is characterized by hypoglycemia related to inappropriate insulin secretion. Focal and diffuse forms of hyperinsulinism share a similar clinical presentation, but their treatment is dramatically different. Preoperative differential diagnosis was based on pancreatic venous sampling, a technically demanding technique. OBJECTIVE: Positron emission tomography (PET) after injection of [18F]fluoro-L-DOPA (L-dihydroxyphenylalanine) has been evaluated for the preoperative differentiation between focal and diffuse HI, by imaging uptake of radiotracer and the conversion of [18F]fluoro-L-dopa into dopamine by DOPA decarboxylase. We propose to validate this test by immunohistochemical approach. PATIENTS AND METHODS: Pancreatic surgical specimens of four focal and three diffuse HI were studied, using anti-DOPA decarboxylase and proinsulin antibodies. The effect of an inhibitor of DOPA decarboxylase (carbidopa) on insulin secretion was evaluated in vivo and in cultured INS-1 cells. RESULTS: Immunohistochemical detection of DOPA decarboxylase showed diffuse staining of Langerhans islets in the whole pancreas in all diffuse cases, in contrast with dense focal staining in all focal cases. Staining of Langerhans islets outside the focal lesion was diffusely but weakly positive. We correlated the localization of DOPA decarboxylase and proinsulin in normal pancreas and in both diffuse and focal HI tissues. The diffuse PET uptake found before treatment in one child with diffuse HI disappeared completely after carbidopa administration, suggesting in vivo that pancreatic cells can take up amine precursors and contain DOPA decarboxylase. The insulin secretion measured in the supernatant was the same whether INS-1 cells were treated by dopamine or Lodosyn or untreated. CONCLUSION: We validate PET with as a consistent test to differentiate diffuse and focal HI.

Impact of liver transplantation on cardiac autonomic denervation in familial amyloid polyneuropathy.

Familial amyloid polyneuropathy (FAP) is a rare and severe hereditary form of amyloidosis, due to the deposition of a genetic variant transthyretin essentially produced by the liver, and characterized by both sensorimotor and autonomic neuropathy. Liver transplantation (LT) is the most effective treatment to stop the progression of the disease. Cardiac amyloid infiltration is usually associated with cardiac denervation, restrictive cardiomyopathy, conduction disturbances, and sometimes sudden death. Whether the cardiac involvement related to amyloid deposition may be altered after LT remains unclear. We conducted the present study to define the outcome of cardiac involvement after LT in 31 patients with FAP (age, 39 +/- 12 yr). Patients were evaluated before and after LT (24 +/- 15 mo). Cardiac sympathetic denervation was assessed by both iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy and heart rate variability (HRV) analysis. The scintigraphic importance of sympathetic denervation was evaluated globally on planar imaging using heart-to-mediastinum activity ratio (H/M) measured 4 hours after injection, and regionally using single-photon emission tomography (SPET) imaging. Amyloid myocardial infiltration was assessed by echocardiography. Diffuse sympathetic denervation was found when using cardiac MIBG planar imaging in patients evaluated before LT and compared with 12 control subjects (H/M: 1.45 +/- 0.29 vs. 1.98 +/- 0.35, p < 0.001). On SPET images, defects were diffuse in 12 patients and focal in 19 patients, with predominance at the inferior and apical segments. No change in sympathetic innervation was found in patients after LT as assessed either with planar imaging (H/M after LT: 1.46 +/- 0.28, p = not significant vs. H/M before LT) or with SPET imaging. HRV nonspectral indexes showed that the standard deviation of all cycles was significantly lower in patients compared with control subjects, and remained unchanged after LT. Conduction disturbances and ventricular arrhythmias were associated with low cardiac MIBG uptake, and progressed after LT. The left ventricular wall was slightly thickened in patients, and a further increase was observed after LT (posterior wall from 9.2 +/- 1.8 to 10.1 +/- 2.3 mm, p = 0.02; septal wall from 10.6 +/- 2.7 to 12.1 +/- 4, p = 0.046). Neurologic status stabilized in 26 patients, but worsened in the 5 patients who had the most severe cardiac sympathetic denervation before LT as measured by MIBG imaging. The magnitude of the cardiac sympathetic denervation remained stable 2 years after LT in patients with FAP, whereas the cardiac amyloid infiltration progressed. The importance of cardiac sympathetic denervation found in FAP patients before LT was associated with a neurologic worsening after LT.

Effects of carvedilol on myocardial sympathetic innervation in patients with chronic heart failure.

UNLABELLED: Carvedilol is a beta-blocking agent with antioxidant properties that has been shown to improve survival in chronic heart failure (CHF). Previous open-label studies have suggested that its use may have positive effects on the abnormalities of cardiac sympathetic innervation integrity and functioning. The present study aimed to test the hypothesis that carvedilol exerts its beneficial effects on hemodynamics in parallel with an action on myocardial sympathetic activity and with its antioxidant property. METHODS: A randomized, multicenter, double-blind, placebo-controlled study of carvedilol was conducted on 64 CHF patients. Patients underwent-before and after 6 mo of therapy with either carvedilol or placebo-measurements of cardiac sympathetic activity, circulating catecholamine level, and hemodynamic indices. Myocardial meta-(123)I-iodobenzylguanidine ((123)I-MIBG) uptake was used to assess the changes in myocardial sympathetic activity. The antioxidant properties of the plasma were assessed by measuring the percentage of nonhemolyzed erythrocytes and the volume of plasma capable of inhibiting 50% of hemolysis after an oxidative stress. Echographic left ventricular (LV) diameters, radionuclide LV ejection fraction (LVEF), and exercise cardiopulmonary capacity were measured to evaluate the hemodynamic response. RESULTS: End-diastolic and end-systolic LV diameters decreased (both P < 0.05) and LVEF increased (P = 0.03) in the carvedilol group, whereas these parameters remained unchanged in the placebo group. Carvedilol did not alter the submaximal exercise cardiopulmonary capacity or the circulating catecholamine level. The beneficial hemodynamic effects in the carvedilol group were associated with an increase in myocardial (123)I-MIBG uptake as assessed by both planar and tomographic imaging (P < 0.01). Carvedilol had no detectable effect on antioxidant properties of the plasma. CONCLUSION: The benefits of carvedilol on resting hemodynamics appear to be associated with a partial recovery of cardiac adrenergic innervation functioning without detectable antioxidant effect in the plasma.

Involvement of the basal ganglia in refractory epilepsy: an 18F-fluoro-L-DOPA PET study using 2 methods of analysis.

UNLABELLED: Studies in animal models and epileptic patients have led to the suggestion that the basal ganglia (BG) are involved in seizures. PET with 6-18F-L-3,4-fluorodihydroxyphenylalanine (18F-fluoro-L-DOPA) has recently demonstrated a reduction of striatal dopamine uptake in drug-resistant epileptic patients with ring chromosome 20 (r20) using a multiple-time graphical analysis. The aim of the present study was to evaluate the involvement of dopamine in other epileptic syndromes using a multiple-time graphical analysis and the all-brain statistical parametric mapping (SPM) analysis. METHODS: Patients with drug-resistant epilepsy were divided into 3 groups: group 1, with r20 epilepsy (n = 16; mean age +/- SD, 21.5 +/- 5.4 y); group 2, with resistant generalized "absence-like" epilepsy (n = 10; mean age, 32.3 +/- 11.4 y); and group 3, with drug-resistant temporal lobe epilepsy with hippocampal sclerosis (n = 9; mean age, 35.2 +/- 10.3 y). We compared 2 strategies of analysis of the 18F-fluoro-L-DOPA uptake constant (K(i), min(-1)) in BG using a multiple-time graphical analysis using regions of interest (the gold-standard method) and an SPM analysis using a voxel-by-voxel statistical t test to avoid a priori hypotheses in the analysis. Each epileptic group was compared with a group of healthy volunteers (n = 10; mean age, 45.1 +/- 16.5 y). RESULTS: A decrease of the mean K(i) value was observed in the striatum in all groups of patients with both types of analysis. With multiple-time graphical analysis, the reduction was evident using the averaged K(i) values over both hemispheres in each BG. Unilateral decreases in each BG were detected in SPM analysis. A ratio of decrease of 18F-fluoro-L-DOPA uptake was observed in the 3 groups of patients. Only the SPM analysis showed a decrease of 18F-fluoro-L-DOPA uptake ipsilateral to the seizure side in patients with temporal lobe epilepsy. Moreover, the all-brain SPM analysis showed a decrease of 18F-fluoro-L-DOPA uptake in the substantia nigra bilaterally (P < 0.001). CONCLUSION: This result confirms the involvement of dopamine neurotransmission in seizure control related to the type of epileptic syndrome. The difference in epileptic types may depend in part on the seizure frequency.

In vivo imaging of human cerebral nicotinic acetylcholine receptors with 2-18F-fluoro-A-85380 and PET.

UNLABELLED: 2-(18)F-fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine (2-(18)F-fluoro-A-85380) is a PET radioligand that is specific for nicotinic acetylcholine receptors (nAChRs) and has a high affinity for the alpha(4)beta(2) subtype. The purpose of this study was to evaluate different strategies to quantify 2-(18)F-fluoro-A-85380 binding in healthy nonsmoking human volunteers. METHODS: After intravenous injection of 189 +/- 30 MBq (0.8-5.7 nmol) of 2-(18)F-fluoro-A-85380, the first dynamic PET scan was acquired over 150 min. The second 30-min PET scan was performed 60 min later. Time-activity curves were generated from volumes of interest. 2-(18)F-Fluoro-A-85380 volume of distribution (DV) was quantified using compartmental kinetic analysis and Logan graphical analysis. In the kinetic analysis, the 1-tissue compartment model (1TCM) and the 2-tissue (2TCM) compartment model were applied. The most appropriate kinetic model was determined using the Akaike Information Criterion. The effect of reducing the PET study duration on the reliability of the DV values computed by the kinetic and the graphical analyses was evaluated. RESULTS: Time-activity curves were better described by the 2TCM. The DV values ranged from 5.2 +/- 0.5 in the occipital cortex, 6.2 +/- 0.2 in the frontal cortex, and 7.3 +/- 0.4 in the putamen to 15.4 +/- 2.1 in the thalamus. These regional DV values were consistent with the distribution of nAChRs in the human brain. Logan graphical analysis provided slightly lower DV values than those of the 2TCM (from -3.5% in the occipital cortex to -6.6% in the thalamus). The minimal study duration required to obtain stable DV estimates in all regions was similar for the 2 methods: 140 min for the 2TCM and 150 min for the Logan analysis. DV estimates obtained with the 2TCM were more stable than those calculated by the Logan approach for the same scan duration. CONCLUSION: These results show that 2-(18)F-fluoro-A-85380 can be used to assess nAChRs binding in the human brain with PET.

Characterization of hyperinsulinism in infancy assessed with PET and 18F-fluoro-L-DOPA.

UNLABELLED: Hyperinsulinism (HI) of infancy is a neuroendocrine disease secondary to either focal adenomatous hyperplasia or a diffuse abnormality of insulin secretion of the pancreas. HI with focal lesions can revert by selective surgical resection in contrast to the diffuse form, which requires subtotal pancreatectomy when resistant to medical treatment. Neuroendocrine diseases are a heterogeneous group of entities with the ability to take up amine precursors and to convert them into biogenic amines. Therefore, the aim of this study was (a) to evaluate the use of PET with 18F-fluoro-L-dihydroxyphenylalanine (18F-fluoro-L-DOPA) and (b) to distinguish between focal and diffuse HI. METHODS: Fifteen patients (11 boys, 4 girls) with neonatal HI were enrolled in this study. All patients fasted for at least 6 h before the PET examination and their medication was discontinued for at least 72 h. The examination was performed under light sedation (pentobarbital associated with or without chloral). The dynamic acquisition started 45-65 min after the injection of 18F-fluoro-L-DOPA (4.0 MBq/kg weight). Four or 6 scans of 5 min each (2 or 3 steps according to the height of the patient) were acquired from the neck to the upper legs. RESULTS: An abnormal focal pancreatic uptake of 18F-fluoro-L-DOPA was observed in 5 patients, whereas a diffuse uptake of the radiotracer was observed in the pancreatic area of the other patients. All patients with focal radiotracer uptake and also 4 of 10 patients with pancreatic diffuse radiotracer accumulation, unresponsive to medical treatment, underwent surgery. The histopathologic results confirmed the PET findings--that is, focal versus diffuse HI. CONCLUSION: The results of this study suggest that 18F-fluoro-L-DOPA could be an accurate noninvasive technique to distinguish between focal and diffuse forms of HI.

FDG PET in patients with cancer of an unknown primary.

BACKGROUND: This prospective study was undertaken to address the capacity of positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) to determine the primary tumour site of carcinomas with unknown primary site. PATIENTS AND METHODS: Twenty-five patients with metastases from adenocarcinoma or undifferentiated carcinoma of unknown primary site (CUP) were included prospectively. For all patients, extensive imaging was unsuccessful in localizing the primary site. Patients received 370 MBq of 18F-FDG intravenously, and whole-body images were acquired 60 min after injection. All hot spots that could not be attributed to a metastatic site were considered as the primary tumour. The evaluation of FDG PET data was based on clinical and radiological outcome or surgery if indicated. RESULTS: Twenty-four patients were eligible for analysis. All known metastases were visualized. In six patients, FDG PET showed a primary tumour site which was confirmed by follow-up or surgery. In five patients, the primary tumour site was suggested by FDG PET but not confirmed by clinical outcome. No primary tumour was found in the other patients, with a mean follow-up of 15 months. CONCLUSION: In our series, FDG PET allowed the identification of primary tumour site in one quarter of patients with CUP (6/24). We conclude that FDG PET has a place in the initial staging of these patients.

Uptake-1 carrier downregulates in parallel with the beta-adrenergic receptor desensitization in rat hearts chronically exposed to high levels of circulating norepinephrine: implications for cardiac neuroimaging in human cardiomyopathies.

UNLABELLED: Imaging techniques have demonstrated in various cardiomyopathies that an altered uptake of radiolabeled norepinephrine (NE) analogs may coexist with beta-adrenergic receptor downregulation, but the relationships between these 2 alterations and their mechanisms remain unclear. The aim of this study was to evaluate the hypothesis of a chronic elevation of circulating NE levels as a mechanism of decreased uptake of radiolabeled NE analogs and reduced beta-adrenergic receptor sites in the heart. METHODS: Osmotic minipumps containing either NE or NaCl were implanted intravenously in rats for 5 d. The uptake-1 function was assessed in vitro by measuring in excised hearts (3)H-NE and (123)I-metaiodobenzylguanidine ((123)I-MIBG) uptakes and uptake-1 carrier density using (3)H-mazindol binding assay. The myocardial beta-adrenergic receptor pathway was assessed in vitro by (3)H-CGP 12177 binding and measurement of adenylyl cyclase activity at baseline and under stimulation. RESULTS: A 34% decrease in (3)H-NE uptake and a 35% decrease in (123)I-MIBG uptake were found in the hearts of rats infused with the NE pump compared with that of rats infused with saline solution (P < 0.05 for both). Moreover, the uptake-1 carrier protein density was decreased by 29% (P < 0.05) and 33% (P < 0.05) in right and left ventricles, respectively, of rats infused with NE compared with those infused with saline solution. Myocardial beta-adrenergic receptor desensitization was associated with a 36% reduction in receptor density in the right ventricle (P < 0.05) and a 31% reduction in the left ventricle (P < 0.05) of rats infused with NE compared with those infused with saline solution. CONCLUSION: The decrease in myocardial beta-adrenergic receptors and radiolabeled NE analog uptake found in different cardiomyopathies using neuroimaging techniques may be related to a functional mechanism of NE-induced downregulation of both beta-adrenergic receptor and uptake-1 carrier sites.

In vivo quantification and parametric images of the cardiac beta-adrenergic receptor density.

UNLABELLED: Previous studies showed that the in vivo concentration of beta-adrenergic receptor sites can be estimated by PET using (-)-4-((S)-3-tert-butylamino-2-hydroxypropoxy)-1,3-dihydrobenzoimidazol-2-one (CGP 12177), a hydrophilic ligand. A graphic method was previously proposed and used by several groups. However, this approach was not completely validated. The purpose of this study was to improve and confirm the validity of this approach through a better knowledge of the associated ligand-receptor model, estimated for the first time using the multiinjection approach. METHODS: The concentration of beta-adrenergic receptor sites was estimated for mini pigs using 2 methods. The first was the usual multiinjection approach, which permits estimation of all model parameters, including receptor concentration. However, this approach needs a complex protocol, including blood sampling, thereby making it difficult to use for studies on patients. The second method was the CGP 12177 graphic method. This approach permits the estimation of only receptor concentration but has the advantage of not requiring blood sampling. Another advantage is the ability to generate parametric images easily. RESULTS: Using the multiinjection approach, we obtained for the first time a complete model describing interactions between CGP 12177 and beta-adrenergic receptors. Knowledge of all parameters of this model permitted good validation of the assumptions included in the graphic method. The concentration of beta-adrenergic receptor sites in mini pigs was estimated at 15.2 +/- 3.4 pmol/mL. CONCLUSION: The graphic method has been improved by taking into account various phenomena, such as protein binding and the nonlinearity between plasma concentration and injected dose. This method is now usable for patient studies and offers the ability to estimate the beta-adrenergic receptor concentration from a single PET experiment without blood sampling. Parametric imaging will enable screening of the receptor site location and observation of potential anomalies in patients.

[18F]FPhEP and [18F]F2PhEP, two new epibatidine-based radioligands: evaluation for imaging nicotinic acetylcholine receptors in baboon brain.

The radioligand 2-[(18)F]fluoro-A-85380 has been developed for imaging alpha(4)beta(2) nAChRs with PET. However, it has slow kinetics and a large fraction of bound activity is nondisplaceable. In an attempt to address these problems, two epibatidine-based alpha(4)beta(2) nicotinic antagonists, coded FPhEP and F(2)PhEP, were evaluated in vivo in baboons. They were radiolabeled with fluorine-18 from the corresponding N-Boc-protected bromo-derivatives and the no-carrier-added K[(18)F]F-Kryptofix(222) complex. Radiochemically pure [(18)F]FPhEP or [(18)F]F(2)PhEP was obtained in 80 min in amounts of 1.11-2.22 GBq (111-185 GBq/micromol). After injection of 215 MBq of [(18)F]FPhEP or [(18)F]F(2)PhEP, dynamic PET data were acquired. Thalamic radioactivity peaked at 20 min (4.9% +/- 0.2% ID/100 mL tissue) for [(18)F]FPhEP. For [(18)F]F(2)PhEP, the peak was at 45 min (3.3% +/- 0.1% ID/100 mL tissue). Regional distribution of both radiotracers was in accordance with the known distribution of nAChRs. In presaturation experiments, nicotine, cytosine, or FPhEP reduced brain radioactivity of [(18)F]FPhEP. In a displacement experiment with nicotine only a small amount of [(18)F]F(2)PhEP was dislodged. In spite of a moderate to high in vitro affinity, both ligands do not fulfill the widely adopted criteria for a PET radioligand.

Acute effects of physostigmine and galantamine on the binding of [18F]fluoro-A-85380: a PET study in monkeys.

2-[18F]fluoro-3-[2S-2-azetidinylmethoxy]pyridine ([18F]fluoro-A-85380) is an alpha4beta2 subtype selective nicotinic cholinergic agonist with potential suitability for studying changes in endogenous acetylcholine synaptic concentration. Physostigmine, a potent AChE inhibitor, and galantamine, an allosteric modulator of nAChRs, are widely used for the treatment of Alzheimer's disease. Before studying patients with this neurodegenerative disease, positron emission tomography (PET) studies in monkeys were performed to assess the impact of these two compounds on the radiotracer distribution volumes. Physostigmine was administered i.v. at two dosages: 150 microg/kg/h and 37.5 microg/kg/h for 160 min. Galantamine was administered i.v. at two dosages: 2 or 4 mg over 20 min. For PET data analysis, a model with one tissue (radioactivity of the parent compound in plasma and radioactivity in brain tissue) compartment was chosen because reliable parameter estimates could not be obtained with a more complex model. The higher dose of physostigmine produced a 40%, 23%, and 30% reduction of distribution volumes in the putamen, the temporal, and frontal cortices, respectively. The lower dose of physostigmine produced a reduction of 33%, 31%, and 24% in the same structures, respectively. Galantamine (4 mg or 2 mg) produced no significant change of distribution volumes in the basal ganglia, the temporal and frontal cortex. The effects of physostigmine, a more potent AChE inhibitor than galantamine, could be interpreted as a desensitization of nAChRs, due to a prolonged exposure to high synaptic concentration of acetylcholine or as a competition with acetylcholine.

Acute inhibition of cardiac monoamine oxidase A after tobacco smoke inhalation: validation study of [11C]befloxatone in rats followed by a positron emission tomography application in baboons.

The in vivo characteristics of [11C]befloxatone were assessed in myocardium of rats and monkeys. A complete multicompartmental model was developed to quantify monkey cardiac monoamine oxidase A (MAO-A) binding sites using positron emission tomography (PET) and was applied to assess the acute effects of inhalation of tobacco smoke. Unknown compounds contained in tobacco smoke inhibit brain MAO. In vitro, befloxatone inhibits selectively, competitively, and reversibly MAO-A in human tissues. [11C]Befloxatone (1.85 MBq) was i.v. injected into rats. Animals were sacrificed, dissected, and samples were assessed for radioactivity. Another group of rats was pretreated with clorgyline (10 mg/kg i.v.). Monkeys were injected with [11C]befloxatone (222-370 MBq), and the chest was imaged with PET for 2 h. Presaturation and displacement experiments were performed using unlabeled befloxatone. For quantification of myocardial binding sites (Bmax), [11C]befloxatone was first injected as a tracer dose (2.7-9.3 nmol) and 20 min later injected as a mixture of labeled and unlabeled befloxatone (labeled, 10.3-41.9 nmol; unlabeled, 407-765 nmol). In rodents, cardiac uptake was high (3.39 +/- 0.5% injected dose/g tissue) and strongly inhibited (80%) by clorgyline. In monkeys, administration of unlabeled befloxatone displaced 85% of cardiac radioactivity. Bmax was found to be 208 +/- 13 pmol ml(-1) tissue. Inhalation of tobacco smoke decreased Bmax: 150 +/- 6.2 pmol ml(-1), whereas nicotine did not. [11C]Befloxatone allows a good visualization of the heart. Cardiac MAO-A Bmax was quantified and a clear effect of acute inhalation of tobacco smoke was evidenced. Therefore, a single cigarette can interfere with the cardiac turnover of catecholamines.

Biodistribution and radiation dosimetry of [11C]raclopride in healthy volunteers.

PURPOSE: This study reports on the whole-body biodistribution and radiation dosimetry of [11C]raclopride, a dopamine D2 receptor antagonist. METHODS: In three healthy male volunteers, whole-body scans were performed up to 2 h following i.v. injection of 320+/-65 MBq [11C]raclopride. Transmission scans (3 min per step, eight or nine steps according to the height of the subject) in 2D mode were used for subsequent attenuation correction of emission scans. Emission scans (1 min per step, eight or nine steps) were acquired over 2 h. Venous blood samples and urine were collected up to 2 h after injection of the radiotracer. For each subject, the percentage of injected activity measured in regions of interest over brain, intestine, lungs, kidneys and liver was fitted to a mono-exponential model, as an uptake phase followed by a mono-exponential washout, for urinary bladder to generate time-activity curves. Using the MIRD method, several source organs were considered in estimating residence time and mean effective radiation absorbed doses. RESULTS: Blood pressure and ECG findings remained unchanged after tracer injection. The analysed blood and urine pharmacological parameters did not change significantly after [(11)C]raclopride injection. The primary routes of clearance were renal and intestinal. Ten minutes after injection, high activities were observed in the gall-bladder, kidneys and liver. High activity was observed in the gall-bladder during the whole study. The kidneys, urinary bladder wall, liver and gall-bladder received the highest absorbed doses. The average effective dose of [11C]raclopride was estimated to be 6.7+/-0.4 microSv/MBq. CONCLUSION: The amount of [11C]raclopride required for adequate dopamine D2 receptor imaging results in an acceptable effective dose equivalent, permitting two or three repeated clinical PET imaging studies, with the injection of 222 MBq for each study.

Long-lasting occupancy of central nicotinic acetylcholine receptors after smoking: a PET study in monkeys.

The aim of this study was to compare the degree of occupancy of central nicotinic acetylcholine receptors (nAChR) in isoflurane anaesthetized baboon brain following inhalation of tobacco smoke (one cigarette containing 0.9 mg nicotine) or i.v. nicotine (0.6 mg i.v.). [18F]Fluoro-A-85380 and positron emission tomography (PET) were used to assess the distribution volumes (DV) of the radiotracer in selected brain areas using a one-compartment model. Eighty minutes after nicotine i.v., DV was reduced by 50 and 66% in the thalamus and putamen, respectively. Six hours after nicotine, a reduction in DV (27% in the thalamus) was still observed. Eighty minutes after inhalation of tobacco smoke, DV was decreased by 52 and 65% in the thalamus and putamen, respectively. Previous PET experiments have demonstrated a short-lasting interaction of [11C]nicotine with nAChRs. Thus, we hypothesized that a metabolite of nicotine with high affinity and long half-live (several hours) could bind at nAChRs. Eighty minutes after a high dose of nornicotine (0.5 mg i.v.), DV was reduced by 53 and 31% in thalamus and putamen, respectively. No significant effect was observed following 0.15 mg nornicotine. Therefore, nornicotine could contribute to the long-lasting occupancy of central nAChRs after smoking.