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The significance of task-induced cerebral blood flow responses, assessed using statistical parametric mapping, depends, among other things, on the signal-to-noise ratio (SNR) of these responses. Generally, positron emission tomography sinograms of (H2O)-O-15 activation studies are reconstructed using filtered backprojection (FBP). Alternatively, the acquired data can be reconstructed using an iterative reconstruction procedure. It has been demonstrated that the application of iterative reconstruction methods improves image SNR as compared with FBP. The aim of this study was to compare FBP with iterative reconstruction, to assess the statistical power of (H2O)-O-15-PET activation studies using statistical parametric mapping. For this case study, PET data originating from a bimanual motor task were reconstructed using both FBP and maximum likelihood expectation maximization (ML-EM), an iterative algorithm. Both resulting data sets were statistically analyzed using statistical parametric mapping. It was found, with this dataset, that the statistical analysis of the iteratively reconstructed data confirm the a priori expected physiological response. In addition, increased Z scores were obtained in the iteratively reconstructed data. In particular, for the expected task-related response, activation of the posterior border of the left angular gyrus, the Z score increased from 3.00 to 3.96. Furthermore, the number of statistically significant clusters doubled while their volume increased by more than 50%. In conclusion, iterative reconstruction has the potential to increase the statistical power in (H2O)-O-15-PET activation studies as compared with FBP reconstruction. (C) 2002 Elsevier Science.

β-Adrenoceptors in human lungs and heart can be imaged with the radioligand 4-[3-[(1,1-dimethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-11C-one (CGP 12177, [11C]I). For quantification of receptor density with compartment models by adjustment of rate constants, an ‘input function’ is required which consists of the integral of the concentration of unmodified ligand in arterial plasma over time. A discrepancy in the literature regarding metabolic stability of [11C]I prompted us to study metabolism in rats by reversed-phase HPLC (RP-HPLC) of trichloroacetic acid extracts of arterial plasma after i.v. injection of [11C]I (> 11.1 TBq/mmol, 11 MBq/kg). Some plasma samples were also directly applied to an internal-surface reversed-phase (ISRP) column. In parallel experiments, tritiated [11C]I was employed and methanol extracts of arterial plasma were analyzed by straight-phase TLC. The three methods were in excellent agreement. Unmodified [11C]I decreased from > 98.5% ( 3 H ) or > 99.9% ( 11 C ) initially to 57 ± 7% at 80 min post injection to formation of two polar metabolites. Using the RP-HPLC method, no metabolism was detectable in humans up to 30 min after injection of [11C]I (1851 MBq). Deproteinization of plasma with acetonitrile resulted in the formation of a radioactive species (artifact) which eluted immediately after the void volume in RP-HPLC and which could be mistakenly interpreted as a metabolite. Plasma protein binding was low (ca. 30%) in both humans and rats. Association of the radioligand to blood cells suggested that equilibrium between receptor-bound and free radioligand was reached within 15 min after high-specific-activity injections, but only after more than 30 min after low-specific-activity injections.

System parameters as spatial resolution, sensitivity, singles and coincidence count rates, signal to noise (S/N) ratio have been measured with positron emitting radiopharmaceuticals in a Siemens MultiSpect2 system with 511 keV collimators, a Siemens ZLC dual-headed uncollimated rotating gamma camera system operated in coincidence mode and a Siemens Ecat 951/31 PET ring system. From these measurements it is evident that the sensitivity and spatial resolution of PET systems are superior to those achieved by SPECT systems. The performance of PET ring systems is superior compared to dual-headed coincidence systems especially if count rate capability and accidental coincidences are considered. The better energy resolution of NaI in comparison with BGO results in a lower scatter fraction at the same energy window. An absolute quantitation is only possible with PET ring systems with an individual attenuation correction.

In both quadrupedal and bipedal walking, cyclic movements Of opposite limbs are made in antiphase, with identical frequency of all four limbs. these kinematical characteristics generated the hypo thesis, that, in humans, the cerebral control of this stereotypic movement pattern. is associated with a common circuitry involved in antiphase movement, independent from execution by dither the two upper or,the two lower limbs. By means of positron emission tomography (PET), we identified cerebral activations related to limb-independent antiphase movement distributed over the right anterior parietal and the eight dorsal premotor cortex. Particularly, involvement of the eight parietal cortex' demonstrates a lateralized brain function for higher-order somatosensory processing enabling the sensorimotor anchoring of stereotypic multilimb movement.

We investigated whether left-hemisphere arachnoid cysts lead to reorganization of the language function using PET. A group analysis demonstrated that patients showed no more right-hemisphere activation than a matched control group. Several patients had clear language localizations in the left hemisphere during language comprehension; none of the patients showed right-hemisphere activation. We conclude that left-hemisphere tissue must suffer considerable compromise before reorganization of language into the right hemisphere becomes necessary. Language activations within the left hemisphere are clearly displaced. This is consistent with mere physical displacement in some patients rather than reorganization within the left hemisphere; in others intrahemispheric reorganization cannot be excluded. (C) 2000 Academic Press.

A story told by his mother was presented on tape to a trauma patient in persistent vegetative state (PVS). During auditory presentation, measurements of regional cerebral blood flow (rCBF) were performed by means of positron emission tomography (PET). Changes in rCBF related to this stimulus condition, as compared to presenting non-word sound, were evaluated by means of statistical parametric mapping (SPM). This analysis indicated activation of rostral anterior cingulate, right middle temporal and right premotor cortices, which may reflect appropriate cortical involvement in processing emotional attributes of sound or speech.

Spinal cord stimulation applied at thoracic level 1 (T1) has a neurally mediated anti-anginal effect based on anti-ischaemic action in the myocardium. Positron emission tomography was used to study which higher brain centres are influenced by spinal cord stimulation. Nine patients with a spinal cord stimulator for angina pectoris were studied using H(2)(15)O as a flow tracer. Relative changes in regional cerebral blood flow related to stimulation compared with non-stimulation were assessed and analysed using the method of statistical parametric mapping. Increased regional cerebral blood flow was observed in the left ventrolateral periaqueductal grey, the medial prefrontal cortex [Brodmann area (BA) 9/10], the dorsomedial thalamus bilaterally, the left medial temporal gyrus (BA 21), the left pulvinar of the thalamus, bilaterally in the posterior caudate nucleus, and the posterior cingulate cortex (BA 30). Relative decreases in rCBF were noticed bilaterally in the insular cortex (BA 20/21 and BA 38), the right inferior temporal gyrus (BA 19/37), the right inferior frontal gyrus (BA 45), the left inferior parietal lobulus (BA 40), the medial temporal gyrus (BA 39) and the right anterior cingulate cortex (BA 24). It is concluded that spinal cord stimulation used as an additional treatment for angina applied at T1 modulates regional cerebral blood flow in brain areas known to be associated with nociception and in areas associated with cardiovascular control.

S-1'-[F-18]fluorocarazolol was administered to healthy volunteers to assess its potential for noninvasive measurement of regional pulmonary and myocardial beta-adrenoceptor densities. Methods: High-specific activity fluorocarazolol was intravenously injected on two separate occasions within a 1-wk interval. The initial injection was without pretreatment, but before the second injection, the volunteers either inhaled salbutamol (2 x 200 mu g aerosol) or they ingested pindolol (3 x 5 mg during a 12-hr interval). Twenty-eight PET time frames of 31 planes were acquired over a period of 60 min after each injection. Blood samples were drawn and analyzed for the presence of fluorocarazolol and radioactive metabolites. Results: Uptake of fluorocarazolol in the target tissues was hardly affected by salbutamol but was strongly depressed by pindolol. Pulmonary and myocardial tissue-to-plasma concentration ratios of fluorocarazolol reached plateau values of 11.6 +/- 0.6 (lungs) and 18.1 +/- 1.0 (heart) at 45-50 min postinjection. These values were reduced to 2.0 +/- 0.4 and 2.0 +/- 0.6 after treatment with pindolol. Conclusion: These data indicate that: 1. Pulmonary and myocardial uptake of radioactivity after intravenous administration of S-1'-[F-18]fluorocarazolol represents radioligand binding to beta-adrenoceptors. 2. Pulmonary binding occurs mainly in alveoli rather than in airway smooth muscle under these conditions. 3. Binding kinetics do not preclude quantification of receptors with compartment models.

It is often difficult to detect a local recurrence of soft-tissue sarcomas due to disturbance of the normal anatomy by previous surgery and radiotherapy. The aim of this study was to assess the value of positron emission tomography (PET) with [18F]fluoro-2-deoxy-D-glucose (FDG) for detecting local recurrences.In the period 1992-1995, 17 patients with proven or suspected local recurrence of soft-tissue sarcoma were examined using FDG-PET. Fifteen of these patients were ultimately proven to have a recurrence.Recurrence was visualized in 14 patients (93%). Small tumors (maximum diameter 0.5 cm) were as easily visible as large lesions (maximum diameter 20 cm). In one patient the PET scan was positive, but the recurrence could not be proven histologically. Recurrence was proven 1 year later. A recurrent low-grade liposarcoma was not visualized. The two patients with benign lesions had a negative PET scan. The mean glucose metabolic rate was calculated to be 13.2 mumol/100 g/min (range 1.9-28.4). A correlation was found between the histological malignancy grade and the metabolic rate (p0.05; Kruskal-Wallis).PET with FDG is a useful addition to the diagnostic armamentarium for detecting local recurrence of soft-tissue sarcomas and provides an indication of the malignancy grade of the recurrent lesion.

Patients with phenylketonuria (PKU) may suffer from cognitive and neurological deficits which are related to reduced intracerebral concentrations of catecholamines. The function of phenylalanine (Phe) as an inhibitor of the uptake of the precursor amino acid tyrosine (Tyr) through the blood-brain barrier as well as an inhibitor of the expression of dopamine receptors in the brain is under investigation. Positron emission tomography (PET) is a method for quantitatively determining biochemical and physiological processes in vivo. In the current pilot study, L-[1-C-11]-Tyr and F-18-fluoro-ethyl-spiperone (FESP) have been used. The metabolic pathway of carboxylic labelled Tyr is mainly incorporation into protein. From the measured tissue and plasma activity as a function of time in combination with a compartimental model the Protein Synthesis Rate (PSR) for Tyr can be calculated. FESP is a ligand which binds irreversibly to the dopamine D-2-receptor and has also a low non specific binding, although affinity to the serotonin receptor has been described, The ratio of FESP concentration in striatum and in cerebellum is a measure of the receptor status in vivo. In patients with plasma Phe levels above the maximum therapeutic concentration (> 700 mu mol/l) the PSR for Tyr was decreased as compared to controls and patients with plasma Phe concentrations within the therapeutic range, indicating a decreased availability of Tyr for neurotransmitter synthesis, and hence explaining the reduced cerebral concentration of catecholamines.

The biodistribution of (-)-4-(3-t-butylamino-2-hydroxypropoxy)-[5,7-H-3-benzimidazol-2-one (CGP12177, a non-selective beta-adrenoceptor antagonist) and 1-[2-(3-carbamoyl-4-hydroxy)-(5-H-3-phenoxy)]-2-propanol methanesulfonate, (CGP26505, a beta1-adrenoceptor antagonist) was studied in rats pretreated with various alpha- and beta-adrenoceptor blocking drugs (5 min before H-3 injection, in dosages at which the drugs demonstrated the expected selectivity). Cardiac and pulmonary radioactivity were measured after 10 min, when specific binding was maximal. Uptake of [H-3]CGP12177 was linked to binding to beta-adrenoceptors since it was not affected by prazosin or yohimbine, and was equally well inhibited by propranolol, unlabelled CGP12177 and isoprenaline. Moreover, atenolol and CGP20712A inhibited [H-3]CGP12177 uptake in heart (predominantly beta1-adrenoceptors) more potently than ICI 118,551, while in lungs (predominantly beta2-adrenoceptors) ICI 118,551 was more potent than atenolol or CGP20712A. In contrast, [H-3]CGP26505 uptake in the target organs was equally effectively inhibited by propranolol and ICI 118,551, and significantly lowered by alpha-adrenoceptor antagonists. We conclude that [C-11]CGP12177, but not [C-11]CGP26505 will be suitable for positron emission tomography imaging of beta-adrenoceptors in animals.

The rise-time method as a position sensitive read-out of a proportional chamber is investigated. An expression is derived for the pulse form at the end of the wire as a function of time and position of the discharge. With a proper termination the response of the line can be made linear. From the pulse form the zero-cross time, linearity and sensitivity are calculated. The calculations were experimentally verified with a 30 cm long resistive wire detector. An expression for the noise is derived and the influence of the filter time constants on the resolution is discussed.

Preparation of a number of cyclotron produced short lived radiopharmaceuticals labelled with11C,18F,13N,123I and81Rb/81Kr are described.

In 13 hemiparkinson patients possible changes in dopamine receptors were investigated in vivo with PET, using [11C]methylspiperone as the receptor labeling ligand. Though in individual patients the specific binding of the tracer differed between both striata, no consistent difference was found. However, the specific binding in the striatum of patients with longterm dopaminergic medication was significantly higher than in non-medicated patients, and close to normal. No correlation with the predominantly unilateral clinical pathology was found. Since the postsynaptic receptor changes in hemiparkinson patients appear not to be uniform, these results suggest that the clinical asymmetry is not only caused by a dysfunction of nigral dopaminergic cells, but by pathology in other cells and probably in other neurotransmitter systems as well. The observed bilateral increase in receptor binding during dopaminergic therapy most likely results from a symmetrical change in local pharmacokinetics or from alteration of the receptor binding. Further studies with PET are needed to determine the exact nature of this change.

To measure the rate of protein synthesis in human neoplasms by positron emission tomography, we prepared no carrier added DL-(1-11C)-tyrosine by 11C-carboxylation of the appropriate alpha-lithioisocyanide followed by hydrolysis of the isocyanide function and removal of the protecting methoxy group. The purification, resolution and solvent switch to saline was performed by high performance liquid chromatography (HPLC). DL-(1-11C)-Tyrosine in 0.1 N NaH2PO4 buffer was prepared with a radiochemical yield of 8%-16% (EOS, 35 min). The enantiomeric separation and solvent switch to saline were achieved in 5 min and 10 min respectively. Consequently L-(1-11C)-tyrosine in physiological saline was obtained in 2%-4% radiochemical yield. Tumor accumulation in rats with the experimental WALKER 256 carcinosarcoma was observed for both the L- and D-isomer. Using positron emission tomography a tumor/muscle ratio of two was observed for the L-isomer 15 min after injection. The corresponding figure for the D-isomer was 2.5. The first clinical results with DL-(1-11C)-tyrosine show accumulation of radioactivity in meningioma, a primary breast carcinoma and in liver metastases of a colonic carcinoma.

The distribution of increased regional cerebral blood flow (rCBF) related to visuomotor coordination was studied by means of positron emission tomography (PET) in normal subjects. An experimental condition, in which a vertically presented zigzag figure had to be copied in a horizontal orientation, was compared with a control condition in which the same horizontal drawing was made, guided by a horizontally presented example. Cognitive components dealing with the mismatch in visual orientation resulted in activation of (i) right dorsal premotor cortex, (ii) right posterior parietal cortex, (iii) visual cortex (area V1) and (iv) left fusiform gyrus. In a second experiment, conditions were compared in which the same horizontal zigzag figure was copied in either a vertical or a horizontal orientation. Now, the motor components of the transformation of orientation appeared to be associated only with left premotor cortex activation. The differential distribution of activations is regarded to reflect the selective effort to cope with either the visual or the motor component of spatial incongruity, and indicates specialization for perceptual and executive components in visuomotor control. We propose that the perceptual component of visuomotor transformation in our experiment relates to a realignment of the coordinates of a percept to an internally defined coordinate system. The executive component relates to guidance of movement within an internal representation of space. In a preceding behavioural experiment, a majority of patients with Parkinson's disease (PD) failed on the task in which they had to make a horizontal copy of a vertically presented picture. This finding may suggest a deficit in the maintenance of an internal spatial representation to guide movement.

We evaluated the suitability of fluorocarazolol for in vivo studies of cerebral beta-adrenoceptors because (S)-1'-[F-18]fluorocarazolol has a higher affinity to beta-adrenoceptors than to serotonergic receptors (pK(i) beta(1) 9.4, beta(2) 10.0, 5HT(1A) 7.4, 5HT(1B) 8.1) and rapidly crosses the blood-brain barrier. Methods: The (S)-[F-18]fluorocarazolol (74 MBq, >37 TBq/mmol) was intravenously administered to healthy volunteers on two separate occasions with an interval of at least 1 wk, The initial injection was without pretreatment, but before the second injection, the volunteers received the beta blocker (+/-)-pindolol (3 x 5 mg orally, during 18 hr). The brain was studied with a PET camera in dynamic mode. Results: Uptake of radioactivity delineated gray matter and was particularly high in the posterior cingulate, precuneus and striatum, Low uptake occurred in the thalamus, whereas the lowest uptake was observed in the white matter of the corpus callosum. After pindolol pretreatment, uptake was reduced and its distribution became homogeneous throughout the brain, The ratio of total-to-nonspecific binding was about 2 at 60 min, increasing to 2.5-2.75 at longer intervals. Conclusion: Fluorocarazolol is the first radioligand that can visualize cerebral beta-adrenoceptors and may enable monitoring of these binding sites during disease.

The applicability of protein synthesis rate (PSR) determination with L-[1-C-11]tyrosine (C-11-TYR) and PET was assessed in patients suspected of a primary or recurrent brain tumor. Methods: Simultaneous to intravenous injection of 265 MBq of C-11-TYR, dynamic PET acquisition was started and continued for 50 min. Arterial samples were taken and analyzed for C-11-TYR and metabolites. Based on this data, a model was proposed and the corresponding PSR calculated. Results: Plasma metabolites were (CO2)-C-11, C-11-proteins and C-11-L-DOPA, constituting more than 50% of total plasma radioactivity at 40 min postinjection. Plasma (CO2)-C-11 reached a plateau of around 25% of total plasma radioactivity at 20 min postinjection. Plasma C-11-protein was not detected before 10 min postinjection, but increased exponentially afterwards to 20% at 40 min postinjection. Plasma C-11-L-DOPA was the only acid-soluble radioactive metabolite detected and was less than 8% at 40 min postinjection. Using a five-compartment model, it was shown that while the net PSR was dependent on the recycling of amino acids from protein, the amino acid incorporation was not, which was thus used for subsequent analysis. It was found that our curve-fitting results were unreliable due to the exchange of C-11-TYR between plasma and erythrocytes whereas the graphical Patlak-Gjedde analysis is hardly influenced by this transport phenomenon. The average amino acid incorporation rate thus calculated was 0.7 nmole/ml . min for nontumor tissue with a tumor versus nontumor average ratio of 1.7. Conclusion: The assessment of the PSR with TYR-PET is valuable and relatively simple to implement clinically.