Regional cerebral L-[14C-methyl]methionine incorporation into proteins: evidence for methionine recycling in the rat brain.

The specific activity (SA) of free methionine was measured in plasma and in different regions of the rat brain at 15, 30, or 60 min after intravenous infusion of L-[14C-methyl]methionine. Within these time periods, an apparent steady state of labeled free methionine in plasma and in brain was reached. However, the brain-to-plasma free methionine SA ratio was found to be approximately 0.5, showing that an isotopic equilibrium between brain and plasma was not attained. This suggests the presence of an endogenous source of brain free methionine (likely originating from protein breakdown), in addition to the plasma source. The contribution of this endogenous source to the content of free methionine varies significantly among the different brain regions. Our results indicate that the regional rates of protein synthesis measured with L-[11C-methyl]methionine using positron emission tomography would be underestimated, since the local fraction of brain methionine derived from protein degradation would not be considered.

Combined study of cerebral glucose metabolism and [11C]methionine accumulation in probable Alzheimer's disease using positron emission tomography.

There is a characteristic decrease in glucose metabolism in associative frontal and temporo-parietal cortices of patients suffering from Alzheimer's disease (AD). The decrease in metabolism might result from local neuronal loss or from a decrease of synaptic activity. We measured in vivo [11C]methionine accumulation into proteins with positron emission tomography (PET) to assess cortical tissue loss in AD. Both global regional activity and compartmental analysis were used to express [11C]methionine accumulation into brain tissue. Glucose metabolism was measures with [18F]fluorodeoxyglucose and autoradiographic method. Combined studies were performed in 10 patients with probable AD, compared to age-matched healthy volunteers. There was a significant 45% decrease of temporo-parietal glucose metabolism in patients with AD, and frontal metabolism was lowered in most patients. Temporo-parietal metabolism correlated to dementia severity. [11C]methionine incorporation into temporo-parietal and frontal cortices was not significantly decreased in AD. There was no correlation with clinical symptoms. Data suggest that regional tissue loss, assessed by the decrease of [11C]methionine accumulation, is not sufficient to explain cortical glucose hypometabolism, which reflects, rather, reduced synaptic connectivity.

Local interrelationships of cerebral oxygen consumption and glucose utilization in normal subjects and in ischemic stroke patients: a positron tomography study.

With the use of positron emission tomography (PET) and the 15O steady-state-[18F]fluorodeoxyglucose combined method, the local interrelationships between the cerebral metabolic rate for oxygen (CMRO2) and the cerebral metabolic rate for glucose ( CMRGlc ) were investigated in control subjects and in stroke patients. In addition to the classic in vivo autoradiographic approach, a kinetic method was used to measure CMRGlc because it was expected to be more reliable in cerebral ischemia. In control subjects local coupling between CBF, CMRO2, and CMRGlc was confirmed, and acceptable values for the CMRO2/ CMRGlc ratio were found; the latter, however, was lower in white matter than in gray. Uncoupling between CMRO2 and CMRGlc was observed in all stroke patients, suggesting that (1) enhanced anaerobic glycolysis occurred both in reperfused recent infarcts and in chronically ischemic tissue, and (2) substrates other than blood-borne glucose were being oxidized at the borders of recent infarcts. However, methodological uncertainties presently make such observations only tentative. Finally, a coupled depression of CMRO2 and CMRGlc was found in the contralateral cerebellum.

Serotonin 5HT2 receptor imaging in the human brain using positron emission tomography and a new radioligand, [18F]altanserin: results in young normal controls.

Changes in serotonin-2 receptors have been demonstrated in brain autopsy material from patients with various neurodegenerative and affective disorders. It would be desirable to locate a ligand for the study of these receptors in vivo with positron emission tomography (PET). Altanserin is a 4-benzoylpiperidine derivative with a high affinity and selectivity for S2 receptors in vitro. Dynamic PET studies were carried out in nine normal volunteers with high-specific activity (376-1,680 mCi/mumol) [18F]altanserin. Arterial blood samples were obtained and the plasma time-activity curves were corrected for the presence of labeled metabolites. Thirty minutes after injection, selective retention of the radioligand was observed in cortical areas, while the cerebellum, caudate, and thalamus had low radioactivity levels. Specific binding reached a plateau between 30 and 65 min postinjection at 1.8% of the injected dose/L of brain and then decreased, indicating the reversibility of the binding. The total/nonspecific binding ratio reached 2.6 for times between 50 and 70 min postinjection. The graphical analysis proposed by Logan et al. allowed us to estimate the binding potential (Bmax/KD). Pretreatment with ketanserin was given to three volunteers and brain activity remained uniformly low. An additional study in one volunteer showed that [18F]altanserin can be displaced from the receptors by large doses of ketanserin. At the end of the study, unchanged altanserin was 57% of the total plasma activity. These results suggest that [18F]altanserin is selective for S2 receptors in vivo as it is in vitro. They indicate that [18F]altanserin is suitable for imaging and quantifying S2 receptors with PET in humans.

Brain regional pharmacokinetics of 11C-labeled diphenylhydantoin: positron emission tomography in humans.

We used positron emission tomography to study the regional cerebral pharmacokinetics of 11C-labeled diphenylhydantoin (11C-DPH), which was given intravenously to 10 patients (8 intractable partial epileptics and 2 nonepileptics). In the nonaffected hemisphere, 11C-DPH concentration in gray matter reached equilibrium with blood within 20 minutes but was still rising at 60 minutes in white matter, where equilibrium was too slow to be detected owing to the fast physical decay of 11C. Brain-blood concentration ratios at 50 minutes were 1.37 and 1.06 in gray and white matter, respectively, similar but less variable than steady-state DPH ratios reported in human brain surgical samples. There was no indication that normal brain regions of medically resistant epileptics bind DPH less effectively than in nonepileptic patients. Brain and blood 11C-DPH concentrations were well correlated, confirming that the latter gives a reliable estimate of the former in unaffected brain regions.

Dopaminergic receptor sites in human brain: positron emission tomography.

Positron emission tomography (PET) and 11C-labeled pimozide were used to study the dopaminergic (DA) receptor sites in the human striatum by comparing the latter with the cerebellum, which lacks DA receptors. Although 11C-pimozide concentration was not different in these two brain structures up to 53 minutes after IV injection (thus implying large nonspecific binding), a significant retention of radioactivity in striatum relative to cerebellum was found in controls but not in subjects pretreated with the unlabeled competitor haloperidol. This suggests that the striatal retention seen in controls was due to specific binding of 11C-pimozide to DA receptor sites, whereas prior occupation of the receptor sites by the unlabeled competitor was achieved in pretreated subjects.

A new generator for ionic gallium-68.

To meet the needs created by the rapid development of positron tomographic techniques, a new Ge-68 leads to Ga-68 generator has been developed. By elution under reduced pressure, this tin dioxide/1 N HCl generator provides a sterile solution of Ga-68 in ionic form, ready for use in the preparation of many radiopharmaceuticals. Since the Ga-68 recovery yield is high (75--80%) and the elution time very short (less than 2 min), these products possess maximum activity. Owing to its very slight Ge-68 leakage (less than 0.0002% per elution), the tin dioxide/HCl generator is long-lasting and, more importantly, the radiotoxicity of the labeled derivatives is kept to a minimum. The ionic Ga-68 obtained in this way has been used to label several radiopharmaceuticals.

Enantioselective synthesis of 6-[fluorine-18]-fluoro-L-dopa from no-carrier-added fluorine-18-fluoride.

METHODS: A trimethylammonium veratraldehyde triflate was synthesized and used as a precursor for the asymmetric synthesis of 6-[18F]fluoro-L-dopa. RESULTS: Its nucleophilic fluorination with 18F-fluoride produced by the 18O(p,n)18F nuclear reaction on enriched 18O-water led to the corresponding no-carrier-added [18F]fluoroveratraldehyde (45 +/- 5% EOB). Diiodosilane was used to prepare the corresponding [18F]fluorobenzyl iodide (36.5 +/- 5.3% EOB). Akylation of (S)-1-tert-boc-2-tert-butyl-3-methyl-4-imidazolidinone with this electrophilic agent, hydrolysis and purification by preparative high-pressure liquid chromatography made 6-[18F]fluoro-L-dopa ready for human injection, in a 23% +/- 6% decay-corrected radiochemical yield. The enantiomeric purity and the specific activity were above 96% and 1 Ci/mumole respectively. CONCLUSION: Through this procedure, starting from 250 mCi of 18F-fluoride, multimillicurie amounts (32 +/- 8.5 mCi) of no-carrier-added 6-[18F]fluoro-L-dopa are now available at the end of synthesis (90 min) with a good radiochemical purity (more than 98%).

Radiation dosimetry for bolus administration of oxygen-15-water.

UNLABELLED: We describe the development of a biokinetic model which permits an estimation of organ activities and the dosimetry of a bolus of 15O-water. The aim of this study was to estimate time-activity functions and deduce the cumulated activities in different organs so that the radiation absorbed dose values can be estimated. METHODS: The model we used includes the right heart chambers, lungs, left heart chamber, brain, liver, kidneys, muscles, gastrointestinal tract and the remainder of the body. Activity in an organ will decay by physical decay with the decay constant, lambda, and can diffuse in the organ. An exception is the heart, where blood is ejected from the heart chambers. Depending on the location of the organ in relation to the blood sampling point, organ activities can be calculated by convolution or deconvolution. RESULTS: The radiation absorbed dose values were estimated and an effective dose equivalent HE of 1.16 microSv/MBq (4.32 mrem/mCi) as well as an effective dose E of 1.15 microSv/MBq (4.25 mrem/mCi) were calculated. The cumulated activities in select organs measured by PET gave good agreement with the values calculated by this model. CONCLUSION: The values of effective dose equivalent and effective dose for bolus administration of 15O-water calculated from the absorbed doses estimated by the proposed kinetic model are almost three times higher than those previously published. A total of 8700 MBq (235 mCi) of 15O-water can be administered if an effective dose of 10 mSv (1 rem) is accepted.

In vivo analysis of bone calcium by local neutron activation of the hand: results in normal and osteoporotic subjects.

Mineral loss from bone can be measured accurately and reproducibly by neutron activation of the hand bones using a 5-min irradiation (10(6) n/cm2-sec) with two 200-microgram sources of Cf-252. The hand dose is 7.5 rad equivalent and the dose to the rest of body is 1.5 mrem. Controls (132) and osteoporotic patients (45) were compared. Between ages 20 and 60 the control group showed a bone calcium concentration of 0.177 +/- 0.025 g/cm3, independent of age. Between 60 and 70 the content remained unchanged in men but declined in women to 0.15 +/- 0.2 g/cm3. In all age groups osteoporotic patients in general showed lower calcium content. Comparison of our findings ("Ca") with estimates of bone mineral content obtained by photon absorptiometry ("BMC") yields 0.07 Ca + 0.262 (r = 0.87). Activation analysis of hand bone appears more precise than BMC for the monitoring of bone-mineral loss in each individual and as a measure of treatment efficacy.

Comparability of FDG PET studies in probable Alzheimer's disease.

Results of studies with positron emission tomography (PET) of 18F-2-fluoro-2-deoxy-D-glucose (FDG) in patients with probable Alzheimer's disease (AD) were compared among three European centers with different PET scanners (in-plane resolution ranging between 6.75 mm and 9.2 mm). A ratio of glucose metabolism in the most typically affected regions over the least typically affected regions was calculated to quantitatively analyze the characteristic pattern of AD. Diagnostic accuracy of this composite ratio was high (95.8%) and was superior to that of most ratios derived from single regions. Correspondingly, there was a consistent, highly significant difference between patients (mean ratio 0.77 +/- 0.11) and normals (mean 0.99 +/- 0.04) without significant differences among laboratories. Possible small effects of rate constant variation and region size were analyzed by computer simulation. The results demonstrate that a common investigation protocol may yield FDG PET data in different laboratories that are closely comparable in spite of differences between scanners and imaging equipment.

Differential diagnosis of Alzheimer's disease with PET.

UNLABELLED: PET studies have demonstrated bilateral temporo-parietal hypoperfusion and hypometabolism in probable and definite Alzheimer's disease (AD), a pattern that may help differentiate AD from other dementias. METHODS: To evaluate the diagnostic power of cerebral metabolic distribution patterns for "cortical" degenerative dementias, PET scans obtained from 129 patients referred for differential diagnosis of dementia were analyzed visually. RESULTS: Sixty-five patients had a final clinical diagnosis of probable AD. Ninety-seven percent (97%) of those had abnormal metabolic scans and 94% showed a suggestive pattern of bilateral or unilateral temporo-parietal hypometabolism (with or without frontal involvement). Hypometabolism was unilateral in 23% of patients. Five subjects with a neuropathologically proven diagnosis of Alzheimer's disease had a suggestive metabolic pattern. One of those was an early case with frontal hypometabolism exceeding temporo-parietal involvement. Two patients with Alzheimer's-type dementia had isolated bilateral frontal hypometabolism. CONCLUSIONS: This alternative metabolic pattern may correspond to a non-Alzheimer pathology occurring in 10%-20% of patients suffering from clinically probable Alzheimer's disease. Most of the patients with possible but atypical Alzheimer's-type dementia showed isolated bilateral frontal involvement. This metabolic pattern probably corresponds to different diseases, such as Pick's disease, frontal lobe dementia or progressive subcortical gliosis.

[11C]methionine pancreatic scanning with positron emission computed tomography.

By the use of [11C]methionine and positron computed tomography (PCT), images of the pancreas were obtained in 32 patients. The injection of between 10 and 20 mCi of this product enables four to six transverse sections to be obtained. Seventeen of the patients studied had no exocrine pancreatic disease, and in all these cases the pancreas was clearly visible. In four cases of pancreatic carcinoma and one of retroperitoneal tumor, there were abnormalities visible. In five cases of chronic pancreatitis, no pancreatic uptake was observed. In a sixth case, concentration was visible, but only in the head of the pancreas. One case of acute pancreatitis, which showed no concentration during the acute phase, returned to normal after recovery. When visible, the pancreas was easily located and distinguishable from the intestinal image, except in two cases that were uninterpretable for technical reasons. No false positive or negative was observed, but a differential diagnosis between cancer and pancreatitis was impossible.

Myocardial kinetics of potassium-38 in humans and comparison with copper-62-PTSM.

UNLABELLED: The aim of this study was to define the kinetics of 38K and its suitability to evaluate myocardial blood flow at rest and during pharmacological vasodilation in normal subjects. Potassium-38's kinetic characteristics were also compared to those of a 62Cu-pyruvaldehyde bis(n4-methyl-thio-semicarbazone) copper (II) (PTSM) flow tracer. METHODS: Potassium-38 and 62Cu-PTSM were injected at rest and after pharmacological vasodilation in six healthy volunteers. Dynamic PET acquisition was performed over 20 min and myocardial tracer retention calculated. Homogeneity of regional myocardial tracer distribution was also evaluated. RESULTS: High image quality of the heart was observed at rest and after dipyridamole with both tracers. Potassium-38 demonstrated prolonged myocardial retention with minimal lung and liver accumulation. In contrast to 38K, 62Cu-PTSM demonstrated high liver uptake which may hinder observation of the inferior wall of the myocardium. Copper-62-PTSM dipyridamole-to-rest retention ratio was 1.49. CONCLUSIONS: Potassium-38 and 62Cu-PTSM display suitable kinetics for the qualitative evaluation of blood flow and flow reserve in the human heart. Compared to 62Cu-PTSM, potassium-38, which does not show high liver uptake, may more accurately estimate blood flow in the inferior wall of the heart. However, accurate quantification of myocardial blood flow using 38K or 62Cu-PTSM retention appears to be limited to decreasing retention fraction at hyperhemic states.

[76Br]bromolisuride: a new tool for quantitative in vivo imaging of D-2 dopamine receptors.

Bromolisuride, an ergoline derivative, was labeled with the positron emitter radionuclide, bromine 76. In vitro and in vivo binding and competition studies in rats demonstrated a high affinity (KD = 0.3 nM) and a high specificity of this new radioligand for D-2 dopamine receptors. PET kinetic studies in baboons showed an accumulation of [76Br]bromolisuride in the striatum which reached a maximum 30 min post-injection and which could be displaced by haloperidol. All these results indicated that this new ligand is certainly suitable for the non-invasive in vivo quantitative imaging of D-2 dopamine receptor sites in human brain.

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

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

The kinetics and displacement of [11C]flunitrazepam in the brain of the living baboon.

The distribution and kinetics of [11C]flunitrazepam in the brain were studied by positron emission tomography in the living baboon. Flunitrazepam was labelled on the methyl group with the 20 min positron emitter carbon 11. Fifteen to 25 mCi corresponding to 15-30 nmol were injected i.v. and sequential tomographic pictures of the brain were obtained. In some experiments, therapeutic doses of various benzodiazepines were injected i.v. subsequently in order to study the displacement of the radioactive ligand from brain structures. Lorazepam was shown to displace [11C]flunitrazepam from brain tissue, although other benzodiazepines (chlordiazepoxide, Ro 116896 and Ro 116893) led to a redistribution of the radioactive ligand in the body accompanied by an increase of brain radioactivity.

Paradoxical metabolic response of the human brain to a single electroconvulsive shock.

Regional brain protein synthesis was evaluated with positron emission tomography (PET) and L-(S-[11C]methyl)methionine ([11C]MET) in depressive patients, before and 3 h after an electroconvulsive shock (ECS), when energy supply is restored, and in healthy volunteers. Depressive patients presented apparent lower protein synthesis than normals, in agreement with known reduction of cerebral activity. In contrast, ECS resulted in a significant increase (56%, P < 0.05) in global cortical protein synthesis. This paradoxical hyperactivation of cellular protein metabolism in response to seizures and the fact that synaptic activity is further reduced after electroconvulsive therapy (ECT), may provide new insights for understanding the mechanism of action of ECT.

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

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

Comparison study of CT and positron emission tomographic data in recent cerebral infarction.

To better understand the pathophysiologic correlates of the computed tomographic (CT) scan changes seen in recent cerebral infarction, 17 patients (20 studies) underwent both x-ray transmission and positron emission CT investigations within 18 days after clinical onset of complicated ischemic stroke in the internal carotid artery territory. The density changes before and after contrast study measured within the CT lesion were correlated to the local cerebral blood flow (CBF), oxygen utilization (CMRO2), and oxygen extraction fraction (OEF) measured with the oxygen-15 steady-state positron technique. Statistically significant linear correlations were found between hypodensity and CBF, hypodensity and CMRO2, and contrast enhancement and CBF, such that the more CBF and CMRO2 were depressed, the more marked was the hypodensity; and the more CBF was elevated, the more marked was the contrast enhancement. Although marked contrast enhancement was associated with decreased OEF (luxury perfusion), it was only rarely associated with increased CBF. Various hypotheses are discussed to explain these findings.