The effects of beta(1)-blockade on oxidative metabolism and the metabolic cost of ventricular work in patients with left ventricular dysfunction: A double-blind, placebo-controlled, positron-emission tomography study.

Background: The mechanism for the beneficial effect of beta-blocker therapy in patients with left ventricular (LV) dysfunction is unclear, but it may relate to an energy-sparing effect that results in improved cardiac efficiency. C-11 acetate kinetics, measured using positron-emission tomography (PET), are a proven noninvasive marker of oxidative metabolism and myocardial oxygen consumption (MVO(2)). This approach can be used to measure the work-metabolic index, which is a noninvasive estimate of cardiac efficiency.

Synthesis of 2-iodo- and 2-phenyl-[11C]melatonin: potential PET tracers for melatonin binding sites.

Two 11C-labelled melatonin derivatives, 2-iodo-[11C]melatonin (2-iodo-5-methoxy-N[11C-acetyl]-tryptamine, an agonist) and 2-phenyl-[11C]melatonin (2-phenyl-5-methoxy-N[11C-acetyl]tryptamine, a putative antagonist) were synthesized from [11C]carbon dioxide. The reaction sequence was common to both compounds and consisted of three steps: (i) carbonylation of methyl magnesium bromide with [11C]carbon dioxide, (ii) conversion of the adduct to [11C]acetyl chloride, (iii) acetylation of the amine precursors (2-iodo-5-methoxy-tryptamine or 2-phenyl-5-methoxy-tryptamine) with [11C]acetyl chloride. The precursors were especially prepared.

Dopamine D2 receptors quantified in vivo in human narcolepsy.

Assays in brain tissues from humans suffering from narcolepsy, and from genetically narcoleptic dogs have suggested that dopamine function may be disturbed in this condition. We have used the specific D2 receptor ligand N-(3-[18F]fluoropropyl)-spiperone and positron tomography to study a group of 6 well-characterized medication-free, HLA-DR2 DRW15 DW6-positive narcoleptic patients and a group of age- and sex-matched control individuals during life. We found no difference in striatal D2 receptor binding between these two groups.

Direct radiofluorination of dopamine: 18F-labeled 6-fluorodopamine for imaging cardiac sympathetic innervation in humans using positron emission tomography.

Fluorine-18 labeled fluorodopamine (FDA) was synthesized by the direct fluorination with [18F]F2 [produced by the nuclear reaction 18O(p,n)18F] of dopamine in anhydrous hydrogen fluoride containing boron trifluoride at -65 degrees C. Reverse-phase high-performance liquid chromatography (HPLC) was used to separate [18F]6-FDA from the reaction mixture containing 18F-labeled 2- and 5-FDA. The radiochemical yield of [18F]6-FDA, with respect to [18F]F2, was 10 +/- 2% at the end of the 120-min synthesis from EOB1.

Regional distribution and kinetics of [18F]6-flurodopamine as a measure of cardiac sympathetic activity in humans.

Objectives: To determine whether an increase in cardiac sympathetic activity produced by exercise or sublingual glyceryl trinitrate causes an increased rate of loss of fluorine-18 from the myocardium after intravenous [18F]6-fluorodopamine ([18F]F-DA) in normal volunteers. In addition, to determine the contribution of non-specific uptake of [18F]F-DA in the myocardium in patients with recent heart transplant.

Protocol: [18F]F was prepared by direct electrophilic fluorination of dopamine.

A probe for intracerebral aromatic amino-acid decarboxylase activity: distribution and kinetics of [18F]6-fluoro-L-m-tyrosine in the human brain.

Positron tomography, using [18F]6-fluoro-L-dopa as a tracer, has been used for the study of Parkinson's disease. Unfortunately, the analysis of data obtained with this agent is bedeviled because it readily forms labeled methylated metabolites that enter the brain. We have evaluated [18F]6-fluoro-L-m-tyrosine (FmT) as an alternative tracer to study intracerebral dopamine metabolism with positron tomography.

Electrophilic 18F from a Siemens 11 MeV proton-only cyclotron.

Because more and more PET centres are using small proton cyclotrons there is a renewed interest in methods for the production of electrophilic 18F by proton irradiation of [18O]O2. A method for the routine production of clinically useful quantities of [18F]F2 having a specific activity of 35 Ci/mmol has been developed and implemented using an 11 MeV proton cyclotron and [18O]O2. Based on the yield, purity, reproducibility, and specific activity of [18F]F2 this is the most efficient method reported thus far.

The distribution and kinetics of [18F]6-fluoro-3-O-methyl-L-dopa in the human brain.

The analysis of positron tomographic studies of 3,4-dihydroxyphenylethylamine (dopamine) metabolism in which [18F]6-fluoro-L-3,4-dihydroxyphenylalanine (F-dopa) is used as a tracer is confounded by the presence of [18F]6-fluoro-3-O-methyl-L-3,4-dihydroxyphenylalanine (OMFD). This labeled molecule, formed by the action of peripheral catechol-O-methyltransferase on F-dopa, crosses the blood-brain barrier and contributes to the radioactivity measured by the tomograph. Corrections for this radioactivity in the brain have been proposed.

Noninvasive measurement of lung carbon-11-serotonin extraction in man.

The fraction of serotonin extracted on a single passage through the lungs is being used as an early indicator of lung endothelial damage but the existing techniques require multiple arterial blood samples. We have developed a noninvasive technique to measure lung serotonin uptake in man. We utilized the double indicator diffusion principle, a positron camera, 11C-serotonin as the substrate, and 11CO-erythrocytes as the vascular marker.

New 18F tracers for the investigation of brain functions.

Advances in the synthetic methodology of radiofluorination have increased the number of clinically useful 18F labeled tracers for positron emission tomography of the brain. It is now possible to measure in vivo with 18F tracers regional cerebral blood flow (18F-fluoromethane), dopamine metabolism (6-18F-fluoro-L-dopa) and dopamine D-2 receptor density (N-18F-fluoroethylspiperone). At present 18F tracers are being developed that will, in the near future, make accessible to investigation cerebral serotonin metabolism, serotonin receptor density, melatonin receptor density, activity of L-aromatic acid decarboxylase, and protein synthesis rate.

Increased frontal and reduced parietal glucose metabolism in acute untreated schizophrenia.

Frontal and parietal lobe metabolism was measured by [18F] fluorodeoxyglucose positron emission tomography in 8 never-medicated DSM-III schizophrenic patients and in 10 control subjects. Patients were in a psychotic episode at the time of this scan. Seven of eight had been ill less than 2 years and had only mild neurocognitive impairment.

Patterns of cerebral glucose metabolism using 18FDG and positron tomography in the neurologic investigation of the full term newborn infant.

18F fluorodeoxyglucose (18FDG) and positron tomography (PT) were used in 20 full term babies with seizures or hypotonia to describe regional cerebral glucose metabolism. Among babies with seizures, birth asphyxia was the most common cause. PT was performed at age 6-17 days.

Effect of neuroleptics on altered cerebral glucose metabolism in schizophrenia.

This study examines whether the duration of treatment with antipsychotic drugs influences the regional distribution of cerebral [18F]2-fluoro-2-deoxy-D-glucose utilization as measured by positron emission tomography. Two groups of schizophrenic patients are compared with normal volunteers (n = 10). One group (n = 5) consisted of patients treated for one year, and the second (n = 12) of patients medicated for four to 14 years (mean +/- SD duration, 7.

Metabolites of 6-[18F]fluoro-L-dopa in human blood.

The metabolites of 6-[18F]fluoro-L-dopa in the blood plasma of healthy humans have been identified as 3-O-sulfato-6[18F]fluoro-L-dopa, 3-O-methyl-6-[18F]fluoro-L-dopa, 6-[18F] fluorodopamine, and 6-[18F]fluorohomovanillic acid. The time course of these metabolites was followed up to 2 hr. The findings have implications for the use of 6-[18F]fluoro-L-dopa as tracer for cerebral dopamine metabolism.

A rostrocaudal gradient for aromatic acid decarboxylase in the human striatum.

The local concentration of 6-[18F]fluoro-L-dopa(18F) reflects the activity of aromatic acid decarboxylase (AADC), the enzyme that generates dopamine from its precursor amino acid, L-dopa. In young healthy adults, the local concentration of 18F, and hence AADC activity, is constant in coronal slices taken in a rostrocaudal direction. With increasing age a gradient representing decreasing activity in the putamen develops.

Cerebral metabolism of 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine in the primate.

The tracers 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine (6-[18F]fluoro-L-DOPA) and L-[14C]DOPA were injected simultaneously into rhesus monkeys, and the time course of their metabolites was measured in the striatum and in the occipital and frontal cortices. In the striatum, 6-[18F]fluoro-L-DOPA was metabolized to 6-[18F]fluorodopamine, 3,4-dihydroxy-6-[18F]fluorophenylacetic acid, and 6-[18F]fluorohomovanillic acid. The metabolite pattern was qualitatively similar to that of L-[14C]DOPA.

Regional cerebral glucose metabolism in SLE chorea: further evidence that striatal hypometabolism is not a correlate of chorea.

The pathophysiology of chorea in systemic lupus erythematosus (SLE) is uncertain. Pathologic examination has not identified a specific location for the causative lesion(s) and immunologic mechanisms have been suggested in its etiology. In other choreic disorders, such as Huntington's disease and benign hereditary chorea, glucose hypometabolism in the striatum has been demonstrated by positron computed tomography (PCT) using [18F]deoxyglucose.

Brain dopamine metabolism in patients with Parkinson's disease measured with positron emission tomography.

L-[18F] fluorodopa was administered in trace amounts intravenously to healthy control subjects and to patients with Parkinson's disease. Striatal uptake of radioactivity was measured using positron emission tomography. The capacity of the striatum to retain tracer was severely impaired in patients compared to controls.

High yield synthesis of 6-[18F]fluoro-L-dopa.

The radiofluorination of L-dopa with [18F]F2 was investigated with the purpose of improving the yield of 6-[18F]fluoro-L-dopa. When boron trifluoride was added to the reaction mixture in hydrogen fluoride (HF), the yield was increased threefold. Nine millicuries of 6-[18F]fluoro-L-dopa were produced from 100 mCi [18F]F2 routinely and reliably after 2 hr of preparation.

[18F]fluoro-L-dopa for the in vivo study of intracerebral dopamine.

6-[18F]Fluoro-L-dopa was designed to trace the dopamine metabolism in the brain with positron tomography. 6-[18F]Fluoro-L-dopa resembles natural L-dopa biochemically, it crosses the blood-brain barrier with the similar kinetics, it is decarboxylated by dopa decarboxylase and is stored intraneuronally in vesicles. In addition the rate of O-methylation of 6-[18F]fluoro-L-dopa by catechol-O-methyl transferase is only 1/4 of that of natural L-dopa.

Estimation of the radiation dose in man due to 6-[18F]fluoro-L-dopa.

The radiation dose to the organs of the human body after an intravenous administration of 6-[18F]fluoro-L-dopa was estimated using the recommendations of the International Committee on Radiological Protection (ICRP). The bladder wall received the highest dose, 6.95E-10 Sv/Bq (2,600 mrem/mCi), and as a consequence the dose to the genitalia was 1.

Striatal dopamine distribution in parkinsonian patients during life.

Eleven neuropsychologically normal Parkinsonian patients were studied with [18F]6-fluoro-L-dopa and positron tomography. In all of the patients dopaminergic activity was reduced in the putamen on the side opposite to the major motor signs. The reduction was similar in tremulous and rigid patients.