The neurotransmitter dopamine has biological attributes that make it amenable to study by positron emission tomography, unlike many of the 40 or so neurotransmitters that have been identified in the brain. Dopamine deficiency in the nigrostriatal system is a characteristic of Parkinson's disease, and a disturbance of dopamine metabolism is still widely held to be responsible for the syndrome of schizophrenia. Despite its importance in the regulation of locomotion and mood, it has been impossible to visualize the intracerebral distribution of dopamine and measure its regional metabolism in man. In the first demonstration of the regional distribution of a neurotransmitter in the brain of conscious normal man, we show here that L-3,4-dihydroxyphenylalanine (L-dopa) labelled in the 6-position with the positron-emitting radionuclide fluorine-18, localizes specifically in the dopaminergic pathways of the human brain where its turnover could be measured atraumatically by positron emission tomography.

Background-The mechanism for the beneficial effect of ␤-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 (MV O 2 ). This approach can be used to measure the work-metabolic index, which is a noninvasive estimate of cardiac efficiency. Methods and Results-The aim of this study was to determine the effect of metoprolol on oxidative metabolism and the work-metabolic index in patients with LV dysfunction. Forty patients (29 with ischemic and 11 with nonischemic heart disease; LV ejection fraction Ͻ40%) were randomized to receive metoprolol or placebo in a treatment protocol of titration plus 3 months of stable therapy. Seven patients were not included in analysis because of withdrawal from the study, incomplete follow-up, or nonanalyzable PET data. The rate of oxidative metabolism (k) was measured using C-11-acetate PET, and stoke volume index (SVI) was measured using echocardiography. The work-metabolic index was calculated as follows: (systolic blood pressureϫSVIϫheart rate)/k. No significant change in oxidative metabolism occurred with placebo (kϭ0.061Ϯ0.022 to 0.054Ϯ0.012 per minute). Metoprolol reduced oxidative metabolism (kϭ0.062Ϯ0.024 to 0.045Ϯ0.015 per minute; Pϭ0.002). The work-metabolic index did not change with placebo (from 5.29Ϯ2.46ϫ10 6 to 5.14Ϯ2.06ϫ10 6 mm Hg ⅐ mL/m 2 ), but it increased with metoprolol (from 5.31Ϯ2.15ϫ10 6 to 7.08Ϯ2.36ϫ10 6 mm Hg ⅐ mL/m 2 ; PϽ0.001). Conclusions-Selective ␤-blocker therapy with metoprolol leads to a reduction in oxidative metabolism and an improvement in cardiac efficiency in patients with LV dysfunction. It is likely that this energy-sparing effect contributes to the clinical benefits observed with ␤-blocker therapy in this patient population.

2-, 5-and 6-L-[(8F] fluorodopa was used. The relative isomeric proportions were 35, 5 and 60% respectively. The radioactivity, 2-6 mCi, was associated with 8-10 mg L-fluorodopa. The estimated mean specific activity was 103-0 -+ 22-9 mCi/mmol. This mixture was injected intravenously in a volume of 10 ml over two minutes using a constant infusion Harvard pump.Construction of arterial curve A Teflon (gauge 21) cannula was inserted into one radial artery, and 3 ml blood samples were taken at 20 second intervals during the first three minutes following tracer injection, and then every 30 to 60 seconds for a further seven minutes. Arterial sampling times were then gradually spaced out via 5 and 10, to 20 minute intervals. Usually a total of 25 samples were taken. The samples were spun and the concentration of isotopes in plasma was measured in a well-counter cross calibrated with the tomograph.

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. 6-[18F]Fluorodopamine was synthesized faster than [14C]dopamine. In the frontal cortex, the major metabolite was also 6-[18F]fluorodopamine or [14C]dopamine. In the occipital cortex, the major metabolite was 3-O-methyl-6-[18F]fluoro-L-DOPA. On the basis of these data, the images obtained with 6-[18F]fluoro-L-DOPA and positron emission tomography in humans can now be interpreted in neurochemical terms.

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ABSTRACT:[ l8 F] 6-fluoro-L-dopa and positron emission tomography has been used to study intracerebral dopamine distribution in five control subjects and six patients with hemiparkinsonism. In the control subjects striatal, frontal and cingulate accumulations were clearly seen. In addition l8 F concentrated in the region of the insula and the parietal lobe.In the patients striatal accumulation l8 F was reduced in the contralateral striatum, especially in the putamen. The uniformity of distribution of 18 F in the striatum on the side of the parkinsonian signs was also irregular. This finding is consonant with the suggestion that intracerebral compensatory mechanisms prevent the manifestation of intracerebral dopamine deficiency from becoming obvious until a late stage of the disease. RESUME: Le [18 F] -6-fluoro-L-dopa et la tomographie a emission de positrons ont et6 utilises pour etudier la distribution de la dopamine au niveau du cerveau de cinq sujets normaux et de six sujets souffrants de la maladie de Parkinson unilat6rale. Chez le sujet normal, la fixation du [ l8 F] est clairement demontree dans le corp strie, le lobe frontal et la circonvolution cingulate, et aussi dans la region de l'insula et le lobe parietal.Chez le sujet souffrant de la maladie de Parkinson unilateral, une diminution de la fixation du [ l8 F] a ete identified dans le corp stri6 contralateral, particulierement dans le putamen. La distribution du [ l8 F] dans le corp strie ipsilateral est aussi irreguliere. Ces r6sultats sont concordants avec la these que des mecanismes intracerebraux compensatoires retardent la manifestation des symptomes resultants d'une carence de dopamine cerebrale jusqu'a un stade avance de la maladie.