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.

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.

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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.