[ ¹⁸ F]Fluoro-dopa, an analogue of dopa, and its use in direct external measurements of storage, degradation, and turnover of intracerebral dopamine

Abstract

3,4-Dihydroxy-5-fluorophenylalanine, fluorodopa, was injected into rats in which unilateral lesions of the nigrostriatal pathway had been made. The rats rotated towards the side with the lesions, thus providing further evidence that fluoro-dopa is an analogue of dopa. ['8F]Fluoro-dopa was then injected intravenously into fully conscious baboons. A wellcollimated scintillation detector, aligned along the occipitomental axis, recorded the accumulation of 18F in the brain. prevented the accumulation of 18F; reserpine, known to release stored intracerebral dopamine, discharged 18F; pargyline, a monoamine oxidase inhibitor, and haloperidol, a Known augmentor of intracerebral dopamine turnover, increased the rate of accumulation of 18F. These changes in the accumulation of intracerebral 18F, after were commensurate with the known action of the drugs used to induce them and demonstrate the use of a y-emitting precursor of a neurotransmitter to monitor simply, atraumatically, and externally the intracerebral metabolism of the transmitter in fully conscious primates. When applied to man, the same technique shouldbe able to provide more conclusive evidence than is presently available for the role of catecholamines in schizophrenia and depression. It should also provide further insight into the natural history of nigrostriatal diseases and the action of drugs used in their treatment. There is no direct atraumatic method by which the localization or metabolism of intracerebral neurotransmitters can be measured during life in man. However, if a neurotransmitter were labeled with a Ry-emitting radionuclide it would be possible, using standard nuclear medicine techniques, to define both the intracerebral distribution and the regional rate of turnover of the molecule. Few of the neurotransmitters cross the bloodbrain barrier and, further, the half-lives of the Ry-emitting isotopes of their constituent atoms are too short to be used readily. MATERIALS AND METHODSResponse of Rats with Unilateral Lesions in the Substantia Nigra to Fluoro-dopa. Unilateral lesions of the substantia nigra of male Sprague-Dawley rats, 250-300 g, were made with 6-hydroxy-dopamine according to the method of Ungerstedt (5). After recovery each rat was treated with carbidopa (100 mg/kg of body weight) and placed in a round glass jar, 30-cm diameter. The rate at which the rats circled in the jar was recorded visually during a control period, after DL-dopa (100 mg/kg), and after apomorphine (10 mg/kg). Only rats that circled in response to both DL-dopa and apomorphine were used in subsequent experiments. These rats were then given intraperitoneally fluoro-dopa, 230 mg/kg, dissolved in saline with 1% ascorbic acid, and the rate at which each rat rotated was recorded for 1 hr after it had begun to circle. The dose of fluoro-dopa was chosen to be equivalent to 100 mg of dopa per kg on the assumption that at physiological pH approximately half of the fluoro-dopamine derived from fluoro-dopa would be un-ionized whereas almost all of the dopamine ma...

On‐off phenomenon: Relation to levodopa pharmacokinetics and pharmacodynamics

“…However, the interpretation of PET studies is clouded by not knowing exactly what levodopa metabolites contain the fluorine isotope visualized by PET at various times after injection of (18F)fluorodopa nor the effect of introducing the fluorine into the catechol ring on the affinity of levodopa for various enzymes and transporter proteins. Evidence, however, is accumulating that 1 "F)fluorodopa is an appropriate tracer for levodopa [8,25) and more information on the central pharmacokinetics of levodopa should soon be forthcoming.…”

Presynaptic Dopamine in Schizophrenia

“…L‐DOPA is then decarboxylated by aromatic acid decarboxylase (AADC) to DA (Figure 1). The first positron emission tomography (PET) tracer developed for studies of DA synthesis and/or storage in the human brain was [ 18 F]DOPA [8–10]. [ 18 F]DOPA, a radioactive analogue of L‐DOPA, the precursor of DA, is taken up by presynaptic monoaminergic neurons and is metabolized by AADC to 18 F‐Dopamine, which is trapped and stored within vesicles in the nerve terminals.…”

Dopa decarboxylase activity of the living human brain.

“…The accumulation of metabolites of 6-[18F]fluoro-L-dopa (Fdopa) in brain reflects the activity of dopa decarboxylase (DDC; aromatic-L-amino-acid carboxy-lyase, EC 4.1.1.28), the enzyme responsible for the formation of dopamine from dopa (3,4-dihydroxyphenylalanine) (1)(2)(3). Unlike tyrosine hydroxylase, this enzyme is believed not to be regulated in response to the intensity of dopaminergic neurotransmission (4).…”