6-18F-L-DOPA imaging of the dopamine neostriatal system in normal and clinically normal MPTP-treated rhesus monkeys

SummaryPositron emission tomography following intravenous administration of 6-[18F]-L-fluorodopa was used to investigate the usefulness of PET for the assessment of normal and abnormal dopaminergic function. For this purpose, the incracerebral distribution of 6-[18F]-L-fluorodopa and its metabolites was evaluated in normal control and asymptomatic MPTP-treated rhesus monkeys. MPTP is a neurotoxic compound which destroys selectively the dopaminergic neurons of the nigrostriatal pathways in primates. The 18F accumulation was found to be significantly reduced in the striatum, putamen more than caudate, of the MPTP-treated animals compared to the normal controls. The 18F accumulation in dopamine-poor areas did not differ between the two groups. The ratios of striatum to dopamine-poor brain area were highly correlated to the concentrations of the dopamine metabolite, homovanillic acid, in the cerebrospinal fluid of the same animals. The findings are consistent with the hypothesis that “silent damage” to the dopaminergic nigral neurons may precede the onset of parkinsonism by many years and that PET scanner examination using 6-[18F]-L-fluorodopa may be useful in the detection of subtle dopaminergic dysfunctions as may exist in DA-related motor syndromes and neuropsychiatric disorders.

[1]  J. Krystal.  Monoamine Innervation of the Cerebral Cortex , 1985, The Yale Journal of Biology and Medicine.

[2]  G. Firnau,et al.  [18F]fluoro-dopa, an analogue of dopa, and its use in direct external measurements of storage, degradation, and turnover of intracerebral dopamine. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[3]  C Nahmias,et al.  [18F]fluoro-L-dopa for the in vivo study of intracerebral dopamine. , 1986, International journal of radiation applications and instrumentation. Part A, Applied radiation and isotopes.

[4]  J W Langston,et al.  MPTP: current concepts and controversies. , 1986, Clinical neuropharmacology.

[5]  E. Melamed,et al.  Regional cerebral blood flow in patients with Parkinson's disease under chronic levodopa therapy: measurements during "on" and "off" response fluctuations. , 1986, Journal of neurology, neurosurgery, and psychiatry.

[6]  M. Horne,et al.  The cerebral metabolism of L-dihydroxyphenylalanine. An autoradiographic and biochemical study. , 1984, Pharmacology.

[7]  R. Chirakal,et al.  Radiofluorination with 18F-labelled acetyl hypofluorite: [18F]L-6-fluorodopa , 1984 .

[8]  B. Pate,et al.  Routine synthesis of L-[18F]6-fluorodopa with fluorine-18 acetyl hypofluorite. , 1986, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[9]  Sanford P. Markey,et al.  Chronic parkinsonism secondary to intravenous injection of meperidine analogues , 1979, Psychiatry Research.

[10]  Michael J. Adam,et al.  Positron emission tomography after MPTP: observations relating to the cause of Parkinson's disease , 1985, Nature.

[11]  D. Jacobowitz,et al.  A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[12]  H. Chapel,et al.  CLINICAL RELEVANCE OF SPECIFIC IgG ANTIBODIES TO CARDIOLIPIN , 1989, The Lancet.

[13]  T Jones,et al.  Brain dopamine metabolism in patients with Parkinson's disease measured with positron emission tomography. , 1986, Journal of neurology, neurosurgery, and psychiatry.

[14]  C. Nahmias,et al.  Central Dopaminergic Pathways in Hemiparkinsonism Examined by Positron Emission Tomography , 1984, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[15]  T. Jones,et al.  Regional impairment of cerebral oxidative metabolism in Parkinson's disease. , 1979, Journal of neurology, neurosurgery, and psychiatry.

[16]  M. Bergstrom,et al.  Positron emission tomography in Parkinson's disease: glucose and DOPA metabolism. , 1987, Advances in neurology.

[17]  J. Langston,et al.  Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. , 1983, Science.

[18]  C. Nahmias,et al.  Striatal dopamine metabolism in living monkeys examined by positron emission tomography , 1983, Brain Research.

[19]  C. Nahmias,et al.  Blood-brain barrier transport and cerebral utilization of dopa in living monkeys. , 1980, The American journal of physiology.

[20]  C. Nahmias,et al.  Dopamine visualized in the basal ganglia of living man , 1983, Nature.

[21]  C. Marsden.  The mysterious motor function of the basal ganglia , 1982, Neurology.

[22]  O. Hornykiewicz.  Brain neurotransmitter changes in Parkinson's disease , 1981 .

[23]  T Jones,et al.  Alterations of regional cerebral blood flow and oxygen metabolism in Parkinson's disease , 1985, Neurology.

[24]  J. Saint-Cyr,et al.  Frontal lobe dysfunction in Parkinson's disease. The cortical focus of neostriatal outflow. , 1986, Brain : a journal of neurology.

[25]  R. Wurtman,et al.  The site of dopamine formation in rat striatum after L-dopa administration. , 1981, The Journal of pharmacology and experimental therapeutics.

[26]  Guillermo M. Alexander,et al.  Changes in the local cerebral metabolic rate for glucose in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinson's disease , 1985, Brain Research.

[27]  G. Firnau,et al.  [18F]Fluoro-dopa, an analogue of dopa, and its use in direct external measurements of storage, degradation, and turnover of intracerebral dopamine , 1978 .

[28]  V. Yong,et al.  Asymptomatic striatal dopamine depletion: PET scans in unilateral MPTP monkeys , 1988, Synapse.

[29]  M. Horne,et al.  A new autoradiographic approach for imaging forebrain dopamine distribution , 1982 .

[30]  C. Nahmias,et al.  Reduced striatal glucose consumption and prolonged reaction time are early features in Huntington's disease , 1984, Journal of the Neurological Sciences.

[31]  L. Forno.  Pathology of Parkinson's disease , 1981 .

[32]  M. Scheinin,et al.  Simultaneous determination of 3-methoxy-4-hydroxyphenylglycol, 5-hydroxyindoleacetic acid, and homovanillic acid in cerebrospinal fluid with high-performance liquid chromatography using electrochemical detection. , 1983, Analytical biochemistry.

[33]  B. Bioulac,et al.  MPTP primate model of Parkinson's disease: a mechanographic and electromyographic study , 1985, Brain Research.

[34]  A J Cross,et al.  N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in the monkey: neurochemical pathology and regional brain metabolism. , 1986, Journal of neural transmission. Supplementum.

[35]  D E Kuhl,et al.  Patterns of local cerebral glucose utilization determined in Parkinson's disease by the [18F]fluorodeoxyglucose method , 1984, Annals of neurology.

[36]  D Comar,et al.  Local cerebral glucose utilisation in treated and untreated patients with Parkinson's disease. , 1984, Journal of neurology, neurosurgery, and psychiatry.

[37]  F. Colpaert,et al.  Symptoms and behavioral features induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in an old java monkey [Macaca cynamolgus fascicularis (Raffles)] , 1986, Brain Research Bulletin.

[38]  D. Calne,et al.  AETIOLOGY OF PARKINSON'S DISEASE , 1983, The Lancet.

[39]  D. Jewett,et al.  A gas-solid-phase microchemical method for the synthesis of acetyl hypofluorite , 1984 .

[40]  J. Langston,et al.  Parkinsonism Induced By l-Methyl-4-Phenyl-l ,2,3,6-Tetrahydropyridine (MPTP): Implications for Treatment and the Pathogenesis of Parkinson's Disease , 2004 .

[41]  D. Murphy,et al.  Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma, and their responses to inhibition of monoamine oxidase. , 1986, Clinical chemistry.

[42]  P. Ballard,et al.  Parkinsonism Induced By 1-Methyl-4-Phenyl-1, 2, 3, 6-Tetrahydropyridine (MPTP): Implications for Treatment and the Pathogenesis of Parkinson’s Disease , 1984, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[43]  C Nahmias,et al.  Cerebral Metabolism of 6–[18F]Fluoro‐l‐3,4‐Dihydroxyphenylalanine in the Primate , 1987, Journal of neurochemistry.

[44]  G. E. Alexander,et al.  Parallel organization of functionally segregated circuits linking basal ganglia and cortex. , 1986, Annual review of neuroscience.

[45]  B. Maziére,et al.  Where have we got to with neuroreceptor mapping of the human brain? , 2004, European Journal of Nuclear Medicine.

[46]  I. Kopin,et al.  6-Fluorocatecholamines as false adrenergic neurotransmitters. , 1983, The Journal of pharmacology and experimental therapeutics.

[47]  A. Lang,et al.  Striatal dopamine distribution in Parkinsonian patients during life , 1985, Journal of the Neurological Sciences.