Gabriel Leger

Pharmacokinetics of Plasma 6-[¹⁸F]Fluoro-l-3,4-Dihydroxyphenylalanine ([¹⁸F]FDOPA) in Humans

Publisher: SAGE Publications

Date: 07-1993

DOI: 10.1038/JCBFM.1993.85

Abstract: Like native DOPA, [ 18 F]-6-fluoro-l-3,4-dihydroxyphenylalanine ([ 18 F]FDOPA) is subject to methylation and decarboxylation. To determine the rates of formation and elimination of [ 18 F]FDOPA metabolites, plasma from human subjects undergoing positron emission tomographic (PET) studies was analyzed by high-performance liquid chromatography (HPLC). In addition to the principal metabolite O-methyl-[ 18 F]FDOPA (OMe-[ 18 F]FDOPA), two decarboxylated metabolites were detected in plasma from carbidopa pretreated subjects. The concentrations of each metabolite during 90 min following tracer injection could be described as a function of the concentration of [ 18 F]FDOPA, and two rate constants k 0 , the rate of formation, and k –1 , the rate of clearance. Plasma metabolite time series generated from total plasma activity curves and measured rate constants were in close agreement with the actual concentrations determined by HPLC fractionation. Population means for k 0 (0.011 ± 0.002 min −1 ) and k –1 , (0.010 ± 0.003 min −1 ) were used to generate “simulated” plasma curves. The measured and generated plasma curves were used as inputs for estimation of partition and decarboxylation coefficients of [ 18 F]FDOPA in brain. The use of generated input functions from normal population means of transfer coefficients did not introduce a systematic error into the estimate of the enzyme activity. However, the high variability of these estimates in patients precludes the use of this technique as an alterative to in idual HPLC measurements.

6-[¹⁸F]fluoro-l-DOPA Metabolism in Living Human Brain: A Comparison of Six Analytical Methods

Publisher: SAGE Publications

Date: 1993

DOI: 10.1038/JCBFM.1993.8

Abstract: In 11 normal volunteers and six patients with Parkinson's disease, we compared six different analyses of dopaminergic function with l-3,4-dihydroxy-6-[ 18 F]fluorophenylalanine (FDOPA) and positron emission tomography (PET). The caudate nucleus, putamen, and several reference regions were identified in PET images, using magnetic resonance imaging (MRI). The six analyses included two direct determinations of DOPA decarboxylase activity ( k D 3 , k* 3 ), the slope–intercept plot based on plasma concentration ( K), two slope–intercept plots based on tissue content ( k r 3 , k s 3 ), and the striato–occipital ratio [ R( T)]. For all analyses, the difference between two groups of subjects (normal volunteers and patients with Parkinson's disease) was larger in the putamen than in the caudate. For the caudate nucleus, the DOPA decarboxylase activity ( k D 3 , k* 3 ), tissue slope–intercept plots ( k r 3 , k s 3 ), and striato–occipital ratio [ R( T)] analyses significantly discriminated between the normal volunteers and the patients with Parkinson's disease ( p 0.005) [with least significance for k* 3 ( p 0.05)], while the plasma slope–intercept plot ( K) failed to do so. For the putamen, the values for k D 3 , k* 3 , K, k r 3 , k s 3 and R( T) of normal volunteers were significantly higher than those of patients ( p 0.005) [with least significance for K ( p 0.025)]. Linear correlations were significant between k D 3 and k s 3 k D 3 and k r 3 k D 3 and R( T) and k D 3 and k* 3 , in this order of significance. We found no correlation between k D 3 and K values in the caudate nucleus.

Human Striatal l-DOPA Decarboxylase Activity Estimated in vivo Using 6-[¹⁸F]fluoro-DOPA and Positron Emission Tomography: Error Analysis and Application to Normal Subjects

Publisher: SAGE Publications

Date: 1993

DOI: 10.1038/JCBFM.1993.7

Abstract: DOPA decarboxylase is the enzyme directly responsible for the synthesis of the neurotransmitters dopamine and serotonin, and indirectly of noradrenaline, in brain. We used the decarboxylation coefficient ( k D 3 ) of 6-[ 18 F]fluoro-DOPA (FDOPA) to denote the relative activity of l-DOPA decarboxylase in vivo in the human brain. To determine the relative enzyme activity with positron emission tomography (PET), we evaluated the model that separates the metabolism into compartments of nondiffusible and diffusible (i.e., transient) tracer metabolites. Error analysis indicated that the least-squares optimization alone was not sufficient to yield accurate estimates of k D 3 in the presence of the inherent error of PET. To improve the accuracy of the k D 3 estimates by optimizing the number of parameters, we introduced biological constraints which included a tracer partition volume ( V e ) common to frontal cortex and striatum, and a fixed ratio ( q) between the blood–brain barrier transport coefficients of O-methyl-[ 18 F]fluoro-DOPA and FDOPA, the two sources of radioactivity in plasma. We found that a two-step analysis yielded sufficiently accurate estimates of k D 3 . The two steps include the initial estimation of the partition volume in frontal cortex and the subsequent use of this value to determine k D 3 in striatum and other structures. We studied twelve healthy controls (age 45 ± 15 years). The average k D 3 value was 0.081 ± 0.024 min −1 (coefficient of variation (COV) 30%) for caudate nucleus, 0.074 ± 0.013 min“ 1 (COV 18%) for putamen, and 0.010 ± 0.005 min −1 (COV 50%) for cerebral cortex.

Striatal L‐DOPA Decarboxylase Activity in Parkinson's Disease In Vivo: Implications for the Regulation of Dopamine Synthesis

Publisher: Wiley

Date: 10-1993

DOI: 10.1111/J.1471-4159.1993.TB13651.X

Abstract: L-DOPA is a large neutral amino acid subject to transport out of, as well as into, brain tissue. Competition between dopamine synthesis and L-DOPA egress from striatum must favor L-DOPA egress if decarboxylation declines relatively more than transport in Parkinson's disease. To test this hypothesis, we injected patients with Parkinson's disease with a radiolabeled analogue of L-DOPA and recorded regional brain radioactivity as a function of time by means of positron emission tomography. We simultaneously estimated the activity of the decarboxylating enzyme and the amino acid transport. In the striatum of patients, we found the L-DOPA decarboxylase activity to be reduced in the head of the caudate nucleus and the putamen. However, the rate of egress of the DOPA analogue was unaffected by the disease and thus inhibited dopamine synthesis more than predicted in the absence of L-DOPA egress.

The identification and deletion of the polyketide synthase‐nonribosomal peptide synthase gene responsible for the production of the phytotoxic triticone A/B in the wheat fungal pathogen

Publisher: Wiley

Date: 21-11-2019

DOI: 10.1111/1462-2920.14854

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0347922

Start Date: 2002

End Date: 12-2002

Amount: $630,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0453722

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End Date: 12-2005

Amount: $385,240.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0560987

Start Date: 03-2005

End Date: 12-2005

Amount: $156,697.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE120100092

Start Date: 01-2012

End Date: 12-2012

Amount: $240,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0230245

Start Date: 2001

End Date: 12-2002

Amount: $600,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0989071

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End Date: 07-2012

Amount: $600,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE140100096

Start Date: 03-2014

End Date: 03-2015

Amount: $180,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0986139

Start Date: 2009

End Date: 12-2011

Amount: $230,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE140100036

Start Date: 2014

End Date: 12-2015

Amount: $771,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0239218

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End Date: 12-2002

Amount: $340,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP0883556

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End Date: 03-2012

Amount: $76,881.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE150100158

Start Date: 2015

End Date: 12-2015

Amount: $670,000.00

Funder: Australian Research Council