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P Deep

Publications and source records attributed to P Deep.

10 recordsLinked to original sources
PubMed2000

Effect of partial volume correction on estimates of the influx and cerebral metabolism of 6-[(18)F]fluoro-L-dopa studied with PET in normal control and Parkinson's disease subjects.

The poor spatial resolution of positron emission tomography (PET) is a limiting factor in the accurate assay of physiological processes investigated by compartmental modeling of tracer uptake and metabolism in living human brain. The radioactivity concentration in a region-of-interest is consequently altered by loss of signal from that structure and contamination from adjacent brain regions, phenomena known as partial volume effects. We now apply an MRI-based algorithm to compensate for partial volume effects in the special case of compartmental modeling of the cerebral uptake of 6-[(18)F]fluoro-L-dopa (FDOPA), an exogenous substrate of dopa decarboxylase. High-resolution MRI scans were obtained from normal volunteers (n = 4) and patients with Parkinson's disease (n = 4) in order to segment specific brain regions and calculate the partial volume correction factors. Dynamic 2D PET scans were acquired during 90 min following intravenous infusion of FDOPA. After partial volume correction, the apparent net blood-brain clearance of FDOPA (K(i)) was greatly increased in caudate and putamen of normal subjects and in caudate of Parkinson's disease patients. The equilibrium distribution volume of FDOPA (V(D)(e)) in cerebral cortex increased by 35% in all subjects. Using a two-compartment model, the relative activity of dopa decarboxylase with respect to FDOPA (k(D)(3)) in the basal ganglia was increased 2-3 times in normal subjects, to the range obtained previously in brain of living rat. The partial volume correction also increased the magnitude of k(D)(3) in caudate of Parkinson's disease patients, but did not alter k(D)(3) in putamen. A three-compartment model correcting for elimination of decarboxylated metabolites also yielded higher estimates of k(D)(3), but with a penalty in precision of the estimates. Together, these observations suggest that the limited spatial resolution of PET results in substantial underestimation of the true rate of FDOPA uptake and metabolism in vivo, and may also tend to obscure regional heterogeneity in the neurochemical pathology of Parkinson's disease.

Adult↗
PubMed1999

Stimulation of dopa decarboxylase activity in striatum of healthy human brain secondary to NMDA receptor antagonism with a low dose of amantadine.

The efficacy of amantadine in alleviating motor symptoms of Parkinson's disease may be mediated in part by stimulation of cerebral dopa decarboxylase (DDC) activity, secondary to antagonism of N-methyl-D-aspartate (NMDA) type glutamate receptors. We tested the specific hypothesis that amantadine increases the decarboxylation rate of 6-[(18)F]fluoro-L-DOPA (FDOPA), an exogenous substrate for DDC, in healthy human brain. Radioactivity concentrations in brain tissue of neurologically normal volunteers (n = 5) injected intravenously with FDOPA ( approximately 4.5 mCi) were recorded by positron emission tomography (PET) for 120 min, first in a baseline condition, and again following three consecutive days of treatment with amantadine (100 mg/day, p.o.). Data from four telencephalic regions of interest containing appreciable DDC activity were analyzed with the tissue slope-intercept plot, using cerebellar cortex as the reference tissue, to estimate a coefficient of in situ FDOPA decarboxylation (k(3)(r), min(-1)). Mean estimates of k(3)(r) were increased following amantadine treatment in caudate nucleus (+12%), putamen (+28%), ventral striatum (+27%), and frontal cortex (+9%). For an initial confidence level of 95%, paired one-sided Student's t-tests with Bonferroni correction for multiple comparisons revealed a statistically significant drug effect in ventral striatum. Present results are consistent with stimulation of DDC activity in striatum of healthy human brain secondary to NMDA receptor antagonism with a low dose of amantadine, and suggest that this response is an important mechanism underlying the anti-parkinsonian properties of amantadine. Nonetheless, PET studies in parkinsonian patients using higher, clinically effective doses of amantadine may reveal more pronounced enhancements of cerebral DDC activity.

Adult↗
PubMed1999

Pharmacokinetics of radiotracers in human plasma during positron emission tomography.

Many radiopharmaceuticals for positron emission tomography (PET) are substantially metabolized in peripheral organs. Pharmacological treatments intended to alter cerebral metabolism might also alter radiotracer metabolism, consequently altering the cerebral uptake. First-order rate constants for the metabolism of PET tracers can be calculated by a linear graphical method from the precursor and metabolite concentrations measured in plasma extracts fractionated by HPLC. We tested the effects of specific pharmacological challenges on the plasma kinetics of six tracers used for PET studies of neurotransmission. The rate of O-methylation of circulating [(18)F]fluorodopa, a tracer of dopa decarboxylase activity in brain, was unaffected by pretreatment with amantadine, an antagonist of glutamate receptors. [(11)C]Deprenyl, a tracer of monoamine oxidase activity, was rapidly metabolized to [(11)C]methamphetamine and polar metabolites in healthy volunteers. The net rate constant of this metabolism was three times higher in a group of subjects under treatment for epilepsy, consistent with induction of hepatic microsomal enzymes by antiepileptic drugs. [(11)C]Sch 23390, a ligand for dopamine D1 receptors, was rapidly metabolized to polar metabolites. The net rate constant of metabolism was unaffected by pretreatment with lorazepam. [(11)C]-(S)-Nicotine, a ligand for nicotinic receptors, was rapidly metabolized to [(11)C]-(S)-cotenine, which is less polar than the parent compound. Pretreatment with mazindol, a dopamine uptake inhibitor, was without effect on peripheral metabolism of [(11)C]-(S)-nicotine. [(11)C]WIN 35,428, a tropane derivative which labels dopamine uptake sites, was metabolized to a nonpolar metabolite, but so slowly that the rate constant of this process could not be calculated. [(11)C]Raclopride, a ligand for dopamine D2 receptors, was first metabolized to a nonpolar metabolite, which then yielded two hydrophilic metabolites. The initial metabolic step was substantially blocked by pretreatment with amphetamine, possibly indicative of competitive inhibition of microsomal oxidation. Together, these results indicate that the linear graphic method is useful for estimating the kinetics of the plasma metabolism of many widely used PET tracers. Drug-drug interactions were revealed in subjects treated with specific pharmacological agents prior to tracer administration.

Benzazepines↗
PubMed1997

The kinetic behaviour of [3H]DOPA in living rat brain investigated by compartmental modelling of static autoradiograms.

The kinetic behaviour of [3H]DOPA in living rat brain was investigated by compartmental modelling of measured activities from combined metabolite pools in a time-series (180 min) of static autoradiograms from right cerebral hemispheres. Two models of [3H]DOPA uptake and metabolism that incorporated the removal of the decarboxylation product, [3H]dopamine, from brain were significantly more accurate than a model in which [3H]dopamine accumulated irreversibly in situ. Present estimates of [3H]DOPA kinetic constants were compared to previously published results based on the analysis of measured activities from individual metabolite pools separated by chromatographic fractionation of [3H]DOPA metabolites in the left cerebral hemispheres of the same rats. Autoradiographic estimates of DOPA decarboxylase activity with respect to [3H]DOPA in brain (k3DOPA) were under-estimated several-fold relative to chromatographic estimates; this discrepancy is explained by post-mortem enzyme activity and omission of biological compartments from the models. However, autoradiographic estimates of the unidirectional blood-brain clearance of [3H]DOPA (K1DOPA) and monoamine oxidase activity with respect to [3H]dopamine in brain (k7DA') agreed with chromatographic estimates. This concordance represents the first empirical validation of compartmental modelling of autoradiographic data as a method for quantitatively investigating the kinetic behaviour of radiolabelled L-DOPA in living mammalian brain.

Animals↗
PubMed1997

On the accuracy of an [18F]FDOPA compartmental model: evidence for vesicular storage of [18F]fluorodopamine in vivo.

The biological accuracy of a nonlinear compartmental model describing the in vivo kinetics of L-3,4-dihydroxy-6-[18F]fluorophenylalanine ([18F]FDOPA) metabolism was investigated. Tissue activities for [18F]FDOPA and its labeled metabolites 3-O-methyl-[18F]FDOPA ([18F]OMFD), 6-[18F]fluorodopamine ([18F]FDA), L-3,4-dihydroxy-6-[18F]fluorophenylacetic acid ([18F]FDOPAC), and 6-[18F]fluorohomovanillic acid ([18F]FHVA) were calculated using a plasma [18F]FDOPA input function, and kinetic constants estimated previously by chromatographic fractionation of 18F-labeled compounds in plasma and brain extracts from rat. Present data accurately reflected the measured radiochemical composition in rat brain for tracer circulation times past 10 min. We formulated the hypothesis that the discrepancy between calculated and measured fractions of [18F]FDOPA and the deaminated metabolite [18F]FDOPAC at times earlier than 10 min reflected storage of [18F]FDA in vesicles without monoamine oxidase. This hypothesis explained the initially rapid appearance of [18F]FDOPAC in striatum by delayed transfer of [18F]FDA from cytosol into vesicles. We conclude that the simpler model of [18F]FDOPA compartmentation is accurate when the cytosolic and vesicular fractions of [18F]FDA are at steady-state; the approach to equilibrium has a time constant of 15-30 min. The present model is valid for positron emission tomography studies of [18F]FDOPA metabolism in living brain.

Animals↗