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J S Fowler

Publications and source records attributed to J S Fowler.

At least 145 records · Page 8Linked to original sources
PubMed1995

Carbon-11-d-threo-methylphenidate binding to dopamine transporter in baboon brain.

UNLABELLED: The more active d-enantiomer of methylphenidate (dl-threo-methyl-2-phenyl-2-(2-piperidyl)acetate, Ritalin) was labeled with 11C(t1/2:20.4 min) to characterize its binding, examine its specificity for the dopamine transporter and evaluate it as a radio-tracer for the presynaptic dopaminergic neuron. METHODS: PET studies were carried out in the baboon. The pharmacokinetics of [11C]dl-threo-methylphenidate, [11C]l-threo-MP and with its racemate ([11C]dl-threo-methylphenidate, [11C]MP). Nonradioactive methylphenidate was used to assess the reversibility and saturability of the binding. GBR 12909, 3 beta-(4-iodophenyl)tropane-2-carboxylic acid methyl ester (beta-CIT), tomoxetine and citalopram were used to assess the binding specificity. RESULTS: The ratio between radioactivity in the striatum and that in the cerebellum (ST/CB) after injection of [11C]d-threo-MP was higher than that for [11C]MP and [11C]l-threo-MP (3.3 for d-, 2.2 for racemic and 1.1 for l- in the same baboon). Most of the striatal binding of [11C]d-threo-MP was displaceable by injection of nonradioactive MP. Pretreatment with nonradioactive MP (0.5 mg/kg), GBR12909 (1.5 mg/kg) and RTI-55 (0.3 mg/kg) markedly reduced striatal but not cerebellar uptake of [11C]d-threo-MP. In all cases, the ST/CB after pretreatment was reduced by about 60% compared to 43% for [11C]MP. The ratios of distribution volumes at steady-state for the ST/CB for the three separate studies in the same baboon were reduced by about 50%, as compared with 37% for [11C]MP. In contrast, pretreatment with tomoxetine (3.0 mg/kg) or citalopram (2.0 mg/kg) did not change [11C]d-threo-MP kinetics; the ST/CB after pretreatment was similar to that for the control. CONCLUSION: These results demonstrate the saturable, reversible and specific binding of [11C]d-threo-MP to the dopamine transporter on the baboon brain, suggesting that [11C]d-threo-MP will be a useful PET tracer for the presynaptic dopaminergic neuron in living human brain.

Animals↗
PubMed1994

Binding of bromine-substituted analogs of methylphenidate to monoamine transporters.

We synthesized the o-, m- and p-bromo derivatives of dl-threo-methylphenidate from the corresponding bromophenylacetonitriles by modification of the literature synthesis of methylphenidate (Panizzon, Helv. Chim. Acta 1944, 27, 1748). In in vitro binding assays all three dl-threo bromo compounds had higher affinities than methylphenidate for dopamine transporter sites labeled with [3H]2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane ([3H]WIN 35,428; IC50 = 13, 4, 20 and 82 nM for o-, m-, and p-bromo compounds, and unsubstituted methylphenidate, respectively). They also bound more strongly than methylphenidate to norepinephrine reuptake sites labeled with [3H]nisoxetine (IC50 = 32, 20, 31 and 440 nM, respectively), but were weak ligands (IC50 > or = 1 microM) at the serotonin transporter labeled with [3H]paroxetine. In addition, the bromine substituted derivatives demonstrated similar activity to methylphenidate in vivo in rodents in terms of inhibition of heart uptake of [3H](-)-norepinephrine, elevation of striatal extracellular dopamine, and stimulation of locomotor activity.

Animals↗
PubMed1994

Decreased dopamine transporters with age in health human subjects.

The effects of aging on brain dopamine transporters was evaluated in 26 healthy male volunteers (age range, 21-63 years) using positron emission tomography and [11C]cocaine. The ratio of the distribution volume for [11C]cocaine in basal ganglia to that in cerebellum was used as a model parameter for dopamine transporter availability and showed a significant negative correlation with age (r = 0.65, p < 0.0005). This results document an age-related decline in dopamine transporters in healthy individuals.

Adult↗
PubMed1994

Imaging endogenous dopamine competition with [11C]raclopride in the human brain.

This study images dopamine release in response to a neurochemically specific challenge with the psychostimulant drug methylphenidate. Changes in synaptic dopamine induced by methylphenidate were evaluated with positron emission tomography and [11C]raclopride, a D2 receptor radioligand that is sensitive to endogenous dopamine. Methylphenidate significantly decreased striatal [11C]raclopride binding. The decrease was variable and was negatively correlated with age. Mood and anxiety at baseline, were also correlated with methylphenidate-induced DA changes. This strategy provides a tool to investigate the responsiveness of the dopamine system in the normal and diseased human brain and to investigate the neurochemical correlates of behavior.

Adult↗
PubMed1994

PET studies of cocaine inhibition of myocardial norepinephrine uptake.

Positron emission tomography (PET), [11C]cocaine, and (-)-6-[18F]fluoronorepinephrine [(-)-6-[18F]NE] were used to determine the extent to which the binding of labeled cocaine in the baboon heart represents binding to the norepinephrine transporter and to characterize the functional consequences of cocaine administration on the norepinephrine transporter. Peak heart binding of [11C]cocaine was high (0.038-0.055%/g) and clearance was rapid (t1/2 from peak: 2.5-9 min) for both tracer doses and a pharmacological dose. The binding of a tracer dose of labeled cocaine could not be inhibited by desipramine, tomoxetine, cocaine, nomifensine, or benztropine. The behavior of a pharmacological dose of [11C]cocaine could not be distinguished from a tracer dose and also could not be inhibited by tomoxetine. However, pretreatment with cocaine profoundly inhibited norepinephrine uptake as assessed by (-)-6-[18F]NE. Recovery was slow with only 48% of the baseline (-)-6-[18F]NE uptake being recovered by 78 minutes after cocaine administration. [11C]Benzoylecgonine, a vasoactive metabolite of cocaine, showed negligible retention in heart. The results of this study (i.e., the rapid clearance of cocaine from the heart, the inability to inhibit cocaine binding with desipramine and tomoxetine, and its relatively long-lasting effects on norepinephrine uptake) reinforce the need to understand the link between cocaine pharmacokinetics and norepinephrine transporter function and its relationship to cardiotoxicity.

Animals↗
PubMed1994

Slow recovery of human brain MAO B after L-deprenyl (Selegeline) withdrawal.

L-Deprenyl (Selegeline) is an enzyme-activated irreversible inhibitor of monoamine oxidase B (MAO B; EC 1.4.3.4). It is used to treat Parkinson's disease at a dose of 5 mg twice a day. Since enzyme inhibition is irreversible, the recovery of functional enzyme activity after withdrawal from L-deprenyl requires the synthesis of new enzyme. We have measured a 40 day half-time for brain MAO B synthesis in Parkinson's disease and in normal subjects after withdrawal from L-deprenyl. This is the first measurement of the synthesis rate of a specific protein in the living human brain. L-Deprenyl is currently used by 50,000 patients with Parkinson's disease in the United States and its use is expected to increase with reports that it may be beneficial in Alzheimer's disease. The slow turnover of brain MAO B suggests that the current clinical dose of L-deprenyl may be excessive and that the clinical efficacy of reduced dosing should be evaluated. Such an evaluation may have mechanistic importance as well as an impact on reducing the side effects and the costs arising from excessive drug use.

Aged↗
PubMed1994

Pharmacokinetics and in vivo specificity of [11C]dl-threo-methylphenidate for the presynaptic dopaminergic neuron.

dl-threo-Methylphenidate (Ritalin) was labeled with carbon-11 (t1/2:20.4 minutes) in order to measure its pharmacokinetics, to evaluate it as a radiotracer for the presynaptic dopaminergic neuron, and to examine its sensitivity to the loss of dopaminergic neurons. Positron emission tomographic (PET) studies were carried out in the baboon to determine specificity for the presynaptic dopaminergic neuron and in humans to assess sensitivity to neuronal loss. Studies with [11C]dl-threo-methylphenidate ([11C]MP) in baboon demonstrated high regional uptake in the striatum. Peak uptake (0.04%/cc) occurred at 5-15 minutes post-injection. The half-time for clearance from peak uptake for [11C]MP was 60 minutes and the ratio between the radioactivity in the striatum and that in the cerebellum (ST/CB) ranged from 2.2 to 2.6 at 40 minutes. Repeated measures in the same baboon showed < or = 8% variability in the ST/CB ratio. Pretreatment with unlabeled methylphenidate (0.5 mg/kg) or GBR12909 (1.5 mg/kg) 30 minutes prior to [11C]MP injection markedly reduced the striatal but not the cerebellar uptake of [11C]MP, demonstrating the saturable and specific binding of [11C]MP to a site on the dopamine transporter in the brain. In both cases, the ratio of striatum to cerebellum (ST/CB) after pretreatment was reduced by about 43%. The ratios of distribution volumes at the steady-state for the striatum to cerebellum (ST/CB) for these two separate studies in the same baboon were reduced by 37 and 38%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

Methylphenidate decreases regional cerebral blood flow in normal human subjects.

To assess the effects of methylphenidate (MP) on cerebral blood flow (CBF), 5 healthy males were studied using 15O-water and positron emission tomography before and after MP (0.5 mg/kg iv). MP significantly decreased whole brain CBF at 5-10 minutes (25 +/- 11%) and at 30 minutes (20 +/- 10%) after its administration. Decrements in CBF were homogeneous throughout the brain (regional decrements 23-30%) and probably reflect the vasoactive properties of MP. The vasoactive properties of MP should be considered when prescribing this drug chronically and/or when giving it to subjects with cerebrovascular compromise.

Adult↗
PubMed1994

Positron emission tomography study of human prostatic adenocarcinoma using carbon-11 putrescine.

To evaluate [1-11C]putrescine ([11C]PUT) as a potential tracer for imaging and characterization of human prostatic adenocarcinoma, positron emission tomography (PET) was performed in eight patients and three normal controls. In addition, four of the patients and the three normal controls also had a prostate scan with 2-deoxy-2-[18F]fluoro-D-glucose (18FDG). Three of the patients had undergone resection of the prostate tumor and all of the patients except for one had bone metastasis. Carbon-11 rapidly accumulated in prostate, bone and rectum after injection of [11C]PUT. Maximal uptake was achieved 5 min after injection with minimal washout during the 50 min study period. The uptake of carbon-11 in the prostate of normal controls was significantly higher than that in the patients. However, three of the four patients scanned for metastatic bone lesions showed higher uptake in bone metastasis than in normal bone. Quantitation of 18FDG uptake in the prostate was hindered by the high accumulation of activity in the urinary bladder. [11C]PUT does not appear to be a useful tracer for assessing proliferation of human prostate adenocarcinoma. Its utility in the imaging of other cancers with high polyamine concentration remains to be investigated.

Adenocarcinoma↗
PubMed1994

Effects of blood flow on [11C]raclopride binding in the brain: model simulations and kinetic analysis of PET data.

To assess the stability of different measures of receptor occupancy from [11C]raclopride (a D2 antagonist) studies with positron emission tomography, we analyze data from five test/retest studies in normal volunteers in terms of individual model parameters from a three-compartment model, the distribution volume (DV) and the ratio of DVs from a receptor-containing region of interest to a non-receptor-containing region. Large variations were found in the individual model parameters, limiting their usefulness as an indicator of change in receptor systems. The DV ratio showed the smallest variation. Individual differences were reflected in the greater intersubject variation in DV than intrasubject variation. The potential effects of blood flow on these measurements were addressed both experimentally and by simulation studies using three models that explicitly incorporate blood flow into a compartmental model that also includes receptor-ligand binding. None of the models showed any variation in the DV with changes in blood flow as long as flow was held constant during the simulation. Experimentally, blood flow was significantly reduced by hyperventilation in a human subject. The DV was found to be reduced relative to baseline in the hyperventilation study, but the DV ratio remained unchanged. The effect of elevated and reduced flow was also tested in two baboon experiments in which PCO2 was varied. Some variability in the DV ratio was observed but was not correlated with changes in blood flow. This raises the possibility that other factors indirectly related to changes in blood flow (or PCO2) may cause changes in DV, and these effects need to be considered when evaluating experimental results.

Animals↗
PubMed1994

Studies with differentially labeled [11C]cocaine, [11C]norcocaine, [11C]benzoylecgonine, and [11C]- and 4'-[18F]fluorococaine to probe the extent to which [11C]cocaine metabolites contribute to PET images of the baboon brain.

The psychostimulant drug of abuse, cocaine (benzoylecgonine methyl ester), is rapidly metabolized by cleavage of its two ester groups, to give benzoylecgonine (BE) and ecgonine methyl ester, and by N-demethylation, to give N-norcocaine (NC). The recent use of [N-methyl-11CH3]cocaine to image brain cocaine binding sites with positron emission tomography (PET) raises the question of whether PET images partially reflect the distribution and kinetics of labeled cocaine metabolites. We prepared [O-methyl-11CH3]cocaine by methylation of the sodium salt of BE with [11C]CH3I, and showed that PET baboon brain scans, as well as regional brain kinetics and plasma time-activity curves corrected for the presence of labeled metabolites, are nearly identical to those seen with [N-methyl-11CH3]cocaine. This strongly suggests that 11C metabolites do not significantly affect PET images, because the metabolite pattern is different for the two labeled forms of cocaine. In particular, nearly half the 11C in blood plasma at 30 min was [11C]CO2 when [N-methyl-11CH3]cocaine was administered, whereas [11C]CO2 was not formed from [O-methyl-11CH3]cocaine. Only a trace of [11C]NC was detected in plasma after [O-methyl-11CH3]cocaine administration. Nearly identical brain PET data were also obtained when 4'-[N-methyl-11CH3]fluorococaine and 4'-[18F]fluorococaine (prepared by nucleophilic aromatic substitution from [18F]fluoride- and 4'-nitrococaine) were compared with [N-methyl-11CH3]cocaine. In vitro assays with rat brain membranes showed that cocaine and 4'-fluorococaine were equipotent at the dopamine reuptake site, but that 4'-fluorococaine was about 100 times more potent at the 5-hydroxytryptamine reuptake site.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Recovery of brain glucose metabolism in detoxified alcoholics.

OBJECTIVE: To differentiate withdrawal-related abnormalities in brain glucose metabolism among alcoholics from abnormalities that may be irreversible or antedate alcohol use, the authors evaluated metabolic recovery during alcohol detoxification. METHOD: Regional brain glucose metabolism was measured with positron emission tomography and 2-deoxy-2-[18F]fluoro-D-glucose in 10 male alcoholics at 8-15 days, 16-30 days, and 31-60 days after last use of alcohol. The alcoholics' metabolic values were compared with those of 10 age-matched male healthy volunteers. RESULTS: Brain metabolism increased significantly during detoxification. There were significant differences in global and regional measures between the first and last time points but not between the second and third points, suggesting that recovery occurred predominantly within 16-30 days. Regional increases in metabolism were greater in the frontal regions. Whereas during the first evaluation the alcoholics showed significantly lower metabolism in various brain regions than the comparison group, at the end of detoxification the alcoholics showed significantly lower absolute and relative metabolic values in the basal ganglia and lower relative metabolic values in the parietal cortex. Among the alcoholics, but not the comparison group, metabolism in the frontal, parietal, and left temporal cortexes was negatively correlated with years of alcohol use and with age. CONCLUSIONS: This study shows significant increases in brain metabolism during alcohol withdrawal and documents persistent low metabolic levels in the basal ganglia of detoxified alcoholics.

Adult↗
PubMed1994

Effects of haloperidol challenge on regional cerebral glucose utilization in normal human subjects.

OBJECTIVE: Positron emission tomography and the fluorodeoxyglucose (FDG) method were used to determine the brain's metabolic response to neuroleptic challenge in a normal, disease-free state. METHOD: FDG measurements were obtained before and 12 hours after administration of 5 mg of haloperidol to 12 young normal men. These values were compared with test-retest FDG measures obtained from nine normal male control subjects who received no drug intervention. RESULTS: After haloperidol administration, the haloperidol subjects showed significantly lower glucose utilization in the neocortex, limbic cortex, thalamus, and caudate nucleus but not in the putamen or cerebellum. After adjustment for global effects, significant reductions were still evident in the frontal, occipital, and anterior cingulate cortex, whereas the putamen and cerebellum showed significant increases. CONCLUSIONS: This study, measuring the brain's metabolic response to acute receptor blockade, is a first step in the development of an assay of CNS pharmacological activity. By determining the response to neuroleptic challenge in a normal state, the study establishes a comparison group for determining response to challenge in various psychiatric conditions.

Adult↗
PubMed1993

Effects of central cholinergic blockade on striatal dopamine release measured with positron emission tomography in normal human subjects.

Previously we demonstrated that positron emission tomography (PET) can be used to measure changes in the concentrations of synaptic dopamine and acetylcholine. Whether induced directly or indirectly through interactions with other neurotransmitters, these studies support the use of PET for investigating the functional responsiveness of a specific neurotransmitter to a pharmacologic challenge. In an extension of these findings to the human brain, PET studies designed to measure the responsiveness of striatal dopamine release to central cholinergic blockade were conducted in normal male volunteers using high-resolution PET and [11C]raclopride, a D2-dopamine receptor antagonist. [11C]Raclopride scans were performed prior to and 30 min after systemic administration of the potent muscarinic cholinergic antagonist, scopolamine (0.007 mg/kg). After scopolamine administration, [11C]raclopride binding decreased in the striatum (specific binding) but not in the cerebellum (nonspecific binding) resulting in a significant decrease, exceeding the test/retest variability of this ligand (5%), in the ratio of the distribution volumes of the striatum to the cerebellum (17%). Furthermore, scopolamine administration did not alter the systemic rate of [11C]raclopride metabolism or the metabolite-corrected plasma input function. These results are consistent not only with the known inhibitory influence that acetylcholine exerts on striatal dopamine release but also with our initial 18F-labeled N-methylspiroperidol and benztropine studies. Thus these data support the use of PET for measuring the functional responsiveness of an endogenous neurotransmitter to an indirect pharmacologic challenge in the living human brain.

Adult↗
PubMed1993

Striatal binding of the PET ligand 11C-raclopride is altered by drugs that modify synaptic dopamine levels.

Bilateral decreases in striatal 11C-raclopride binding were observed in adult female baboons with high resolution PET following administration of drugs that act centrally on dopaminergic neurons. At baseline and following administration of d-amphetamine (a dopamine-releasing drug), GBR-12909 (a potent dopamine reuptake inhibitor), or tetrabenazine (a biogenic amine depleting drug) PET scans of 11C-raclopride binding were obtained in a CTI 931 positron tomograph. In all studies, the ratio of the distribution volumes for the striatum to the cerebellum for 11C-raclopride binding decreased significantly by an average of 16.2% for d-amphetamine, 22.1% for GBR-12909, and 28.3% for tetrabenazine while there were no significant changes observed in the cerebellum or in the rate of systemic metabolism of the radiotracer. These decreases exceed the test/retest variability of striatal 11C-raclopride binding measured in the same animals under identical experimental conditions (Dewey et al., 1992b). Together these studies demonstrate that PET measurements of striatal 11C-raclopride binding can be used to indirectly and non-invasively monitor changes in synaptic dopamine concentrations that result from a variety of neurophysiologic mechanisms.

Animals↗
PubMed1993

Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers.

Decreased dopaminergic function has been postulated to underlie cocaine addiction. To examine the possibility that dysfunction of brain regions subserved by the dopamine system could promote cocaine self-administration, positron emission tomography and a dual-tracer approach was used to examine dopamine D2 receptor availability and regional brain glucose metabolism in cocaine abusers. When compared to normal controls, cocaine abusers showed significant decreases in dopamine D2 receptor availability which persisted 3-4 months after detoxification. Decreases in dopamine D2 receptor availability were associated with decreased metabolism in several regions of the frontal lobes, most markedly orbito-frontal cortex and cingulate gyri. Dopamine dysregulation of these brain areas which are involved in the channeling of drive and affect could lead to loss of control resulting in compulsive drug-taking behavior.

Adult↗