Biomedical subjects

R F Dannals

Publications and source records attributed to R F Dannals.

At least 127 records · Page 7Linked to original sources

PubMed1991

L-methionine uptake by human cerebral cortex: maturation from infancy to old age.

Age-associated changes in amino acid transport from blood to normal frontal cortex were studied using positron emission tomography (PET). Seventeen patients, 1.8-71 yr, were injected intravenously with tracer doses of [11C] L-methionine and a baseline PET scan was obtained. To assess competitive inhibition of [11C]L-methionine uptake, patients received either oral L-phenylalanine or an i.v. infusion of amino acids 1 hr before a second PET study. Uptake of [11C]L-methionine by frontal cortex decreased seven-fold between 1.8 and 71 yr (r = -0.71; p less than 0.05). Blood-to-brain transfer of [11C]L-methionine, at 4.5 yr, exceeded mean adult values by more than five-fold. Competitive inhibition reduced L-methionine uptake in all patients older than 4.6 yr. These developmental changes parallel findings in animals. The neutral amino acid transport system may modulate human brain amino acid levels to meet changing developmental metabolic needs.

Adult↗

PubMed1991

In vitro and in vivo characterization of 4-[125I]iododexetimide binding to muscarinic cholinergic receptors in the rat heart.

4-[125I]iododexetimide binding to muscarinic cholinergic receptors (mAChR) was evaluated in the rat heart. 4-[125I]iododexetimide displayed high in vitro affinity (Kd = 14.0 nM) for rat myocardial mAChR. In vivo, there was high accumulation of 4-[125I]iododexetimide in the rat atrium and ventricle which could be blocked by approximately 60% by preinjection of atropine. In contrast, accumulation of the radiolabeled stereoisomer, 4-[125I]iodolevetimide, was 63% lower than 4-[125I]iodolevetimide and was not blocked by atropine. The blood clearance of 4-[125I]iododexetimide was rapid, providing heart-to-blood ratios of up to 14:1; however, heart-to-lung and heart-to-liver ratios were below unity. The data indicate that 4-[125I]iododexetimide binds potently to rat mAChR. However, since nonspecific binding is relatively high, it is not clear whether iododexetimide labeled with 123I will be useful in SPECT imaging studies of myocardial mAChR. Further studies in humans are indicated.

Animals↗

PubMed1991

Imaging histamine H1 receptors in the living human brain with carbon-11-pyrilamine.

The brain distribution and kinetics of the H1 receptor antagonist, carbon-11-pyrilamine (11C-pyrilamine) were examined in vivo in two baboons and one human by positron emission tomography. After i.v. administration of the tracer, brain activity peaked within 20 min after injection and subsequently decreased, reflecting reversible binding to the receptor. Pretreatment with 1 mg/kg diphenhydramine reduced the brain activity at 70 min by 33%, 29%, 26%, and 23% of the control values in frontal cortex, temporal cortex, hippocampus, and cerebellum, respectively. Coinjection of 1 and 5 mg/kg cold pyrilamine reduced the activity at 70 min by 40%, 36%, 34%, and 30% in frontal, temporal, hippocampus and cerebellum, respectively. The in vivo specific binding to the H1 receptors in different brain regions at 70 min after injection correlated with the in vitro H1 histamine receptors distribution in human brain tissue obtained at autopsy, with high values in the frontal and temporal cortex and low values in cerebellum and brain stem. In the healthy human volunteer study, the value of washout of radioactivity increased by about 50% after injection of 0.7 mg/kg diphenhydramine.

Adult↗

PubMed1990

Localization of peripheral cholecystokinin receptors in vivo using the cholecystokinin antagonist [3H](+/-)-MK-329.

Cholecystokinin (CCK) regulates various gastrointestinal functions through specific receptors. The mechanisms responsible for disorders of these functions could be elucidated by non-invasively localizing CCK receptors and quantifying their number in vivo. MK-329 is a highly selective and very high affinity antagonist at the peripheral CCK receptor. We investigated the in vivo binding of [3H](+/-)-MK-329 in mice to determine if binding to CCK receptors could be detected after systemic administration of the tracer. The uptake of [3H](+/-)-MK-329 increased in the pancreas from 5 min to 4 h after administration. The binding was saturable, stereospecific, and more than 80% specific. A total/non-specific binding ratio of 43 was reached at 8 h post-injection. The pancreas was the only organ where specific binding could be detected. Our results suggest that MK-329 labeled with a positron emitter such as C-11 could be used with positron emission tomography to image and quantify peripheral CCK receptors in man.

Animals↗

PubMed1990

Morphine-induced metabolic changes in human brain. Studies with positron emission tomography and [fluorine 18]fluorodeoxyglucose.

Morphine sulfate effects (30 mg, intramuscularly) on cerebral glucose utilization and subjective self-reports were examined in 12 polydrug abusers by positron emission tomography and [fluorine 18]fluorodeoxyglucose in a double-blind placebo-controlled crossover study. During testing, subjects sat with eyes covered, listening to white noise and "beep" prompts. Morphine significantly reduced glucose utilization by 10% in whole brain and by about 5% to 15% in telencephalic areas and the cerebellar cortex, assuming no contribution of hypercapnia. When the contribution of PaCO2 (45 minutes after morphine was administered) was partialled out, significant morphine-induced reductions persisted in whole brain and six cortical areas. Irrespective of morphine, left-greater-than-right asymmetry occurred in the temporal cortex, and an interaction between hemisphere and drug was noted in the postcentral gyrus. In most cases, effects on glucose utilization were not significantly related to measures of euphoria.

Blood Pressure↗

PubMed1990

Cocaine-induced reduction of glucose utilization in human brain. A study using positron emission tomography and [fluorine 18]-fluorodeoxyglucose.

We examined the effects of cocaine hydrochloride (40 mg intravenously) on regional cerebral metabolic rates for glucose and on subjective self-reports of eight polydrug abusers in a double-blind, placebo-controlled, crossover study. The regional cerebral metabolic rate for glucose was measured by the [fluorine 18]-fluorodeoxyglucose method, using positron emission tomography. With eyes covered, subjects listened to a tape that presented white noise, "beep" prompts, and questions about subjective effects of cocaine or saline. Cocaine produced euphoria and reduced glucose utilization globally (mean reduction, 14%). Twenty-six of 29 brain regions (all neocortical areas, basal ganglia, portions of the hippocampal formation, thalamus, and midbrain) showed significant decrements (5% to 26%) in the regional cerebral metabolic rate for glucose. No significant effects of cocaine were observed in the pons, the cerebellar cortex, or the vermis. Right-greater-than-left hemispheric asymmetry of regional cerebral metabolic rates for glucose occurred in the lateral thalamus. The findings demonstrate that reduced cerebral metabolism is associated with cocaine-induced euphoria.

Adult↗

PubMed1990

Mania after brain injury: neuroradiological and metabolic findings.

We present a consecutive series of 8 patients who developed a manic episode after a brain injury. Five patients had cortical lesions (4 with damage to the right basotemporal region, and 1 with bilateral damage to the orbitofrontal area). While the other 3 patients had subcortical lesions (white matter of the right frontal lobe, right anterior limb of the internal capsule, and right head of the caudate), a fluorodeoxyglucose positron emission tomography scan showed hypometabolism in the right lateral basotemporal region in all 3 patients. These findings suggest a major role for the basal region of the right temporal lobe in the modulation of mood.

Adult↗

PubMed1990

Selective hypometabolism in the inferior frontal lobe in depressed patients with Parkinson's disease.

Depression is a frequent finding in patients with Parkinson's disease (PD). Regional cerebral glucose metabolism was measured in depressed and nondepressed patients with PD and in age-comparable normal control subjects using 2-[18F]-fluoro-2-deoxy-D-glucose and positron emission tomography (PET). Relative metabolic activity in the caudate and orbital-inferior region of the frontal lobe was significantly lower in the depressed patients with PD as compared to both nondepressed patients and control subjects. There was a significant inverse correlation between relative glucose metabolism in the orbital-inferior area of the frontal lobe and depression scores. This study suggests that depression in PD is associated with dysfunction in the caudate and orbital-inferior area of the frontal lobe. This metabolic pattern is unlike that seen in patients with PD who have other behavioral deficits such as dementia, and suggests that disruption of basal ganglia circuits involving the inferior region of the frontal lobe may affect the regulation of mood.

Aged↗

PubMed1990

Facile synthesis of [11C]buprenorphine for positron emission tomographic studies of opioid receptors.

We have developed a simple and rapid method for the production of buprenorphine (BPN), a potent opioid partial agonist, labelled with carbon-11 at the 6-methoxy position. The procedure uses a precursor synthesized in high yield (89%) from BPN in two steps and employs [11C]iodomethane as the radiolabelling reagent. [11C]BPN of 97% radiochemical purity can be prepared in high specific activity (41 GBq/mumol; 1120 mCi/mumol) in a radiochemical yield of 10% at end-of-synthesis (not decay corrected). The [11C]BPN is available for use in studies of cerebral opioid receptors by positron emission tomography within 24 min from end-of-bombardment, including radiosynthesis, purification, formulation for i.v. injection and determination of specific activity.

Buprenorphine↗

PubMed1990

Synthesis of a selective serotonin uptake inhibitor: [11C]citalopram.

Citalopram, a selective serotonin uptake inhibitor, was labeled with 11C for non-invasive in vivo studies of serotonin uptake sites in the human brain using positron emission tomography. The synthesis was completed in approximately 17 min using [11C]methyl iodide as the precursor. The synthesis, purification, characterization, and determination of specific activity are described.

Brain↗

PubMed1990

Comparison of [11C]diprenorphine and [11C]carfentanil binding to opiate receptors in humans by positron emission tomography.

The kinetics and regional distribution of [11C]carfentanil, a mu-selective opiate receptor agonist, and [11C]diprenorphine, a nonselective opiate receptor antagonist, were compared using paired positron emission tomography studies in two normal volunteers. Kinetics of total radioactivity (counts/mCi/pixel) was greater for [11C]diprenorphine than [11C]carfentanil in all regions. [11C]Carfentanil binding (expressed as the total/nonspecific ratio) reached near equilibrium at approximately 40 min, whereas [11C]diprenorphine showed a linear increase until approximately 60 min. Kinetics of specific binding demonstrated significant dissociation of [11C]carfentanil from opiate receptors, whereas little dissociation of [11C]diprenorphine was observed during the 90-min scan session. Regional distributions of [11C]carfentanil and [11C]diprenorphine were qualitatively and quantitatively different: Relative to the thalamus (a region with known predominance of mu-receptors), [11C]diprenorphine displayed greater binding in the striatum and cingulate and frontal cortex compared to [11C]carfentanil, consistent with labeling of additional, non-mu sites by [11C]diprenorphine. We conclude from these studies that [11C]diprenorphine labels other opiate receptor subtypes in addition to the mu sites selectively labeled by [11C]carfentanil. The nonselective nature of diprenorphine potentially limits its usefulness in defining abnormalities of specific opiate receptor subtypes in various diseases. Development of selective tracers for the delta- and kappa-opiate receptor sites, or alternatively use of unlabeled inhibitors to differentially displace mu, delta, and kappa subtypes, will help offset these limitations.

Adult↗

PubMed1990

Dopamine transporter: biochemistry, pharmacology and imaging.

In recent years, there has been substantial progress in studying the dopamine transporter, a unique component of the functioning dopaminergic nerve terminal. The transporter has been studied by direct binding techniques using a variety of ligands which function as inhibitors of transport. Analogues of these ligands have been used as photoaffinity labels to solubilize and further characterize the transporter. While a variety of drugs bind to the transporter, it is clear that the transporter may serve as an important drug receptor, particularly for the reinforcing properties of some psychostimulants such as cocaine. An extension of the in vitro ligand-binding studies reveals that it is possible to preferentially label the transporter in vivo. The success of in vivo labeling has lead to successful positron emission tomographic scanning studies of the transporter. These studies in turn have revealed the usefulness of imaging the transporter, a measure of the presence of dopaminergic nerve terminals, as a potential diagnostic tool in Parkinson's disease.

Animals↗

PubMed1990

D2 receptors in Huntington's disease: positron emission tomography findings and clinical correlates.

The relationship of dopamine receptor binding in the caudate nucleus and the putamen to neurological and neuropsychological functioning was examined in 21 patients with Huntington's disease (HD) and eight individuals at risk of developing Huntington's disease. A significant reduction in relative binding of [11C]3-N-methylspiperone to the dopamine receptor was found in both the caudate and putamen of HD patients. Binding in the caudate was correlated only with tests of rapid coding and set alternation, while binding in the putamen was correlated only with duration of illness. The findings indicate that the well-described atrophic changes in the striatum of Huntington's disease patients are accompanied by receptor alterations. They also support previous animal and human studies indicating that the caudate nucleus plays a larger role in cognition than in motor functions.

Adult↗

PubMed1990

In vivo labeling of the dopamine D2 receptor with N-11C-methyl-benperidol.

A new dopamine D2 receptor radiotracer, N-11C-methyl-benperidol (11C-NMB), was prepared and its in vivo biologic behavior in mice and a baboon was studied. Carbon-11-NMB was determined to bind to specific sites characterized as dopamine D2 receptors. The binding was saturable, reversible, and stereospecific. Kinetic studies in the dopamine D2 receptor-rich striatum showed that 11C-NMB was retained five times longer than in receptor-devoid regions, resulting in a high maximum striatal-to-cerebellar ratio of 11:1 at 60 min after injection. From frontal cortex and cortex, on the other hand, the tracer washed out as rapidly as it did from cerebellum, resulting in tissue-to-cerebellar ratios close to one in these regions at any time after injection. Blocking studies confirmed the specificity and selectivity of the 11C-NMB binding to the dopamine D2 receptor. A PET study with 11C-NMB of the baboon brain revealed highly selective labeling of dopamine D2 receptor sites which was blocked by preinjection of raclopride.

Animals↗

PubMed1989

Mu opiate receptors are selectively labelled by [3H]carfentanil in human and rat brain.

[11C]Carfentanil is a potent opioid agonist currently in use as a specific PET (position emission tomography) scan radioligand for brain mu opioid receptors. In order to investigate the receptor interactions of carfentanil in detail [3H]carfentanil was used as a radioligand for labelling receptors in rat and human brain tissue homogenates. [3H]Carfentanil was found to bind saturably and with high affinity (KD = 0.08 +/- 0.01 nM) to membranes prepared from human cortical (Bmax = 42 +/- 3 fmol/mg) and thalamic (Bmax = 84 +/- 3 fmol/mg) tissues and rat cortex (Bmax = 82 +/- 4 fmol/mg) and diencephalon (Bmax = 105 +/- 5 fmol/mg). Association (1.23 +/- 0.19 X 10(10) Mol-1 X min-1 and dissociation rate (0.19 +/- 0.03 min-1) constants were determined in human cortical tissues; results from studies in rat cortical, and rat diencephalon tissue homogenates produced similar kinetic rate constants. Competition studies with a variety of drugs indicated that [3H]carfentanil interacts primarily with mu opioid receptors in the four tissues studied; the affinities of a series of non-radioactive opioid ligands were essentially identical in the four tissues (correlation coefficients = 0.88-0.93). Naloxone, morphine, DAGO [( D-Ala2-MePhe4-Gly-ol5]enkephalin), DADL [( D-Ala2-D-Leu5]enkephalin) and EKC (ehtylketazocine) potently displaced specific [3H]carfentanil binding with nM potency while the kappa agonist U-69593, the sigma agonists (+)-SKF 10047, (+)-3-PPP [3-hydroxyphenyl)-N-propylpiperidine) and haloperidol and PCP (phencyclidine) were less potent displacing agents. The higher affinities of DAGO and morphine versus DADL for the [3H]carfentanil binding sites indicates that delta opioid receptors are not being labelled.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

[125]I-spectramide: a novel benzamide displaying potent and selective effects at the D2 dopamine receptor.

The new substituted benzamide Spectramide, (N-[2-[4-iodobenzyl-N-methylamino]-2-methoxy-4-ethyl]-5-chloro- methylamine] benzamide) labelled with 125I was used as a potent and highly selective dopamine-D2 receptor antagonist in rat striatal homogenates for in vitro receptor binding. Kinetic experiments demonstrated the reversibility of the binding and the estimated Kd from saturation analysis was 25 pM, with a Bmax of 20 pmol/g of tissue. Competition studies showed that spectramide did not interact potently with the D1 or dopamine-uptake site. Drugs known to interact with other receptor systems were weak competitors of the binding, while binding was potently inhibited by other D2 antagonists, such as spiperone and eticlopride. These data indicate that Spectramide binds selectively and with high affinity to the dopamine D2 receptors, and may prove to be a useful tool for the study of these receptors in vivo using PET or SPECT.

Animals↗

PubMed1989

Preparation of [11C]- and [125I]IMB: a dopamine D-2 receptor antagonist.

A new dopamine D-2 receptor ligand, N-[2-(N'-4-iodobenzyl-N'-methyl)aminoethyl]-5-chloro-2-methoxy-4- (methylamino)benzamide (IMB) was synthesized and labelled with 11C and 125I at high specific activities. Both radiotracers were prepared by alkylation reactions with [11C]iodomethane and [125I]4-iodobenzyl bromide and appropriate 2 degrees amine precursors. Isolated radiochemical yields of 12-20% for [11C]IMB and 35-50% for [125I]IMB were achieved in 24 and 130-150 min respectively. [11C]IMB and [123I]IMB may prove suitable for a direct comparison of PET and SPECT in the localization and quantification of neuroreceptors.

Benzamides↗

PubMed1989

Biodistribution and radiation absorbed dose of (N-methyl[11C])pyrilamine: a histamine H-1 receptor radiotracer.

The in vivo biodistribution for (N-methyl[11C])pyrilamine in mice is reported for various times after i.v. bolus injection, together with estimates of the radiation absorbed dose for the same radiotracer in man. More than 60% of the injected dose was excreted via the kidneys in urine after 90 min post injection. The brain regional distribution in mice showed a favorable hypothalamus-to-cerebellum ratio, indicative of H-1 receptor binding, encouraging in vivo histamine H-1 receptor imaging studies in man.

Aminopyridines↗