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Biomedical subjects

R F Dannals

Publications and source records attributed to R F Dannals.

At least 145 records · Page 8Linked to original sources
PubMed1989

Synthesis and in vivo characterization of D-(+)-(N1-[11C]methyl)-2-Br-LSD: a radioligand for positron emission tomographic studies of serotonin 5-HT2 receptors.

D-(+)-N1-Methyl-2-Br-LSD (MBL), which displays high affinity and selectivity for serotonin receptors in vitro, has been labeled with carbon-11 for localization of cerebral serotonin 5-HT2 receptors by positron emission tomography. [11C]MBL was prepared from [11C]iodomethane and D-(+)-2-Br-LSD within 20 min from end of bombardment. The average specific activity of [11C]MBL was 2300 mCi/mumol and the average radiochemical yield was 17%, both at end of synthesis. The in vivo regional distribution of radioactivity in brain after i.v. administration of [11C]MBL to mice paralleled the known density of serotonin 5-HT2 receptors. The maximum specific binding, defined by a frontal cortex to cerebellum radioactivity concentration ratio of 5.4 to 1, was reached 30 min postinjection. Administration of ketanserin, a potent serotonin 5-HT2 receptor antagonist, markedly blocked radioligand binding in all brain regions examined except cerebellum.

Animals↗
PubMed1989

Synthesis and biological evaluation of [125I]- and [123I]-4-iododexetimide, a potent muscarinic cholinergic receptor antagonist.

A series of halogenated racemic analogues of dexetimide (1) was synthesized and their affinity for the muscarinic cholinergic receptor measured. One analogue, 4-iododexetimide (21), was efficiently labeled with 125I and 123I at high specific activity. In vitro binding studies and in vivo biodistribution studies suggest that 123I-labeled 21 may be useful for imaging muscarinic cholinergic receptors in the living human brain with single photon emission computed tomography.

Animals↗
PubMed1989

Multicompartmental analysis of [11C]-carfentanil binding to opiate receptors in humans measured by positron emission tomography.

[11C]-Carfentanil is a high affinity opiate agonist that can be used to localize mu opiate receptors in humans by positron emission tomography (PET). A four-compartment model was used to obtain quantitative estimates of rate constants for receptor association and dissociation. PET studies were performed in five normal subjects in the absence and presence of 1 mg/kg naloxone. Arterial plasma concentration of [11C]-carfentanil and its labeled metabolites were determined during each PET study. The value of k3/k4 = Bmax/kD was determined for each subject in the presence and absence of naloxone. There was a significant reduction in the value of k3/k4 from 3.4 +/- 0.92 to 0.26 +/- 0.13 in the thalamus (p less than 0.01) and from 1.8 +/- 0.33 to 0.16 +/- 0.065 in the frontal cortex (p less than 0.001). Mean values of frontal cortex/occipital cortex and thalamus/occipital cortex ratios were determined for the interval 35-70 min after injection when receptor binding is high relative to nonspecific binding. The relationship between the measured region/occipital cortex values and the corresponding values of k3/k4 in the presence and absence of naloxone was: regions/occipital cortex = 0.95 + 0.74 (k3/k4) with r = 0.98 (n = 20). Simulation studies also demonstrated a linear relationship between the thalamus/occipital cortex or frontal cortex/occipital cortex ratio and k3/k4 for less than twofold increases or decreases in k3/k4. Simulation studies in which thalamic blood flow was varied demonstrated no significant effect on the region/occipital cortex ratio at 35-70 min for a twofold increase or fourfold decrease in blood flow. Therefore, the region/occipital cortex ratio can be used to quantitate changes in k3/k4 when tracer kinetic modeling is not feasible.

Adult↗
PubMed1988

Mu-opiate receptors measured by positron emission tomography are increased in temporal lobe epilepsy.

Neurochemical studies in animal models of epilepsy have demonstrated the importance of multiple neurotransmitters and their receptors in mediating seizures. The role of opiate receptors and endogenous opioid peptides in seizure mechanisms is well developed and is the basis for measuring opiate receptors in patients with epilepsy. Patients with complex partial seizures due to unilateral temporal seizure foci were studied by positron emission tomography using 11C-carfentanil to measure mu-opiate receptors and 18F-fluoro-deoxy-D-glucose to measure glucose utilization. Opiate receptor binding is greater in the temporal neocortex on the side of the electrical focus than on the opposite side. Modeling studies indicate that the increase in binding is due to an increase in affinity or the number of unoccupied receptors. No significant asymmetry of 11C-carfentanil binding was detected in the amygdala or hippocampus. Glucose utilization correlated inversely with 11C-carfentanil binding in the temporal neocortex. Increased opiate receptors in the temporal neocortex may represent a tonic anticonvulsant system that limits the spread of electrical activity from other temporal lobe structures.

Adolescent↗
PubMed1988

Synthesis of radiotracers for studying muscarinic cholinergic receptors in the living human brain using positron emission tomography: [11C]dexetimide and [11C]levetimide.

Dexetimide (Fig. 1a), a potent muscarinic cholinergic receptor antagonist, and levetimide (Fig. 1b), its pharmacologically inactive enantiomer, were labeled with 11C for non-invasive in vivo studies of muscarinic cholinergic receptors in the human brain using positron emission tomography. The syntheses were completed in approximately 32 min using [alpha-11C]benzyl iodide as the precursor. The synthesis, purification, characterization and determination of specific activity are presented and discussed.

Brain↗
PubMed1988

(N-methyl-[11C])pyrilamine, a radiotracer for histamine H-1 receptors: radiochemical synthesis and biodistribution study in mice.

The histamine H-1 receptor antagonist, pyrilamine (N-((4-methoxyphenyl)methyl)-N',N'-dimethyl-N-2-pyridinyl-1,2-ethaned i ami ne) was labeled with carbon-11 by N-alkylation of desmethylpyrilamine with [11C]iodomethane, and purified by preparative high performance liquid chromatography. The chemically and radiochemically pure labeled pyrilamine was obtained with specific activity of approximately 2500 mCi/mumol (EOS). In vivo distribution studies in mice suggest that the distribution of this compound parallels the known histamine H-1 receptor density in the brain.

Aminopyridines↗
PubMed1988

Assessment of [11C]-L-methionine transport into the human brain.

Neutral amino acid transport into human brain was measured using a dual-probe positron detection system or positron emission tomography (PET). Rate constants (ml/min/cc) for brain accumulation of [11C]L-methionine measured with the dual detector ranged from 0.012 to 0.078 (average 0.031) under baseline conditions and from 0.010 to 0.017 (average 0.014) after administration of nonradioactive L-phenylalanine (100 mg/kg). The net rate of brain accumulation of L-methionine ranged from 0.42 to 2.89 (average 1.28) nmol/min/cc, and decreased by 27.5-91.2% (average 53.9%) after L-phenylalanine. PET-estimated accumulation rates (ml/min/cc) of [11C]L-methionine ranged from 0.004 to 0.028 (average 0.016) baseline and from 0.010 to 0.021 (average 0.017) after L-phenylalanine. Initial volumes of distribution (ml/cc) of [11C]L-methionine (dual detector) were 0.044-0.070 (average 0.058) baseline and 0.032-0.074 (average 0.051) after phenylalanine and (PET) 0.026-0.098 (average 0.051) baseline and 0.021-0.061 (average 0.042) after phenylalanine. PET permits more accurate measurement of tracer accumulation by brain, excluding noncerebral regions included in dual-detector measurements. The dual-detector system permits better temporal resolution, facilitating kinetic analysis, and requires only one-fortieth the dose of tracer needed for PET. Multiple studies in the same patient are thus possible at low cost.

Biological Transport↗
PubMed1988

PET imaging of cortical S2 serotonin receptors after stroke: lateralized changes and relationship to depression.

Patients with right-hemisphere strokes (N = 9) more than 1 year after injury had greater cortical binding of (3-N-[11C]methyl)spiperone than a similar group of patients with left-hemisphere strokes (N = 8) or normal control subjects (N = 17). The higher S2 serotonin receptor binding occurred in uninjured regions of the right parietal and temporal cortex. The ratio of binding in the ipsilateral to contralateral cortex showed a significant negative correlation with severity of depression scores in the left temporal cortex. These findings suggest that the biochemical response of the brain may be different depending on which hemisphere is injured and that some depressions may be a consequence of the failure to upregulate serotonin receptors after stroke.

Adult↗
PubMed1988

Duration of occupancy of opiate receptors by naltrexone.

To determine the duration of blockade of mu-opiate receptors by naltrexone, we measured the binding of [11C]carfentanil in the brain of five normal volunteers with a positron radiation detection system before and 1, 48, 72, 120, and 168 hr after naltrexone administration. The half-time of blockade by naltrexone in the brain ranged from 72 to 108 hr which is greater than the fast plasma clearance components (4-12 hr) of naltrexone or its metabolite, beta-naltrexol, but corresponds well to the half-time of the terminal phase of plasma naltrexone clearance (96 hr). These results are consistent with the duration of the pharmacologic effects of naltrexone in response to heroin administration and indicate that 50 mg/day of oral naltrexone results in plasma levels in excess of that needed to saturate opiate receptors. This is the first example of the use of a simple dual-detector system with positron-emitting radioactive drugs to provide information regarding the duration of action of the drug on its specific receptor site. The plasma clearance half-time of a drug may not give an accurate reflection of the duration of action of the drug on a specific neuroreceptor site. Direct measurement of drug effects on recognition sites greatly extend current studies of pharmacokinetics.

Administration, Oral↗
PubMed1988

Labeled plasma metabolites of L-methyl-hydrogen-3-methionine and L-methyl-carbon-14-methionine in the dog.

The validity of the mathematical models that attempt to describe positron emission tomography (PET) images produced with [11CH3] methionine in terms of rates of local cerebral protein synthesis has yet to be established. A major objection to current models is that the use of methionine labeled at the methyl position results in the dispersal of the label among various methyl-accepting compounds that appear in the plasma and may then enter the brain. One approach to overcoming this problem has been the use of "standard" corrections for the activity contributed to plasma by labeled plasma protein and labeled serine. In order to determine the validity of this approach, the metabolic fate of labeled methionine was studied in six dogs. After injection with either [C3H3] methionine or [14CH3] methionine arterial blood was sampled. Plasma fractions containing protein were separated by fast gel filtration, counted with standard scintillation techniques, and their radioactivity was compared with total plasma radioactivity. Plasma was also separated by high-pressure liquid chromatography into methionine, serine, and nonmethionine or serine-containing fractions. These fractions were counted, and their radioactivity was compared with total plasma radioactivity. Labeled protein appeared in plasma about 20 minutes postinjection and then increased steadily. Labeled serine also appeared and reached a peak value of 9.4 +/- 2.1% of plasma activity at 40 minutes. Of greatest interest was the appearance in later plasma samples of increasing amounts of activity contained in nonserine low molecular weight metabolites of methionine. At 40 minutes, those metabolites made up 27 +/- 6.9% of total plasma activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

In vivo binding of 3H-N-methylspiperone to dopamine and serotonin receptors.

3H-N-methylspiperone (3H-NMSP) was used to label dopamine-2 and serotonin-2 in vivo in the mouse. The striatum/cerebellum binding ratio reached a maximum of 80 eight hours after intravenous administration of 3H-NMSP. The frontal cortex/cerebellum ratio was 5 one hour after injection. The binding of 3H-NMSP was saturable in the frontal cortex and cerebellum between doses of 10 and 1,000 micrograms/kg. Between 0.01 and 10 micrograms/kg the ratio total/nonspecific binding increased from 14 to 21. Inhibition of 3H-NMSP binding in the frontal cortex and striatum by ketanserin, a selective serotonin-2 antagonist, demonstrated that 20% of the total binding in the striatum was to serotonin-2 receptors and 91% of the total binding in the frontal cortex was to serotonin-2 receptors. Compared to 3H-spiperone, 3H-NMSP results in a much higher specific/nonspecific binding ratio in the striatum and frontal cortex and displays more than a two-fold higher brain uptake.

Animals↗
PubMed1987

Localization of serotonin 5-HT2 receptors in living human brain by positron emission tomography using N1-([11C]-methyl)-2-Br-LSD.

N1-([11C]-Methyl)-2-Br-LSD ([11C]-MBL) has been developed as a positron emission tomography (PET) imaging agent for serotonin 5-HT2 receptors. In vitro receptor binding assays with nonradioactive MBL show high-affinity binding to serotonin 5-HT2 receptors (Ki = 0.5 nM), a secondary interaction of 8-fold lower affinity with dopamine D2 receptors, and low-affinity interactions with alpha 1-adrenergic as well as serotonin 5-HT1 receptors. Intravenous injection of [11C]-MBL in a baboon led to selective labeling of cortical regions that was markedly blocked by prior administration of ketanserin, a selective 5-HT2 receptor antagonist. Clinical trials with [11C]-MBL have been conducted in seven normal human volunteers, and the regional distribution of radioactivity in the brain was distinctly serotonergic. Labeling was highest in frontal, temporal, and parietal cortex with lower levels observed in caudate and putamen. The tracer rapidly washed from the cerebellum and the low levels of activity in this brain region were used to define nonspecific binding. The maximum specificity was reached between 30 and 60 minutes postinjection when frontal cortex to cerebellum ratios ranged from 1.7 for a 52-year-old male to 2.7 for a 30-year-old male. In agreement with previous studies, a trend towards lower ratios (lower serotonin 5-HT2 receptor levels) was observed in older volunteers. These studies indicate that [11C]-MBL is a selective radioligand that can be used to monitor serotonin 5-HT2 receptor densities in vivo in most regions of the human brain.

Animals↗
PubMed1987

Radiosynthesis of a selective dopamine D-1 receptor antagonist: R(+)-7-chloro-8-hydroxy-3-[11C]methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3 -benzazepine ([11C]SCH 23390).

Carbon-11 labeled SCH 23390, a selective dopamine D-1 receptor antagonist (Fig. 1b), was prepared by N-alkylation of the nor-methyl precursor with [11C]iodomethane. The product was purified by semi-preparative HPLC and shown to be radiochemically pure at the end of synthesis. The synthesis was completed in approximately 22 min with an average radiochemical yield of 28% (based on [11C]iodomethane) and an average specific activity of approximately 1950 microCi/mumol calculated at the end of synthesis.

Benzazepines↗
PubMed1986

Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics.

In postmortem studies of patients with schizophrenia, D2 dopamine receptors in the basal ganglia have been observed to be more numerous than in patients with no history of neurological or psychiatric disease. Because most patients with schizophrenia are treated with neuroleptic drugs that block D2 dopamine receptors in the caudate nucleus, it has been suggested that this increase in the number of receptors is a result of adaptation to these drugs rather than a biochemical abnormality intrinsic to schizophrenia. With positron emission tomography (PET), the D2 dopamine receptor density in the caudate nucleus of living human beings was measured in normal volunteers and in two groups of patients with schizophrenia--one group that had never been treated with neuroleptics and another group that had been treated with these drugs. D2 dopamine receptor densities in the caudate nucleus were higher in both groups of patients than in the normal volunteers. Thus, schizophrenia itself is associated with an increase in brain D2 dopamine receptor density.

Adult↗