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R F Dannals

Publications and source records attributed to R F Dannals.

At least 163 records · Page 9Linked to original sources
PubMed1986

Positron emission tomographic study of D2 dopamine receptor binding and CSF biogenic amine metabolites in Rett syndrome.

We report on the first positron emission tomographic study of dopamine receptor binding in Rett syndrome. The patient is a 25 year old Austrian woman diagnosed at age 2 and followed since then by Rett. A computed axial tomogram (CT scan) showed cortical atrophy, and enlarged ventricles but normal structure of the caudate/putamen. Following the CT scan 20 mCi of 11 C N-methyl spiperone, a butyrophenone with a high affinity for dopamine D2 receptors was administered intravenously. The patient was found to have dopamine D2 receptor binding activity in the low normal range. The caudate/cerebellar activity ratio was below the mean regression line (p = 0.10) that relates the CA/CB ratio as a function of age. Levels of cerebrospinal fluid neurotransmitter metabolites were normal.

Adult↗
PubMed1986

An improved synthesis of (3-N-[11C]methyl)spiperone.

An improved radiochemical synthesis of (3-N-[11C]methyl) spiperone is reported. The radiotracer was prepared by N-alkylation of spiperone in dimethylformamide in the presence of equimolar aqueous tetrabutylammonium hydroxide and was purified by semi-preparative reversed phase high performance liquid chromatography (C-18 HPLC). The average radiochemical yield was approximately 21% end-of-synthesis (EOS) with an average specific activity of over 2750 mCi/mumol EOS. The total time for synthesis and specific activity determination was approximately 21 min.

Carbon Radioisotopes↗
PubMed1986

Quantification of Neuroreceptors in the living human brain. II. Inhibition studies of receptor density and affinity.

A method for estimating receptor density (Bmax) in the living human brain by positron emission tomography was exemplified by a ligand, 3-N-[11C]methylspiperone ([11C]NMSP), that binds to D2 dopamine receptors with high affinity. The ligand binds essentially irreversibly (i.e., with very little dissociation) to the receptors during the 2-h scanning period. Transfer constants were estimated at steady state. In a previous article, we presented a method for the determination of k3, the rate of binding of the labeled ligand. In the present work, we varied k3 by reducing the number of available receptors with a previously administered receptor blocking agent, haloperidol. We calculated a receptor density of 9.2 pmol g-1 in the caudate nucleus of four normal volunteers, and an inhibitory constant of haloperidol of 1.4 nM by comparing tracer accumulation in the absence and the presence of the blocking agent. The values agreed with measurements of NMSP receptor density and haloperidol inhibitory potency in vitro in brain homogenates from human autopsy material.

Adolescent↗
PubMed1986

3H-3-N-methylspiperone labels D2 dopamine receptors in basal ganglia and S2 serotonin receptors in cerebral cortex.

Detailed studies of the properties of 3H-3-N-methylspiperone (NMSP) binding in rat and human brain homogenates were performed at 37 degrees C. In homogenates of rat striatum and frontal cortex and human caudate and frontal cortex tissues, the specific binding was found to be saturable. Rat caudate contained 33.2 pmol/gm wet-weight tissue and displayed an equilibrium dissociation constant (Kd) of 8.7 X 10(-11) M; rat frontal cortex contained 18.5 pmol/gm wet-weight tissue and displayed a Kd of 1.5 X 10(-10) M. Human caudate contained 8.96 pmol/gm wet-weight tissue and displayed a Kd of 1.1 X 10(-10) M; human frontal cortex possessed 9.8 pmol/gm wet-weight tissue and a Kd of 4.4 X 10(-10) M. Kinetic studies revealed a very rapid rate of association in all the tissues studied. The rate of dissociation was relatively slow in all 4 tissue preparations; the dissociation rate was somewhat slower in rat striatum and human caudate relative to rat and human frontal cortex. This was consistent with the somewhat higher affinity, relative to frontal cortex, displayed by 3H-NMSP in rat striatal and human caudate tissue. The pharmacological properties of the specific binding in rat striatal and human caudate tissues were very similar and indicated the presence of brain D2 dopamine receptors. In rat and human frontal cortex tissue homogenates, the pharmacological characteristics of the specific binding indicated the presence of 5-HT2 receptors.

Animals↗
PubMed1986

Simplified detection system for neuroreceptor studies in the human brain.

A simple, inexpensive dual-detector system has been developed for measurement of positronemitting receptor-binding drugs in the human brain. This high efficiency coincidence counting system requires that only a few hundred microcuries of labeled drug be administered to the subject, thereby allowing for multiple studies without an excessive radiation dose. Measurement of the binding of [11C]carfentanil, a high affinity synthetic opiate, to opiate receptors in the presence and in the absence of a competitive opiate antagonist indicates the potential utility of this system for estimating different degrees of receptor occupation in the human brain.

Binding, Competitive↗
PubMed1985

Radiosynthesis of an opiate receptor binding radiotracer: [11C]carfentanil.

Carfentanil, a potent opiate receptor agonist, was labeled with 11C for in vivo studies using positron emission tomography. This synthesis was completed in approximately 30 min using iodomethane as the 11C precursor. The synthesis, purification, characterization, and determination of specific activity are presented and discussed.

Carbon Radioisotopes↗
PubMed1984

Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain.

D2 dopamine and S2 serotonin receptors were imaged and measured in healthy human subjects by positron emission tomography after intravenous injection of 11C-labeled 3-N-methylspiperone. Levels of receptor in the caudate nucleus, putamen, and frontal cerebral cortex declined over the age span studied (19 to 73 years). The decline in D2 receptor in males was different from that in females.

Aging↗
PubMed1984

Assessment of dopamine receptor densities in the human brain with carbon-11-labeled N-methylspiperone.

We describe the use of carbon-11-labeled 3-N-methylspiperone, a ligand that preferentially binds to dopamine receptors in vivo, to image the receptors by positron emission tomography scanning in baboons and, for the first time, in a human. The method has now been used in 58 humans for noninvasive assessment of the state of brain dopamine receptors under normal and pathological conditions.

Animals↗
PubMed1984

In vivo studies of opiate receptors.

To study opiate receptors noninvasively in vivo using positron emission tomography, techniques for preferentially labeling opiate receptors in vivo can be used. The rate at which receptor-bound ligand clears from the brain in vivo can be predicted by measuring the equilibrium dissociation constant (KD) at 37 degrees C in the presence of 100 mM sodium chloride and 100 microM guanyl-5'-imidodiphosphate, the drug distribution coefficient, and the molecular weight. A suitable ligand for labeling opiate receptors in vivo is diprenorphine, which binds to mu, delta, and kappa receptors with approximately equal affinity in vitro. However, in vivo diprenorphine may bind predominantly to one opiate receptor subtype, possibly the mu receptor. To predict the affinity for binding to the opiate receptor, a Hansch correlation was determined between the 50% inhibitory concentration for a series of halogen-substituted fentanyl analogs and electronic, lipophilic, and steric parameters. Radiochemical methods for the synthesis of carbon-11-labeled diprenorphine and lofentanil are presented.

Brain↗
PubMed1984

(3-N-[11C]methyl)spiperone, a ligand binding to dopamine receptors: radiochemical synthesis and biodistribution studies in mice.

Carbon-11-labeled 3-N-methylspiperone, a positron-emitting dopamine-receptor antagonist with potential for use in positron emission tomography studies of human neurotransmitter receptors, was synthesized from 11CO2 in 40 min, with a radiochemical yield of approximately 20-40%. The specific activity of the (3-N-[11C]methyl)-spiperone was determined by ultraviolet spectroscopy to be approximately 270 mCi/mumol at the end of synthesis. In in vitro binding experiments, the Ki for 3-N-methylspiperone was found to be approximately 250 pM (against H-3 spiperone). The brain-to-blood ratios in normal ICR mice were 2.8 or greater at the times studied, and the striatum-to-cerebellum ratio at 60 min after injection was 20:1.

Animals↗
PubMed1983

Imaging dopamine receptors in the human brain by positron tomography.

Neurotransmitter receptors may be involved in a number of neuropsychiatric disease states. The ligand 3-N-[11C]methylspiperone, which preferentially binds to dopamine receptors in vivo, was used to image the receptors by positron emission tomography scanning in baboons and in humans. This technique holds promise for noninvasive clinical studies of dopamine receptors in humans.

Animals↗
PubMed1983

A simple radiometric in vitro assay for acetylcholinesterase inhibitors.

A radiometric method for screening acetylcholinesterase inhibitors has been described. The method is based on the production of [14C]carbon dioxide from the hydrolysis of acetylcholine. The inhibitory concentration at 50% (IC50) values for several known acetylcholinesterase inhibitors were in agreement with literature values. The new radiometric method is simple, inexpensive, and has the potential for automation.

Acetylcholine↗
PubMed1981

Radiolabeled benzoylcholine derivatives as possible myocardial-imaging agents.

Two radioiodinated analogs of benzoylcholine were investigated as possible myocardial-imaging agents. O-([2-125I]Iodobenzoyl)-choline and N-([2-125I]iodobenzoyl)cholamine were prepared by nucleophilic substitution of sodium [125I]iodide for stable iodine in O-(N,N]dimethylaminoethyl)-2-iodobenzoate and N-(N',N'-dimethylaminoethyl)-2-iodobenzamide, respectively, and by methylation with methyl iodide. The in vivo distribution of each compound in mice was determined as a function of time. Favorable heart-to-blood and heart-to-lung ratios were obtained with N-([2-125I]iodobenzoyl)cholamine.

Animals↗
PubMed1980

4-[125I] iodophenyltrimethylammonium ion, an iodinated acetylcholinesterase inhibitor with potential as a myocardial imaging agent.

4-[125I]Iodophenyltrimethylammonium acetate (4-I-125 PTMA) was prepared by chloramine-T iodination of N,N-dimethylaniline and subsequent methylation with methyliodide. Purification by thin layer chromatography afforded a product whose specific activity approached the theoretical carrier-free level. Biodistribution studies in normal ICR mice showed a significant accumulation of 4-I-125 PTMA in the heart tissue, with heart-to-blood ratios of 12.5, 10.4, 7.8, 3.4, 3.4, and 3.3 at 1, 5, 10, 30, 60, and 120 min, respectively. Initial uptake in the heart was greater than 26% of the injected dose per gram. Twenty-five percent of the activity was excreted unchanged by the kidneys during the first 5 min. Less than half of the injected activity was retained in mice at 120 min.

Animals↗
PubMedDate not supplied

Two-phase [11C]L-methionine PET in childhood brain tumors.

Thirteen children (1.8-15.8 years of age) with brain tumors were studied with [11C]L-methionine positron emission tomography (METPET). Patients were injected intravenously with tracer before a baseline PET scan was obtained. To assess the sensitivity of [11C]L-methionine uptake to competitive inhibition, 10 patients received oral L-phenylalanine (100 mg/kg); 1 hour later, a second METPET was obtained. Subjective assessment of [11C]L-methionine uptake closely paralleled results of quantitative examination (r = 0.81). [11C]L-methionine uptake in tumor-containing brain was increased in 11 patients (mean ratio of [11C] radioactivity in tumor to normal brain: 1.5 +/- 0.57; range: 1.13-2.98). Increased tracer uptake occurred in ependymomas (3), medulloblastoma (1), and astrocytomas (5), but was less intense in low-grade tumors. L-phenylalanine reduced L-methionine uptake (25-69%) in 70% of studies. L-methionine uptake was not sensitive to competitive inhibition in brain radiation injury. Two-phase METPET is of potential value in difficult clinical situations evident in children with brain tumors, including the differential diagnosis of tumor recurrence and cerebral radiation injury.

Adolescent↗