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R F Dannals

Publications and source records attributed to R F Dannals.

At least 73 records · Page 4Linked to original sources
PubMed1996

Fenfluramine-induced loss of serotonin transporters in baboon brain visualized with PET.

The present study sought to determine whether or not Positron Emission Tomography (PET) with the newly developed positron emitting serotonin (5-HT) transporter ligand, (+)[11C]McN-5652, could be used to detect fenfluramine-induced 5-HT neurotoxicity in the brain of living primates (baboons). Six PET imaging studies were performed: three before treatment with fenfluramine (5 mg/kg, s.c., twice daily for 4 days) and three after (18, 45, and 81 days after treatment). The dose of fenfluramine used in this study (5 mg/kg) is known to produce 5-HT neurotoxicity in primates, and to be approximately two times higher than a dose of fenfluramine reported to produce small and inconsistent weight loss in baboons (2 mg/kg). Following fenfluramine treatment, marked lasting reductions in regional brain specific binding of (+)[11C]McN-5652 were found by means of PET. Findings with PET corresponded well with post-mortem neurochemical findings indicative of serotonergic neurotoxicity (lasting depletions of regional brain 5-HT, 5-HIAA, and 5-HT uptake sites). These results suggest that PET imaging with (+)[11C]McN-5652 will be useful for evaluating the 5-HT neurotoxic potential of fenfluramine and related drugs in living humans.

Animals↗
PubMed1996

Assessing neuroreceptor occupancy by continuous infusion of carbon-11 labeled radioligands.

In carbon-11 labeled radiotracer studies of neuroreceptors in the brain, a state of practical equilibrium, monitored with a simple dual-probe detector system, was achieved by injection of a bolus of tracer followed by a continuous infusion of the tracer. After investigating several different bolus-to-infusion activity ratios, we observed that a practical equilibrium state could be achieved with a slope of 0.02+/-0.001 cpsxkg/microCi/min for [11C]carfentanil studies in normal human beings. The usefulness of this approach to assess neuroreceptor occupancy was demonstrated in two cases.

Adult↗
PubMed1996

Positron emission tomography of 5-HT reuptake sites in the human brain with C-11 McN5652 extraction of characteristic images by artificial neural network analysis.

The goal of this work was to identify the distribution of serotonin transporters in the human brain with [11C](+)McN5652/PET. Four healthy volunteers were studied. To determine non-specific binding, a PET study was also performed with the inactive enantiomer [11C](-)McN5652 as well as with [11C](+)McN5652 after pretreatment with fluoxetine. For pattern extraction the PET data sets were analyzed by a back-propagation neural network. Two pharmacokinetic patterns and two characteristic images were separated; one representing specific binding, the other representing non-specific binding. The specific binding image showed characteristic distribution of serotonin transporters with [11C](+)McN5652. The pattern images demonstrated an improvement in image quality compared to the original PET images (reduced variance, higher region-to-cerebellum ratio, good correlation with known density of serotonin transporters). The non-specific binding images extracted from [11C](-)McN5652/PET were similar to those of [11C](-)McN5652 and [11C](-)McN5652 with fluoxetine. Thus, PET studies obtained with [11C](+)McN5652 largely represent the regional distribution of the serotonin transporters and the inactive enantiomer [11C](-)McN5652 shows the distribution of its nonspecific binding.

Adult↗
PubMed1996

3 Beta-(p-trimethylsilylphenyl)tropane-2 beta-carboxylic acid methyl ester: a new precursor for the preparation of [123I]RTI-55.

Here we report the synthesis of 3 beta-(p-trimethylsilylphenyl)tropane-2 beta-carboxylic acid methyl ester, a new, easily prepared precursor for the synthesis of radioiodinated versions of RTI-55. In contrast to the 3 beta-(p-trimethylstannylated) precursor for radioiodination, the aryl silane is prepared directly by the 1,4 addition of p-trimethylsilylphenylmagnesium iodide to anhydroecgonine methyl ester in 49% yield (Scheme 1). Radioiododesilylation proceeded smoothly (approx. 85% radioincorporation after 15 min at room temperature) using 1 microgram of the novel precursor in trifluoroacetic acid and chloramine-T as oxidant. Isolated radiochemical yields for 125I and 123I radiolabelings were 72 and 48%, respectively, with a calculated specific activity for [123I]RTI-55 of > 2000 mCi/mumol.

Chromatography, High Pressure Liquid↗
PubMed1996

Development of [11C]L-159,884: a radiolabelled, nonpeptide angiotensin II antagonist that is useful for angiotensin II, AT1 receptor imaging.

[11C]L-159,884 ([11C] N-[[4'[(2-ethyl-5,7-dimethyl-3H- imidazo[4,5-b]pyridin-3-yl) methyl] [1,1'-biphenyl]-2-yl] sulfonyl]-4-methoxybenzamide) and [11C]L-162,574 ([11C] N-[[4'[2-ethyl-5,7- dimethyl-3H-imidazo[4,5-b] pyridin-3-yl)methyl] [1,1'-biphenyl]-2-yl]sulfonyl]-3- methoxybenzamide), both potent and selective ligands for the AT1 receptor, were prepared by C-11 methylation of the corresponding desmethyl phenolic precursors. The radiotracers were purified by semi-preparative reverse-phase HPLC. Non-decay corrected radiochemical yields were 5 and 3% for L-159,884 and L-162,574 respectively, and the average specific activity was 2979 mCi/mumol at end-of-synthesis (EOS). The average time of synthesis was 18 min.

Angiotensin I↗
PubMed1996

Increased mu opioid receptor binding detected by PET in cocaine-dependent men is associated with cocaine craving.

The endogenous opioid system has been recently implicated in the reinforcing actions of cocaine and other addictive drugs. In this study we examined mu opioid receptor binding in ten cocaine-dependent men and seven nonaddicted controls using positron emission tomography and [11C] carfentanil. Mu opioid binding was increased in several brain regions of the cocaine addicts studied 1-4 days after their last use of cocaine. Binding was positively correlated with the severity of cocaine craving experienced at the time. The upregulation of mu opioid receptor binding persisted after 4 weeks of monitored cocaine abstinence. These findings demonstrate for the first time the involvement of the endogenous opioid system in cocaine dependence and cocaine craving in living human subjects.

Adult↗
PubMed1996

Functional sites of neuroleptic drug action in the human brain: PET/FDG studies with and without haloperidol.

OBJECTIVE: The functional pathways through which antipsychotic drugs act in the brain to decrease psychosis remain unknown, despite our knowledge that their site of initial action is through blockade of dopamine D2 receptors. The authors sought to define the brain regions that are functionally altered by neuroleptic drugs. METHODS: Regional cerebral glucose metabolism was studied in 12 subjects with schizophrenia while they were receiving a fixed dose of haloperidol, again 5 days after withdrawal of the drug, and a third time 30 days after withdrawal. Positron emission tomography with an [18F]fluorodeoxyglucose tracer was used in a within-subject design. RESULTS: The analysis demonstrated a decrease in glucose metabolism in the caudate and putamen 30 days after withdrawal, indicating that haloperidol treatment enhanced glucose utilization in these areas. The thalamus, bilaterally but only in anterior areas, showed the same response to haloperidol. Only in the frontal cortex and in the anterior cingulate had metabolism increased 30 days after withdrawal, indicating that in those two cortical areas haloperidol depressed glucose metabolism. In the 5-day drug free scans, no regions differed significantly from those in the haloperidol condition, despite numerical changes. CONCLUSIONS: It appears that 5 days of neuroleptic withdrawal are inadequate to escape the effects of neuroleptic drugs on regional cerebral glucose metabolism. The pattern and localization of changes in metabolic activity between the haloperidol condition and the 30-day drug-free condition suggest that haloperidol exerts its primary antidopaminergic action in the basal ganglia. It is proposed that the additional changes in the thalamus and cortex are secondary to this primary site of drug action, mediated through classically described striato-thalamo-cortical pathways.

Adult↗
PubMed1996

In vivo labeling of angiotensin II receptors with a carbon-11-labeled selective nonpeptide antagonist.

UNLABELLED: Angiotensin II (ANG II) initiates a variety of physiological effects by binding to high affinity receptors. Two ANG II receptor subtypes, AT1 and AT2, have recently been identified. This study was undertaken to evaluate [11C]L-159,884, an AT1 subtype selective nonpeptide antagonist, as a potential PET tracer. METHODS: Carbon-11-L-159,884 was prepared by alkylation of the nor precursor with [11C]methyliodide and was studied for its in vivo binding characteristics, biodistribution and kinetics in mice. The effects of PD-123319, an AT2-selective ANGII antagonist, as well as those of alpha- and beta-adrenergic drugs on [11C]L-159,884 binding were investigated also. RESULTS: Administration of the AT1 antagonists resulted in dose-dependent inhibition of [11C]L-159,884 binding in the kidneys, the organ with the highest density of AT1 receptors. Inhibition was also observed in the lungs and the heart. Adrenergic drugs did not influence [11C]L-159,884 binding to AT1 receptors. Kinetic studies showed rapid tracer uptake in the liver, kidneys, lungs and heart. Excretion of the radioactivity occurred primarily through the intestinal tract (> 20% in 90 min), with less than 8% excreted through the urine. CONCLUSION: The results suggest that [11C]L-159,884 binds in vivo to AT1 receptors in mouse kidneys, lungs and heart. This radiotracer appears to be a promising candidate for studying ANG II receptors in vivo by PET.

Angiotensin Receptor Antagonists↗
PubMed1996

Peptide T and glucose metabolism in AIDS dementia complex.

AIDS dementia complex (ADC) is the most common presenting neurologic manifestation of human immunodeficiency virus (HIV)-1 infection. We report FDG-PET studies in a 39-year-old man who had ADC and completed a 12-wk treatment protocol with 1.2 mg/day of intranasal peptide T, one before and one after 12 wk of treatment with peptide T. Peptide T is an octapeptide under investigation for treatment of ADC patients. Values of rCMRglc were converted to Z scores using the mean and standard deviation of values of rCMRglc in three HIV-seronegative matched controls, each of which was studied twice, at the beginning and end of a 12-wk interval. Thirty-five of 60 regions assayed showed Z scores with absolute values > or = 3 (considered abnormal) in the baseline study. Regions with high absolute values of Z scores were located in subcortical areas and in the limbic system, and to a lesser degree in the frontal, temporal and parietal lobes. Thirty-four of these 35 regions showed remission (decrease in the absolute values of Z scores) after treatment. Only one region showed no improvement in the second study. Three regions with absolute values of Z scores < 3 in the baseline study manifested Z scores with magnitudes > or = 3 in the second study. These preliminary observations suggest that functional neuroimaging techniques provide a useful tool in the evaluation of the response to treatment in ADC patients.

AIDS Dementia Complex↗
PubMed1995

In vivo D2 dopamine receptor density in psychotic and nonpsychotic patients with bipolar disorder.

BACKGROUND: A prior positron emission tomographic study from The Johns Hopkins University, Baltimore, Md, using N-methylspiperone labeled with carbon 11 reported elevated basal ganglia D2 dopamine receptor density (Bmax) values in neuroleptic-naive schizophrenic patients compared with controls. We have now extended these studies to include patients with bipolar disorder. METHODS: Patients with bipolar disorder (n = 14) either had never received neuroleptic medication or had been neuroleptic-free for more than 6 months, and they met DSM-III criteria for currently symptomatic affective disorder. Patients with bipolar disorder were compared with matched schizophrenic patients and normal controls. All received two positron emission tomographic scans, the second of which was preceded by oral administration of haloperidol lactate, to permit the calculation of D2 dopamine receptor Bmax. RESULTS: Diagnostic groups differed in Bmax by analysis of variance (P < .0001); post hoc tests showed higher Bmax values for psychotic patients with bipolar disorder and schizophrenic patients compared with normal controls and for schizophrenic patients and psychotic patients with bipolar disorder compared with nonpsychotic patients with bipolar disorder. Among patients with bipolar disorder, Bmax values correlated significantly with the severity of psychotic symptoms (r = .63) on the Present State Examination but not with the severity of nonpsychotic mood symptoms. CONCLUSIONS: We conclude that, like schizophrenic patients, patients with psychotic bipolar disorder have elevations of D2 dopamine receptor Bmax values and that such elevations in affective disorder are more closely associated with the presence of psychosis than with mood abnormality. Elevations in dopamine receptor values thus may occur in psychiatric states that are characterized by psychotic symptoms rather than being specific to schizophrenia.

Adult↗
PubMed1995

[3H]A-69024: a non-benzazepine ligand for in vitro and in vivo studies of dopamine D1 receptors.

[3H]A-69024 has been prepared as a radioligand for studying the dopamine D1 receptor. [3H]A-69024 binds to rat striatal membranes with a KD = 14.3 +/- 3.2 nM (mean +/- SEM; n = 3) and Bmax = 63.5 +/- 12.8 fmol/mg wet tissue (1.8 +/- 0.3 pmol/mg protein). This ligand binds to only one site with a Hill coefficient close to unity. The in vivo biodistribution of [3H]A-69024 showed a high uptake in the striatum (5.9% ID/g) at 5 min followed by clearance. As a measure of specificity, the striatum/cerebellar ratio reached a maximum of 6.7 at 30 min post-injection. Pre-treatment with the D1 antagonist R(+)SCH 23390 (1 mg/kg) reduced this ratio to unity. The dopamine antagonist (+)butaclamol and unlabeled A-69024 inhibited striatal uptake by 70 and 51%, respectively. Spiperone (D2/5-HT2A) and ketanserin (5-HT2A/5-HT2C) at doses of 1 mg/kg had no inhibitory effect on [3H]A-69024 uptake in the striatum; however, increased uptake of [3H]A-69024 by > 30% in the whole brain was observed. The selectivity and affinity of [3H]A-69024 suggests that this non-benzazepine radioligand may be useful for in vitro and in vivo studies of the dopamine D1 receptor.

Animals↗
PubMed1995

Cerebral glucose utilization in polysubstance abuse.

Regional cerebral glucose metabolism in subjects with histories of polysubstance abuse was compared to that in control subjects who were drawn from the same community. The substance abuse group showed lower absolute metabolic rates for glucose in lateral occipital gyrus and higher normalized metabolic rates in temporal and frontal areas, including orbitofrontal cortex. It is suggested that some patterns of brain function associated with polysubstance abuse may represent consequences of drug exposure, or they could reflect pre-existing differences that may be relevant to the etiology and maintenance of polysubstance abuse.

Adult↗
PubMed1995

[11C]A-69024: a potent and selective non-benzazepine radiotracer for in vivo studies of dopamine D1 receptors.

[11C]A-69024, (+/-)-1-(2-bromo-4,5-dimethoxybenzyl)-7-hydroxy-6-methoxy-2-[11C]methyl- 1,2,3,4-tetrahydroisoquinoline, is a specific and selective dopamine D1 radiotracer. The in vivo biodistribution of this novel radioligand in mice showed a high uptake in the striatum (6.7% ID/g) at 5 min, followed by clearance with a half-life of 16.1 min. As a measure of specificity, the striatal/cerebellar ratio reached a maximum of 7.4 at 30 min post-injection. Radioactivity in the striatum was reduced to the level of the cerebellum by pre-administration of the D1 antagonist SCH 23390 (1 mg/kg). Pretreatment of mice with spiperone (D2), 7-hydroxydipropylaminotetralin (7-OH-DPAT) (D3), clozapine (D4), ketanserin (5-HT2/5-HT2C), mazindol (monoamine reuptake), prazosin (alpha 1), and haloperidol (D2/sigma) had no inhibitory effect on [11C]A-69024 uptake in the striatum. The dextrorotatory enantiomer of the dopamine antagonist butaclamol inhibited striatal uptake, while the less active isomer (-)-butaclamol did not. [11C]A-69024 binding was inhibited by unlabeled A-69024 in a dose dependent manner (ED50 = 0.3 mg/kg) in the striatum while no change occurred in the cerebellum. [11C]A-69024 warrants further investigation as a PET ligand for examination of central dopamine D1 receptors in humans.

Analysis of Variance↗
PubMed1995

An improved method for the synthesis of radiolabeled McN5652 via thioester precursors.

An improved procedure that facilitates routine production and increases the radiochemical yield of [11C]McN5652 (trans-1,2,3,5,6,10b-hexahydro-6-[4-([11C]methylthio)-phenyl]pyrrolo- [2,1-alpha]-isoquinoline) is presented. Specifically, thiol acetate, butyrate, and benzoate derivatives of McN5652 were prepared as the precursors for the [11C]McN5652 synthesis. These thioesters offer greater stability than the previously used thiol precursor (desmethyl McN5652) and enable a single batch of material to be used for multiple radiolabelings. Hydrolysis of the thioester functionality (tetrabutylammonium hydroxide, 10 min) unmasked the free thiol which, without purification, was reacted with [11C]iodomethane in DMF at 40-45 degrees C for 1 min. The average decay-corrected radiochemical yield for [11C]McN5652 was 26% with an average specific activity of 2290 mCi/mumol (end of synthesis). This facile radiolabeling method, utilizing the butyrate thioester of McN5652, was also employed in the preparation of [3H](+)- and (-)McN5652 [trans-1,2,3,5,6S (or 6R),10bR, (or 10bS)-hexahydro-6-[4-([3H]methylthio)phenyl]pyrrolo-[2,1,alpha]- isoquinoline] from [3H]iodomethane.

Carbon Radioisotopes↗
PubMed1995

Synthesis and PET imaging of the benzodiazepine receptor tracer [N-methyl-11C]iomazenil.

The central benzodiazepine receptor tracer [N-methyl-11C]iomazenil (Ro 16-0154) was synthesized by alkylation of the desmethyl precursor noriomazenil with [11C]methyl iodide. The [11C]CH3I (prepared by reduction of [11C]CO2 with LiA1H4 followed by reaction with HI) was reacted with noriomazenil in N,N-dimethylformamide and Bu4N+OH- for 1 min at 80 degrees C and purified by HPLC (C18, 34% CH3CN/H2O 7 mL/min). The product was obtained with synthesis time 35 +/- 5 min (mean +/- SD, n = 7), radiochemical yield (EOB) 36 +/- 16%, radiochemical purity 99 +/- 1%, and specific activity 5100 +/- 2800 mCi/mumol. Absorbed radiation doses were calculated from previously acquired human biodistribution data. The urinary bladder wall received the highest dose (0.099 mGy/MBq) for 4.8 h voiding interval and the effective dose equivalent was 0.015 mSv/MBq. After i.v. injection of [11C]iomazenil in an adult baboon or healthy human volunteer, radioactivity accumulated in the cortex with time-activity curves in agreement with results obtained with [11C]flumazenil PET and [123I]iomazenil SPECT studies. The count rate was sufficient to obtain quantitative images up to 2 h post-injection with a 14 mCi injection. These results suggest that [11C]iomazenil will be a useful agent for measuring benzodiazepine receptors in vivo by positron emission tomography.

Adult↗
PubMed1995

Selective alkylation of pyrimidyl dianions III: no-carrier-added synthesis of [11C-methyl]-thymidine.

A no-carrier-added, high specific activity synthesis of [11C-methyl]-thymidine is reported. Reaction of 3'. 5'-O-bis-(tetrahydropyramyl)-5-bromo-2'-deoxyuridine with n-butylithium produced a diamion which was alkylated with [11C]-methyl iodide, and on subsequent hydrolysis, yielded [IIC-methyl]-thymidine. The labeled compound was isolated from the by-product 2'-deoxymidine by HPLC on a reverse phase C18 semipreparative column with mean radiochemical yield of 18.8% (decay corrected) in 30-35 min and radiochemical purity >99%. This no-carrier-added synthesis can be used to produce [11C-methyl]-thymidine with mean specific activity over 1000 mCi/mumol for positron emission tomography (PET) studies.

Alkylation↗
PubMed1995

Positron emission tomography of 5-HT transporter sites in the baboon brain with [11C]McN5652.

[11C]McN5652 is a new radioligand specific for 5-hydroxytryptamine (5-HT; serotonin) transporters. In this study we used [11C]McN5652 to image the 5-HT transporter sites in baboon brain by positron emission tomography (PET). Dynamic PET studies were performed in three Papio anubis baboons. The animals were injected intravenously first with 11C-labeled (+)-McN5652([11C](+)McN5652), then with pharmacologically inactive enantiomer 11C-labeled (-)-McN5652 ([11C](-)McN5652); two animals received a third study with [11C](+)McN5652 after pretreatment with the specific 5-HT uptake site inhibitor fluoxetine (5 mg/kg). Initial uptake into the brain was similar for both [11C](+)McN5652 and [11C](-)McN5652. At later times (45-120 min after injection), only [11C](+)McN5652 showed a distribution characteristic for 5-HT uptake sites. In contrast, in studies with [11C](-)McN5652 and in those with [11C](+)McN5652 after 5-HT uptake site blockade with fluoxetine, 11C radioactivity concentrations were significantly lower and the distribution pattern was relatively even. The differences between [11C](+)-and (-)McN5652 were calculated for the time interval 95-125 min postinjection and used to estimate specific binding. Specific binding correlated well (r = 0.95, p < 0.001) with the known density of 5-HT uptake sites in human brain. These results indicate that [11C](+)McN5652 is suitable for PET imaging of 5-HT uptake sites in primate brain.

Animals↗