Positron emission tomography evaluation of dopamine D-2 receptors in adults with Tourette syndrome.
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Humans↗
Biomedical subjects
H N Wagner
Publications and source records attributed to H N Wagner.
A noninvasive test of sphincter of Oddi dysfunction in postcholecystectomy patients: the scintigraphic score.
The ideal noninvasive test of sphincter of Oddi dysfunction (SOD) does not exist and the diagnosis of patients with postcholecystectomy pain often relies on invasive procedures. In this paper we describe a scintigraphic test for SOD: the scintigraphic score. This score combines quantitative and visual criteria for interpretation of hepatobiliary scans. Twenty-six consecutive postcholecystectomy patients underwent hepatobiliary imaging, ERCP, and sphincter manometry. Twelve patients had SOD and 14 had normal sphincters determined by clinical findings, ERCP, and manometric studies. All patients with normal sphincter had scores of 0-4, while patients with SOD had values of 5-12 for a perfect sensitivity and specificity of 100%. Hepatobiliary scans scored in this fashion may become the noninvasive test of choice to screen postcholecystectomy patients with suspected SOD.
Adult↗
Annual meeting highlights: molecules with messages.
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Humans↗
Reduced left ventricular cavitary activity ("black hole sign") in thallium-201 SPECT perfusion images of anteroapical transmural myocardial infarction.
Apparently reduced left ventricular (LV) cavitary thallium activity in both planar and tomographic perfusion images has been previously observed by these and other investigators. With single-photon emission computerized tomography, we have clinically noted that this "black hole sign" was associated with an aneurysm in the setting of a transmural anterior or anteroapical perfusion defect. We have now prospectively studied the etiology and predictive value of this sign in 84 consecutive patients with an anterior, anteroapical transmural perfusion defect. Of the 84 patients, 49 had both LV aneurysm (confirmed by contrast ventriculography, echocardiography or gated blood pool studies) and a black hole sign. Only 1 patient with an aneurysm did not have the black hole sign, and 2 without aneurysm did. Thus, it is concluded that this sign is highly accurate in diagnosing LV aneurysm. Because thallium-201 single-photon emission computerized tomography imaging is often performed as one of the first diagnostic tests soon after myocardial infarction, this has important clinical management implications.
Adult↗
Advances in medical imaging for cancer diagnosis and treatment.
Over the last several decades, significant "new eyes" have been developed that improve the diagnosis, treatment, planning, and monitoring of human cancer: computer tomography (CT), magnetic resonance imaging (MRI) and spectroscopy (MRS), single photon emission computed tomography (SPECT), and positron emission tomography (PET). Innovative advances in both morphologic and functional imaging have led to a dramatic improvement in our ability to diagnose and monitor human cancer. Frequently, anatomic detail can be demonstrated in ways that exceed views at surgery, and functional biochemical imaging is being used to show the metabolic activity and receptor status of normal and pathologic states. In vivo functional and biochemical studies differentiate normal from neoplastic or nonviable tissue, and make it possible to measure progression or regression of the disease. Because physiologic changes often precede morphologic findings in many disease processes, the use of in vivo biochemical probes can demonstrate disease before anatomic abnormalities become evident. Gross changes in anatomy are no longer adequate endpoints for therapy protocols. Today, using physiologic imaging, we can evaluate the response to treatment within hours of administration of therapy. Adjuvant metabolic tumor imaging studies provide complimentary information to morphologic evaluation of human cancers that will ultimately lead to better patient care.
Diagnostic Imaging↗
Quantification of mu and non-mu opiate receptors in temporal lobe epilepsy using positron emission tomography.
Alterations in a variety of neurotransmitter systems have been identified in experimental models of epilepsy and in brain tissue from patients with intractable temporal lobe seizures. The availability of new high-affinity radioligands permits the study of some neuroreceptors in vivo with positron emission tomography (PET). We previously characterized the in vivo binding of 11C-carfentanil, a potent and selective mu opiate receptor agonist, and described increases in 11C-carfentanil binding in the temporal neocortex of patients with unilateral temporal lobe epilepsy. These studies have been extended to 11C-diprenorphine, which labels mu, kappa, and delta opiate receptor subtypes. Paired measurements of opiate receptor binding were performed with PET using 11C-carfentanil and 11C-diprenorphine in patients with unilateral temporal lobe seizures. Carfentanil binding, reflecting changes in mu opiate receptors, was increased in the temporal neocortex and decreased in the amygdala on the side of the epileptic focus. Diprenorphine binding, reflecting mu as well as non-mu opiate subtypes, was not significantly different among regions in the focus and nonfocus temporal lobes. Regional glucose metabolism, measured using 18F-2-fluoro-2-deoxyglucose, was decreased in the mesial and lateral aspects of the temporal lobe ipsilateral to the epileptogenic focus. The variation in pattern of carfentanil and diprenorphine binding supports a differential regulation of opiate subtypes in unilateral temporal lobe epilepsy.
Amygdala↗
Effects of endogenous dopamine on kinetics of [3H]N-methylspiperone and [3H]raclopride binding in the rat brain.
Competition by endogenous dopamine with the binding of D2 dopamine receptor ligands may be important in the interpretation of positron emission tomography (PET) neuroreceptor studies. PET studies with N-methylspiperone (NMSP) have revealed increased D2 dopamine receptors in schizophrenia, whereas studies with raclopride (RAC) have not detected such differences. This may be due, at least in part, to differences in competition with endogenous dopamine for ligand binding. To determine effects of endogenous dopamine on in vivo receptor binding, adult male rats were preinjected with amphetamine and reserpine prior to [3H]NMSP or [3H]RAC. Striatal to cerebellar ratios of ligand binding were determined. To approximate the conditions of a PET study, a kinetic model was employed to examine effects of pharmacologically increasing brain dopamine levels (amphetamine pretreatment) on PET ligand binding. In these experiments, tail veins and arteries were cannulated and kinetic parameters determined from normalized integral plots in rats treated with amphetamine prior to radioligand injection. Both [3H]NMSP (43.5%) and [3H]RAC (41.5%) binding were significantly decreased after amphetamine pretreatment, whereas after reserpine pretreatment [3H]RAC binding was increased (52.7%). Kinetic studies revealed a marked resistance of [3H]NMSP to competition with endogenous dopamine released by amphetamine. In contrast, kinetic parameters of [3H]RAC were markedly reduced at all time intervals. This suggests significant differences in competition with endogenous dopamine by [3H]NMSP and [3H]RAC, determined kinetically. These findings may have important implications for the interpretation of PET neuroreceptor studies.
Amphetamine↗
Effects of atropine treatment on in vitro and in vivo binding of 4-[125I]-dexetimide to central and myocardial muscarinic receptors.
Upregulation of muscarinic cholinergic receptors (mAChR) after chronic atropine treatment has been described previously. The present study was designed to evaluate 4-iodine-125 dexetimide as an agent to determine changes in the number of mAChR. Rats were injected subcutaneously with atropine (500 mg/kg) either once or chronically, once daily for 10 days, and sacrificed 24 h later. In vitro binding assays with 4-[125I]-dexetimide showed significant increases in the number of mAChR in cerebra (21%) and ventricles (45%) after chronic atropine treatment but not after acute treatment. The affinity of binding to cerebral and ventricular mAChR declined after acute and chronic atropine treatment. In vivo studies were carried out involving intravenous injection of 4-[125I]-dexetimide 24 h after atropine treatment. Binding was markedly reduced in the brain and heart. Upregulation of mAChR, as seen in in vitro studies, could not be observed because of the remaining atropine. Occupancy of mAChR by atropine persisted as long as 7 days after one dose. The results of these studies indicate that 4-[125I]-dexetimide binding reflects the effects of atropine on central and peripheral muscarinic cholinergic receptors in vitro and in vivo.
Animals↗
Indium-111 myosin-specific antibodies and technetium-99m pyrophosphate in the detection of acute cardiac rejection of transplanted hearts: studies in a heterotopic rat heart model.
111In-labelled myosin-specific antibodies were evaluated as an indicator of early changes in acute rejection in a rat heart heterotopic transplant model. Uptake of antibodies was measured in allograft and isograft hearts of animals undergoing different regimens of cyclosporine treatment and compared with the uptake of technetium-99m pyrophosphate. The data were correlated with histological estimation of the severity of myocyte necrosis and signs of early rejection (venous cuffing and endocardial inflammation, indicators of perivascular infiltrate and intermyocyte extension, respectively). Myocyte necrosis in transplanted hearts was reflected by increases in technetium-99m pyrophosphate accumulation (r = 0.88) but was poorly correlated with labelled antibody uptake (r = 0.58). There was no positive correlation between the degree of early cardiac rejection and uptake of either of the radiopharmaceuticals: accumulation of the labelled antibodies paradoxically declined with increased histological severity scores, whereas that of technetium-99m pyrophosphate remained unchanged. Cyclosporine treatment augmented the uptake of labelled antibodies in transplanted hearts. This may be due to alterations in plasma membrane permeability brought about by the drug, resulting in a rise in antibody binding to intracellular myosin.
Animals↗
Radioiodinated D-(+)-N1-ethyl-2-iodolysergic acid diethylamide: a ligand for in vitro and in vivo studies of serotonin receptors.
Radioiodinated D-(+)-N1-ethyl-2-iodolysergic acid diethylamide ([125I]-EIL) has been evaluated as a ligand for in vitro and in vivo studies of cerebral serotonin 5-HT2 receptors. [125I]-EIL exhibited high affinity (KD = 209 pM) for 5-HT2 receptors with a high degree of specific binding (80-95%) in membranes from rat prefrontal cortex. The regional distribution of [125I]-EIL binding in vivo to seven areas of mouse brain correlated significantly (Rs = 0.93) with known densities of 5-HT2 receptors. In vivo specificity, defined by tissue to cerebellum radioactivity ratios, reached a maximum for frontal cortex at 6 hr (21.2) and persisted through 16 hr (8.8). Ketanserin, a 5-HT2 receptor antagonist, fully inhibited binding in a dose dependent fashion in all brain regions except cerebellum. By contrast, blockers for dopamine D2, alpha- or beta-adrenergic receptors did not significantly inhibit radioligand binding in any region. [125I]-EIL selectively labels 5-HT2 receptors in vivo with the highest specificity of any serotonergic ligand reported to date, indicating that [123I]-EIL should prove applicable to single photon emission computed tomography studies in living brain.
Animals↗
In vivo biodistribution of two [18F]-labelled muscarinic cholinergic receptor ligands: 2-[18F]- and 4-[18F]-fluorodexetimide.
Two [18F]-labelled analogues of the potent muscarinic cholinergic receptor (m-AChR) antagonist, dexetimide, were evaluated as potential ligands for imaging m-AChR by positron emission tomography (PET). Intravenous administration of both 2-[18F]- or 4-[18F]-fluorodexetimide resulted in high brain uptake of radioactivity in mice. High binding levels were observed in m-AChR rich areas, such as cortex and striatum, with low levels in the receptor-poor cerebellum. Uptake of radioactivity was saturable and could be blocked by pre-administration of dexetimide or atropine. Drugs with different sites of action were ineffective at blocking receptor binding. The results indicate that both radiotracers are promising candidates for use in PET studies.
Animals↗
Radiosynthesis and evaluation of N-(3-[18F]fluoropropyl)paroxetine as a radiotracer for in vivo labeling of serotonin uptake sites by PET.
To visualize serotonin uptake sites by positron emission tomography (PET), N-(3-[18F]fluoropropyl)-paroxetine ([18F]FPP), a derivative of the selective serotonin uptake blocker paroxetine, was synthesized from 3-[18F]fluoropropyltosylate and paroxetine via a one-pot procedure. The rate of formation of [18F]FPP was a function of the ratio of the initial amount of paroxetine to that of 1,3-propanediol bistosylate with which [18F]fluoropropyltosylate was synthesized. When the reaction mixture contained an excess amount of paroxetine over that of the propyl-bistosylate, the radiosynthesis followed by HPLC purification, which took approx. 90 min, gave [18F]FPP in a radiochemical yield of approx. 8%, and in high radiochemical and chemical purity. The specific activity was 2640 +/- 360 mCi/mumol. The brain biodistribution of [18F]FPP showed no distinguishable localization in regions with high density of serotonin uptake sites such as hypothalamus or olfactory tubercles. In vitro binding assays revealed that N-fluoropropylation of paroxetine reduced the affinity for the serotonin uptake site by three orders of magnitude.
Animals↗
Comparison of indium-111 antimyosin antibody and technetium-99m pyrophosphate localization in reperfused and nonreperfused myocardial infarction.
Recent imaging studies suggest that technetium-99m (Tc-99m) pyrophosphate yields a considerably larger estimate of myocardial infarct size than does indium-111 (In-111) monoclonal antimyosin antibody. To determine whether Tc-99m pyrophosphate may be taken up by reversibly injured myocytes, particularly in the setting of coronary reperfusion, the tissue localization of Tc-99m pyrophosphate and antimyosin antibody was compared in 11 dogs 24 to 68 h after anterior descending coronary artery occlusion (4 dogs with permanent occlusion, 7 with reperfusion). Technetium-99m pyrophosphate and In-111 antimyosin antibody content was determined in serial 2 to 3 mm wide endocardial and epicardial samples taken through the infarct zone in multiple short-axis left ventricular slices. The number of samples with increased In-111 antimyosin antibody (defined as greater than or equal to mean + 2 SD of normal) was not significantly different from that with increased Tc-99m pyrophosphate. This was true in both reperfused and nonreperfused infarcts. However, the intensity of uptake of Tc-99m pyrophosphate exceeded that of In-111 antimyosin antibody, particularly in the border zones of reperfused infarcts, and the area with moderate to marked increase in tracer uptake (greater than or equal to 2 times normal) was significantly larger with Tc-99m pyrophosphate than In-111 antimyosin antibody (p less than 0.001). A specific zone of abnormal Tc-99m pyrophosphate with normal In-111 antimyosin antibody content could not be identified. Histologic evidence of myocardial necrosis was found in virtually every sample with increased In-111 antimyosin antibody, Tc-99m pyrophosphate, or both.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Radiosynthesis of sigma receptor ligands for positron emission tomography: 11C- and 18F-labeled guanidines.
A series of analogues of the potent and selective sigma receptor ligand 1,3-ditolylguanidine (DTG) were synthesized and demonstrated to have high affinity for the sigma receptor as measured by in vitro [3H]DTG displacement studies using guinea pig brain tissue. Three of these 1-aryl-3-(1-adamantyl)guanidines were radiolabeled--two with carbon-11 and one with fluorine-18. Radiochemical yields and specific activities were sufficient for these radiotracers to be used in positron emission tomography imaging of the haloperidol-sensitive sigma receptor.
Animals↗
Quantification of human opiate receptor concentration and affinity using high and low specific activity [11C]diprenorphine and positron emission tomography.
[11C]Diprenorphine, a weak partial opiate agonist, and positron emission tomography were used to obtain noninvasive regional estimates of opiate receptor concentration (Bmax) and affinity (Kd) in human brain. Different compartmental models and fitting strategies were compared statistically to establish the most reliable method of parameter estimation. Paired studies were performed in six normal subjects using high (769-5,920 Ci/mmol) and low (27-80 Ci/mmol) specific activity (SA) [11C]diprenorphine. Two subjects were studied a third time using high SA [11C]diprenorphine after a pretreatment with 1-1.5 mg/kg of the opiate antagonist naloxone. After the plasma radioactivity was corrected for metabolites, the brain data were analyzed using a three-compartment model and nonlinear least-squares curve fitting. Linear differential equations were used to describe the high SA (low receptor occupancy) kinetics. The k3/k4 ratio varied from 1.0 +/- 0.2 (occipital cortex) to 8.6 +/- 1.6 (thalamus). Nonlinear differential equations were used to describe the low SA (high receptor occupancy) kinetics and the curve fits provided the konf2 product. The measured free fraction of [11C]diprenorphine in plasma (f1) was 0.30 +/- 0.03, the average K1/k2 ratio from the two naloxone studies was 1.1 +/- 0.2, and the calculated free fraction of [11C]diprenorphine in the brain (f2) was 0.3. Using the paired SA studies, the estimated kinetic parameters, and f2, separate estimates of Bmax and Kd were obtained. Bmax varied from 2.3 +/- 0.5 (occipital cortex) to 20.6 +/- 7.3 (cingulate cortex) nM. The average Kd (eight brain regions) was 0.85 +/- 0.17 nM.
Adult↗
Failure of perchlorate to inhibit Tc-99m isonitrile binding by the thyroid during myocardial perfusion studies.
The thyroid gland receives an average radiation dose of 3 rads during two Tc-99m isonitrile (MIBI) myocardial perfusion studies, if 20 mCi is administered both at rest and at peak exercise. In patients with coronary artery disease, multiple myocardial perfusion studies may be required, resulting in a high level of thyroid radiation. We attempted to reduce this radiation exposure by blocking thyroidal Tc-99m MIBI uptake with oral potassium perchlorate (KCIO4). Fourteen normal subjects received 0.6g to 0.8g KCIO4 20-25 minutes before tracer injection. Subjects who received KCIO4 at rest (n = 11) did not receive KCIO4 at their stress study, and vice versa (n = 3). Thyroid uptake values were obtained with a thyroid probe 20 minutes after injection for both rest and stress studies and were corrected for saturation effects. There was no difference between fractional thyroid uptake values with and without preceding perchlorate administration: 1.9 +/- 0.5% and 1.8 +/- 0.3% (mean +/- SD), respectively. Failure to block Tc-99m MIBI uptake after intravenous (IV) injection is probably due to high thyroidal blood flow and nonspecific tracer accumulation. The concentration of this radioisotope in adjacent muscles also contributes to the high thyroid radiation dose. In summary, administration of KCIO4 before Tc-99m MIBI studies does not reduce the thyroidal radiation dose or uptake of this tracer, suggesting that thyroidal uptake of this tracer is not mediated by the iodine trapping mechanism.
Adult↗
Physostigmine in Alzheimer's disease: effects on cognitive functioning, cerebral glucose metabolism analyzed by positron emission tomography and cerebral blood flow analyzed by single photon emission tomography.
The effect of acute, intravenous administration of physostigmine on measures of brain activity and cognitive functioning were investigated in 14 patients with Alzheimer's disease. Regional cerebral glucose metabolism was assessed using (18F)-fluoro-2-deoxy-D-glucose and positron emission tomography, and cerebral blood flow was assessed using 123I-iodoamphetamine single photon emission tomography. Although physostigmine enhanced cerebral blood flow in most patients, only one patient showed significant clinical improvement. This patient, however, also showed a very pronounced improvement in cerebral glucose metabolism. It is concluded that these preliminary findings hold considerable promise for our appreciation of the pathophysiology of dementing illness as well as our understanding of centrally acting compounds of interest in Alzheimer's disease.
Aged↗
Global and regional cerebral metabolic rate of 2-[18F]fluoro-2-deoxy-D-glucose in the presence of ofloxacin, a gamma-aminobutyric acid a receptor antagonist.
We investigated the effects of ofloxacin, a new antibacterial quinolone gamma-aminobutyric acid A receptor antagonist, on the global and regional cerebral metabolic rates of glucose (cMRgl). Twelve healthy normal male volunteers (mean age, 26.7 years) were studied in a double-blind, placebo-controlled protocol of 11 days' duration. Results of a total of 42 positron emission tomography studies were obtained for these subjects: 12 base line, 18 during placebo, and 12 during ofloxacin administration. The conditions under which repeat positron emission tomography studies of the same subject were performed were reproduced as closely as possible. cMRgl was measured in 24 brain regions. The global cMRgl for base line, placebo, and ofloxacin were 8.82 +/- 1.17, 8.24 +/- 1.17, and 8.79 +/- 1.18 mg/min/100 g, respectively (mean +/- 1 standard deviation). The mean global differences between base line and placebo and between ofloxacin and placebo were 5.1 and 6.6%, respectively. Analysis of variance of both the global and the regional cMRgl showed no statistical difference between base-line, placebo, and ofloxacin studies. Variations in cMRgl found in this study were not related to the presence of ofloxacin. Results of our study demonstrate that ofloxacin does not increase or decrease cMRgl beyond the limits of variability of the study.
Adult↗