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Dean F Wong

Publications and source records attributed to Dean F Wong.

35 records · Page 2Linked to original sources

Mechanism of new antipsychotic medications: occupancy is not just antagonism.

Antagonism of D2-like dopamine receptors is the putative mechanism underlying the antipsychotic efficacy of psychotropic drugs. Positron emission tomographic studies suggest that the antipsychotic effect of dopamine receptor antagonists occurs within a therapeutic window between 60% and 80% (striatal) D2 receptor occupancy. The incidence of extrapyramidal side effects increases above the 80% threshold. However, the novel atypical antipsychotic drug, aripiprazole, occupies up to 95% of striatal D2-like dopamine receptors at clinical doses, and the incidence of extrapyramidal side effects with aripiprazole is no higher than with placebo. The most likely explanation for this finding is aripiprazole's weak partial agonism at D2-like dopamine receptors. This particular pharmacologic feature characterizes a new class of atypical antipsychotics that does not match the original concept of a therapeutic occupancy window for antagonist antipsychotics. When not involving pure antagonists, it implies a need to adjust the expected receptor occupancy (measured using positron emission tomography) for the therapeutic window.

Antipsychotic Agents↗

Linear regression with spatial constraint to generate parametric images of ligand-receptor dynamic PET studies with a simplified reference tissue model.

For the quantitative analysis of ligand-receptor dynamic positron emission tomography (PET) studies, it is often desirable to apply reference tissue methods that eliminate the need for arterial blood sampling. A common technique is to apply a simplified reference tissue model (SRTM). Applications of this method are generally based on an analytical solution of the SRTM equation with parameters estimated by nonlinear regression. In this study, we derive, based on the same assumptions used to derive the SRTM, a new set of operational equations of integral form with parameters directly estimated by conventional weighted linear regression (WLR). In addition, a linear regression with spatial constraint (LRSC) algorithm is developed for parametric imaging to reduce the effects of high noise levels in pixel time activity curves that are typical of PET dynamic data. For comparison, conventional weighted nonlinear regression with the Marquardt algorithm (WNLRM) and nonlinear ridge regression with spatial constraint (NLRRSC) were also implemented using the nonlinear analytical solution of the SRTM equation. In contrast to the other three methods, LRSC reduces the percent root mean square error of the estimated parameters, especially at higher noise levels. For estimation of binding potential (BP), WLR and LRSC show similar variance even at high noise levels, but LRSC yields a smaller bias. Results from human studies demonstrate that LRSC produces high-quality parametric images. The variance of R(1) and k(2) images generated by WLR, WNLRM, and NLRRSC can be decreased 30%-60% by using LRSC. The quality of the BP images generated by WLR and LRSC is visually comparable, and the variance of BP images generated by WNLRM can be reduced 10%-40% by WLR or LRSC. The BP estimates obtained using WLR are 3%-5% lower than those estimated by LRSC. We conclude that the new linear equations yield a reliable, computationally efficient, and robust LRSC algorithm to generate parametric images of ligand-receptor dynamic PET studies.

Adult↗

First do no harm: managing antihistamine impairment in patients with allergic rhinitis.

Antihistamines are effective medications that have been used for decades in the management of allergic rhinitis; however, they may be administered or selected in an inappropriate fashion and may be the source of drug-related morbidity. Our objective is to present relevant background information and an expert consensus statement on the use of antihistamines in treatment of allergic rhinitis. In July 2002, 14 experts in allergy, clinical immunology, pharmacology, and impairment assessment were invited to participate in a roundtable conference to present current concepts and develop a consensus statement on the clinical management of allergic rhinitis with antihistamines. Many of the antihistamines used to treat allergic rhinitis, as well as the disease itself, may produce sedation, impairment, and reduced quality of life. Allergic rhinitis is more appropriately managed with the relatively nonimpairing second-generation antihistamines (eg, loratadine, desloratadine, cetirizine, and fexofenadine), because older agents (eg, diphenhydramine, chlorpheniramine, and brompheniramine) produce sedation and impairment and worsen sleep architecture. Although there is some debate surrounding the varying degrees of efficacy of second-generation antihistamines, it is known that some agents may produce varying levels of drowsiness or impairment, especially at higher than recommended doses. The differences with regard to safety among the second-generation antihistamines are smaller than are the differences between the first and second generations. A nonsedating, nonimpairing (even at higher than recommended doses), second-generation antihistamine is preferred for all patients, particularly those with a higher risk for the development of adverse effects. We recommend that primary care and specialist physicians, nurse practitioners, physician assistants, pharmacists, and all other health professionals involved in the diagnosis and treatment of allergic rhinitis follow this consensus document and share this information with patients for whom antihistamine therapy is recommended. In addition, further epidemiologic studies on the effects of antihistamines should be performed.

Diagnosis, Differential↗

Quantification of D2-like dopamine receptors in the human brain with 18F-desmethoxyfallypride.

UNLABELLED: Substituted benzamides such as (11)C-raclopride or (123)I-iodobenzamide are selective radiotracers for PET and SPECT imaging of D(2)-like dopamine (DA) receptors. (18)F-Desmethoxyfallypride ((18)F-DMFP) is a benzamide tracer with the advantage of an (18)F label. We optimized the synthesis and evaluated (18)F-DMFP in PET studies on healthy human volunteers. METHODS: The affinity of DMFP for D(2)-like DA receptors was characterized in vitro using membrane preparations from rat striatum and the DA receptor ligand (3)H-spiperone. PET studies on 10 healthy human volunteers were performed using a whole-body PET scanner after injection of 214 +/- 54 MBq (mean +/- SD) (18)F-DMFP. Brain images were acquired dynamically over 124 min, and metabolite-corrected plasma activity was used as the input function. Data analysis was performed using several different approaches (compartmental, graphical, equilibrium methods). RESULTS: The mean inhibition constant (K(i)) of DMFP was 15 +/- 9 nmol/L. In human brain, the striatum-to-cerebellum ratio reached a maximum of about 4 between 60 and 120 min. When specific binding in the striatum was expressed as the difference between binding in the striatum and the cerebellum, it reached a maximum at approximately 60 min after injection and remained almost constant until the end of data acquisition. The ratio of specific striatal to nonspecific cerebellar binding was about 3:1 at 120 min after injection. A small, but significant specific tracer binding could also be detected in the thalamus. Treatment of a schizophrenic patient with a high dose (1,000 mg/d) of another substituted benzamide, amisulpride, resulted in a reduction of specific tracer uptake of about 90% in striatal regions. With regard to measured distribution volumes and binding potentials, there was an excellent agreement between all applied analytic methods. CONCLUSION: Our study demonstrates that (18)F-DMFP is a highly reliable tracer for PET imaging of D(2)-like DA receptors. It offers the major advantage that it can be used independently of an on-site cyclotron within a PET satellite network. Noninvasive analytic methods without blood sampling provide valid measurements of receptor quantities in human striatum. Because of the (18)F label and the favorable imaging properties, (18)F-DMFP could become an efficient substitute for (11)C-raclopride in a clinical context.

Adult↗

Positron emission tomography--a tool for identifying the effects of alcohol dependence on the brain.

To study alcohol's effects on the structure and function of the brain in living human beings, researchers can use various imaging techniques. Positron emission tomography (PET) is a functional imaging approach used to study the metabolism and physiology of the brain. PET studies have found that both acute and chronic alcohol ingestion alter blood flow and metabolism in various brain regions, including the frontal lobes and cerebellum. Other analyses focusing on alcohol's effects on brain chemical (i.e., neurotransmitter) systems have found that both acute and chronic alcohol consumption alter the activities of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the excitatory neurotransmitters glutamate, dopamine, and serotonin. These alterations may contribute to the reinforcing and rewarding effects of alcohol as well as to symptoms of alcohol withdrawal. Imaging studies also have demonstrated that some of alcohol's adverse effects on brain function can be reversed by abstinence or alcoholism treatment interventions. In addition, imaging studies may help in the development of new medications for alcoholism treatment.

Alcoholism↗

Intravenous nicotine reduces cerebral glucose metabolism: a preliminary study.

Nicotine is self-administered by smoking tobacco products, and enhances positive mood (at least in smokers). Since most drugs of abuse decrease regional cerebral metabolic rate(s) for glucose (rCMRglc) in human subjects, we posited that administration of nicotine would similarly reduce rCMRglc. Positron emission tomography (PET) with [F-18]fluorodeoxyglucose was used to assess the effects of intravenous nicotine (1.5 mg) on cerebral glucose metabolism in six healthy male volunteers (21-38 years of age). Two PET assays (placebo and nicotine) were performed, and subjective self-reports of mood and feeling state were collected. Data were analyzed using analysis of variance. Nicotine reduced global glucose metabolism (by 9.51% of placebo control), with reductions in most of the 30 individual regions tested. Nine regions had bilateral effects that reached statistical significance (p&<0.05, uncorrected for the number of regions tested), although the statistical model used did not separate these effects from a global effect. The subjects reported both positive and negative effects of nicotine on mood/feeling state. The widespread decreases in cerebral metabolism are consistent with the many effects of nicotine on cognition and mood. The findings indicate that nicotine resembles other drugs of abuse in reducing brain metabolism, perhaps by a common mechanism.

Adult↗

Subchronic haloperidol downregulates dopamine synthesis capacity in the brain of schizophrenic patients in vivo.

The antipsychotic effect of neuroleptics cannot be attributed entirely to acute blockade of postsynaptic D(2)-like dopamine (DA) receptors, but may arise in conjunction with the delayed depolarization block of the presynaptic neurons and reduced DA synthesis capacity. Whereas the phenomenon of depolarization block is well established in animals, it is unknown if a similar phenomenon occurs in humans treated with neuroleptics. We hypothesized that haloperidol treatment should result in decreased DA synthesis capacity. We used 6-[(18)F]fluoro-L-dopa (FDOPA) and positron emission tomography (PET) in conjunction with compartmental modeling to measure the relative activity of DOPA decarboxylase (DDC) (k(D)(3), min(-1)) in the brain of nine unmedicated patients with schizophrenia, first in the untreated condition and again after treatment with haloperidol. Patients were administered psychometric rating scales at baseline and after treatment. Consistent with our hypothesis, there was a 25% decrease in the magnitude of k(D)(3) in both caudate and putamen following 5 weeks of haloperidol therapy. In addition, the magnitudes of k(D)(3) in cerebral cortex and thalamus were also decreased. Psychopathology as measured with standard rating scales improved significantly in all patients. The decrease of k(D)(3) in the thalamus was highly significantly correlated with the improvement of negative symptoms. Subchronic treatment with haloperidol decreased the activity of DDC in the brain of patients with schizophrenia. This observation is consistent with the hypothesis that the antipsychotic effect of chronic neuroleptic treatment is associated with a decrease in DA synthesis, reflecting a depolarization block of presynaptic DA neurons. We link an alteration in cerebral catecholamine metabolism in human brain with the therapeutic action of neuroleptic medication.

Adult↗

Improved parametric image generation using spatial-temporal analysis of dynamic PET studies.

The value of parametric images that represent both spatial distribution and quantification of the physiological parameters of tracer kinetics has long been recognized. However, the inherent high noise level of pixel kinetics of dynamic PET makes it unsuitable to generate parametric images of the microparameters of tracer kinetic model by conventional weighted nonlinear least squares (WNLS) fitting. Based on the concept that both spatial and temporal information should be integrated to improve parametric image quality, a nonlinear ridge regression with spatial constraint (NLRRSC) parametric imaging algorithm was proposed in this study. For NLRRSC, a term that penalizes local spatial variation of parameters was added to the cost function of WNLS fitting. The initial estimates and spatial constraint were estimated by component representation model (CRM) with cluster analysis. A hierarchical cluster with average linkage method was used to extract components. The ridge parameter was determined by linear ridge regression theory at each iteration, and a modified Gauss-Newton algorithm was used for minimizing the cost function. Results from a computer simulation showed that the percent mean square error of estimates obtained by NLRRSC can be decreased by 60-80% compared to that of WNLS. The parametric images estimated by NLRRSC are significantly better than the ones generated by WNLS. A highly correlated linear relationship was found between the ROI values calculated from the microparametric images generated by NLRRSC and estimates from ROI kinetic fitting. NLRRSC provided a reliable estimate of glucose metabolite uptake rate with a comparable image quality compared to Patlak analysis. In conclusion, NLRRSC is a reliable and robust parametric imaging algorithm for dynamic PET studies.

Algorithms↗

Brain glucose metabolism in Rett Syndrome.

Rett syndrome is a progressive neurologic disorder affecting girls in early childhood with loss of achieved psychomotor abilities and mental retardation. Six sedated female patients (4 to 15 years of age) with a diagnosis of Rett syndrome were studied with [(18)F]fluorodeoxyglucose (FDG) and underwent positron emission tomography scanning of the brain. Relative tracer concentrations between different areas of the brain were assessed, and results were compared with 18 age-matched control subjects. Patients were divided into two age groups: 3 to 8 years of age and 9 to 15 years of age. A relative decrease in [(18)F]FDG uptake in the lateral occipital areas in relation with the whole brain and a relative increase in the cerebellum was evident in both age groups (P < 0.001, unpaired Student t test). A relative increase in frontal tracer uptake was observed in the younger group. Sensorimotor areas and relations between cortical and subcortical structures were preserved in all patients. Changes in glucose cerebral metabolism resemble the regional distribution of normal children less than 1 year of age, likely reflecting a maturational arrest. Changes in frontal areas parallel those in postmortem N-methyl-D-aspartate receptor densities and could correlate with different clinical stages of the disease. This pattern differs from those described in Down syndrome, autism, and Alzheimer's disease.

Adolescent↗

Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride.

Aripiprazole (OPC 14597) is an antipsychotic drug that has high affinity for dopamine D2 and D3 receptors and the dopamine autoreceptor. It is being developed for treatment of patients with schizophrenia. The purpose of this study was to determine whether a dose response following graduated doses of aripiprazole could be quantified and correlated with its occupancy of the D2 and D3 dopamine receptors in the brain of living humans. Dopamine D2 and D3 receptor occupancy in fifteen normal male human brains was measured using positron emission tomography (PET) with [11C]raclopride. PET studies were performed before and after two weeks of administration of aripiprazole. The dopamine D2 receptor occupancy was quantified with two kinetic modeling methods without using a blood input function. Administration of aripiprazole for 14 days resulted in a dose-dependent receptor occupancy between 40 - 95% after the administration of 0.5mg, 1 mg, 2 mg, 10 mg, and 30 mg per day. These results suggest that an adequate occupancy can be obtained, and this may be useful to predict an appropriate therapeutic dose for an individual patient. Interestingly, even at striatal D2 receptor occupancy values above 90%, which occurred with the higher doses, extrapyramidal side effects (EPS) were not observed. This underlines aripiprazole's unique mechanism of action as a partial dopamine receptor agonist, which might become a novel principle in the treatment of schizophrenia.

Administration, Oral↗

Quantitative MR spectroscopic imaging of brain lesions in patients with AIDS: correlation with [11C-methyl]thymidine PET and thallium-201 SPECT.

RATIONALE AND OBJECTIVES: The purpose of this study was to examine the metabolic basis for magnetic resonance (MR) spectroscopic imaging findings in focal brain lesions of patients with acquired immunodeficiency syndrome (AIDS). MATERIALS AND METHODS: The authors combined MR spectroscopic imaging with [11C-methyl]thymidine positron emission tomography (PET) and thallium-201 single photon emission computed tomography (SPECT) in 10 patients. They sought a characteristic metabolite profile that would enable differentiation of benign lesions from primary central nervous system lymphoma and determined whether PET and SPECT results supported the MR spectroscopic imaging findings. RESULTS: Metabolite compositions of the lesions were similar, likely because the lesions were late stage and tended to be necrotic. Brain lesions in patients with AIDS were nonspecific regarding metabolic profile as determined with MR spectroscopic imaging. All patients with positive PET and SPECT studies had primary central nervous system lymphoma. CONCLUSION: PET and SPECT may be more reliable than MR spectroscopic imaging for differentiating benign lesions from primary central nervous system lymphoma in patients with AIDS.

Acquired Immunodeficiency Syndrome↗

Specific binding of [(11)C]raclopride and N-[(3)H]propyl-norapomorphine to dopamine receptors in living mouse striatum: occupancy by endogenous dopamine and guanosine triphosphate-free G protein.

According to the ternary complex model of G-protein linkage to receptors, agonists increase the affinity of the receptors for the G protein. The model predicts that an endogenous agonist's constant of inhibition toward an agonist radioligand is lower than that toward an antagonistic radioligand. The authors hypothesized that competition from endogenous dopamine in striatum of living mice should have a greater effect on the binding of the D2,3 partial agonist N-[3H]propylnorapomorphine than on the binding of the D2,3 antagonist [(11)C]raclopride. The baseline binding potential (pB(0)), defined as the ratio of bound-to-unbound ligand in the absence of competition from endogenous dopamine, was simultaneously measured in mouse striatum for [(11)C]raclopride (pB(0) = 8.5) and N-[(3)H]propylnorapomorphine (p'B(0) = 5.3). The baseline was established by treatment with alpha-methyl-p-tyrosine and reserpine. Relative to these baseline values in saline-treated mice, the pB of N-[(3)H]propylnorapomorphine decreased 52% whereas the pB of [(11)C]raclopride decreased only 30%, indicating greater sensitivity of the former compound to inhibition by synaptic dopamine. Furthermore, amphetamine decreased the pB of N-[(3)H]propylnorapomorphine to a greater extent (73%) than that of [(11)C]raclopride (43%) relative to the reserpine condition. For both radioligands, the occupancy of the dopamine receptors by endogenous agonist obeyed Michaelis-Menten kinetics over a wide range of agonist concentrations established by the pharmacologic treatments. The apparent inhibition constant of endogenous dopamine depended on the dopamine occupancy and decreased to a value 1.66 times greater for N-[(3)H]propylnorapomorphine than for [(11)C]raclopride at its highest occupancies. The results are consistent with the hypothesis that agonist binding is more sensitive than antagonist binding to competition from endogenous dopamine. Therefore, dopamine agonist ligands may be superior to benzamide antagonist ligands for the estimation of dopamine receptor occupancy by endogenous synaptic dopamine. The analysis of the effect of dopamine occupancy on the inhibition of N-[(3)H]propylnorapomorphine binding indicated a limited supply of G protein with a maximum ternary complex fraction of 40% of maximum agonist binding capacity.

Animals↗

The competition between endogenous dopamine and radioligands for specific binding to dopamine receptors.

The ternary complex model of G-protein-linkage to receptors holds that agonists increase the affinity of the receptors for the G protein. Consequently, an agonist can exert the greatest inhibition of the binding of radioligands which are also agonists. We hypothesized that competition from endogenous dopamine in striatum of living mice should thus have a greater effect on the binding of the D(2,3) agonist N-[(3)H]propylnorapomorphine ([(3)H]NPA), than on the binding of the D(2,3) antagonist [(11)C]raclopride in living brain. The binding potential (p(B(0))), defined as the ratio of bound-to-unbound ligand after reserpine treatment, was measured in mouse striatum for [(11)C]raclopride (p(B(0))(RAC)(C)) = 8.5, and for [(3)H]NPA(p(B(0))(NPA)) = 5.3. Relative to these baseline values after dopamine depletion, saline-treatment decreased the p(B) of [(3)H]NPA by one-half, while the p(B) of [(11)C]raclopride declined by only one-third. Amphetamine decreased the p(B) of [(3)H]NPA to a greater extent than that of [(11)C]raclopride. The apparent inhibition constant of endogenous dopamine depended on the dopamine occupancy and declined to a value 1.66 times greater for [(3)H]NPA than for [(11)C]raclopride at its highest occupancies. Thus, the agonist binding was more sensitive than antagonist binding to competition from endogenous dopamine. Dopamine agonist ligands may be especially useful for PET studies of dopamine receptor occupancy by endogenous synaptic dopamine. Analysis of the effect of dopamine occupancy on the inhibition of agonist indicated a limited supply of G protein, with a maximum ternary complex fraction of 40% of maximum antagonist binding capacity.

Aminoquinolines↗

Elevated intrasynaptic dopamine release in Tourette's syndrome measured by PET.

OBJECTIVE: Dopaminergic abnormalities in frontal-subcortical circuits have been hypothesized as the underlying pathophysiologic mechanism in Tourette's syndrome. The objective of this study was to test the hypothesis that presynaptic dopamine release from the striatum is abnormal in adults with Tourette's syndrome. METHOD: Seven adults with Tourette's syndrome and five age-matched comparison subjects each received two positron emission tomography (PET) scans with high specific activity [11C]raclopride. The first scan followed an intravenous injection of saline; the second followed an intravenous injection of amphetamine. The relative dopamine release was estimated as the percentage difference in binding potential between the postsaline and postamphetamine scans. RESULTS: Binding potential determined after the initial [11C]raclopride scan did not significantly differ between Tourette's syndrome and comparison subjects. After amphetamine challenge, the mean value of intrasynaptic dopamine in the putamen (as determined by true equilibrium bolus estimation) increased by 21% in the subjects with Tourette's syndrome and did not change in the comparison subjects; the mean values increased by 16.9% and decreased by 1.8%, respectively, when measured by the constrained method. Dopamine release in the caudate region was not significantly different in the Tourette's syndrome and comparison subjects. CONCLUSIONS: Greater putamen dopamine release was seen in adults with Tourette's syndrome than in comparison subjects after a pharmacologic challenge with amphetamine. These results suggest that the underlying pathobiology in Tourette's syndrome is a phasic dysfunction of dopamine transmission.

Adult↗

Predicting the success of a radiopharmaceutical for in vivo imaging of central nervous system neuroreceptor systems.

In vivo imaging of the central nervous system (CNS) neuroreceptors in humans began was used in the early 1980s. Now, some twenty years later, the success of radiopharmaceutical imaging is still often one based on empiricism and serendipity. Nevertheless, a number of factors can be identified based on the robot experience in developing these radiotracers. This article will describe some of the issues that may be useful in choosing approaches to radiolabel ligands as future imaging agents of neuroreceptors, transporters and intrasynaptic measures of neurotransmitters. A description of the current process from hypothesis to radiochemical preclinical development, non-human primate imaging development of quantitative procedures finally leading to toxicology, dosimetry and eventually human applications are provided. The role of important factors including metabolism and lipophilicity, affinity and other factors for optimizing radiolabeling strategies is dealt with. Furthermore, issues involving decision making of how far to extend efforts in developing a radiotracer and when might be an appropriate stopping place are discussed. Finally some typical examples of the use of these radiotracers, especially with emphasis on stable drug design and development, are provided. These include occupancy studies and mechanism of action studies. In summary, the prediction of tracer success includes: first, identification of appropriate targets and precursors, then systematic optimization of ligands with continuous feedback from pharmacokinetics and iterative improvement based on unsuccessful tracers. This article is intended to present a pragmatic overview of the radiopharmaceutical development process with emphasis on the CNS.

Animals↗

11C-MCG: synthesis, uptake selectivity, and primate PET of a probe for glutamate carboxypeptidase II (NAALADase).

Imaging of glutamate carboxypeptidase II (GCP II), also known as N-acetylated alpha-linked L-amino dipeptidase (NAALADase), may enable study of glutamatergic transmission, prostate cancer, and tumor neovasculature in vivo. Our goal was to develop a probe for GCP II for use with positron emission tomography (PET). Radiosynthesis of 11C-MeCys-C(O)-Glu or 11C-(S)-2-[3-((R)-1-carboxy-2-methylsulfanyl-ethyl)-ureido]-pentanedioic acid (11C-MCG), an asymmetric urea and potent (Ki = 1.9 nM) inhibitor of GCP II, was performed by C-11 methylation of the free thiol. Biodistribution of 11C-MCG was assayed in mice, and quantitative PET was performed in a baboon. 11C-MCG was obtained in 16% radiochemical yield at the end of synthesis with specific radioactivities over 167 GBq/mmol (4000 Ci/mmol) within 30 min after the end of bombardment. At 30 min postinjection, 11C-MCG showed 33.0 +/- 5.1%, 0.4 +/- 0.1%, and 1.1 +/- 0.2% ID/g in mouse kidney (target tissue), muscle, and blood, respectively. Little radioactivity gained access to the brain. Blockade with unlabeled MCG or 2-(phosphonomethyl)pentanedioic acid (PMPA), another potent inhibitor of GCP II, provided sevenfold and threefold reductions, respectively, in binding to target tissue. For PET, distribution volumes (DVs) were 1.38 then 0.87 pre- and postblocker (PMPA). Little metabolism of 11C-MCG occurred in the mouse or baboon. These results suggest that 11C-MCG may be useful for imaging GCP II in the periphery.

Analysis of Variance↗