ORCID Profile
0000-0002-4231-6316
Current Organisations
Zone Universite Laval
,
University of Toronto
,
Centre for Addiction and Mental Health
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Publisher: American Psychiatric Association Publishing
Date: 04-2000
DOI: 10.1176/APPI.AJP.157.4.514
Abstract: Since all antipsychotics block dopamine D(2) receptors, the authors investigated how well D(2) receptor occupancy in vivo predicts clinical response, extrapyramidal side effects, and hyperprolactinemia. In a double-blind study, 22 patients with first-episode schizophrenia were randomly assigned to 1.0 or 2. 5 mg/day of haloperidol. After 2 weeks of treatment, D(2) receptor occupancy was determined with [(11)C]raclopride and positron emission tomography, and clinical response, extrapyramidal side effects, and prolactin levels were measured. Patients who showed adequate responses continued taking their initial doses, those who did not respond had their doses increased to 5.0 mg/day, and evaluations were repeated at 4 weeks for all patients. The patients showed a wide range of D(2) occupancy (38%-87%). The degree of receptor occupancy predicted clinical improvement, hyperprolactinemia, and extrapyramidal side effects. The likelihood of clinical response, hyperprolactinemia, and extrapyramidal side effects increased significantly as D(2) occupancy exceeded 65%, 72%, and 78%, respectively. The study confirms that D(2) occupancy is an important mediator of response and side effects in antipsychotic treatment. The data are consistent with a "target and trigger" hypothesis of antipsychotic action, i.e., that the D(2) receptor specificity of antipsychotics permits them to target discrete neurons and that their antagonist properties trigger within those neurons intracellular changes that ultimately beget antipsychotic response. While limited to haloperidol, the relationship between D(2) occupancy and side effects in this study helps explain many of the observed clinical differences between typical and atypical antipsychotics.
Publisher: Wiley
Date: 16-10-2004
DOI: 10.1002/SYN.10282
Abstract: Parenterally administered D- hetamine has been used as a challenge drug to release dopamine, which in turns inhibits [11C]raclopride binding to dopaminergic D2 receptors as measured using positron emission tomography (PET) techniques. The primary objective of this study was to determine whether orally administered D- hetamine would inhibit [11C]raclopride binding in a manner similar to that produced by intravenously administered D- hetamine. The secondary objective was to assess the timeline of these effects. Twelve healthy human volunteers participated in this study. Subjects were scanned at baseline and 2 h after D- hetamine administration (n = 5) at baseline, 2 and 6 h postdrug (n = 4) or at baseline, 2 and 24 h postdrug (n = 3). Orally administered D- hetamine caused a significant decrease in [11C]raclopride binding at 2 h (13% +/- 5%). Receptor availability was still decreased at 6 h (18% +/- 6%), even though physiological effects had completely returned to baseline. [11C]Raclopride binding returned to baseline at 24 h. The percentage of [11C]raclopride displacement was not correlated with plasma D- hetamine concentrations. In conclusion, orally administered D- hetamine caused a reliable and prolonged [11C]raclopride displacement, the magnitude of which is similar to that observed after intravenous administration. Possible mechanisms for the observed prolonged displacement may include persistence of intrasynaptic dopamine and/or receptor internalization.
Publisher: Elsevier BV
Date: 06-2004
Publisher: Elsevier BV
Date: 10-2007
Publisher: American Medical Association (AMA)
Date: 06-2009
DOI: 10.1001/ARCHGENPSYCHIATRY.2009.43
Abstract: Most antipsychotics are thought to have an effect on D(2) and D(3) receptors. The development of carbon 11-labeled (+)-4-propyl-9-hydroxynaphthoxazine ([(11)C]-(+)-PHNO), the first agonist radioligand with higher affinity for D(3) than D(2) receptors, allows one to differentiate the effects of antipsychotics on high-affinity vs low-affinity sites of the D(2) receptor and on D(3) vs D(2) receptor subtypes. To examine the effects of antipsychotics (clozapine, risperidone, or olanzapine) on the high- vs high- + low-affinity sites of the D(2) and D(3) receptors by comparing the [(11)C]-(+)-PHNO and [(11)C]raclopride binding in the D(3) receptor-rich (globus pallidus and ventral striatum) and D(2) receptor-rich (caudate and putamen) regions. Two sequential studies with different participants and appropriate controls were performed. The first compared the occupancy produced by 3 antipsychotics as measured with [(11)C]-(+)-PHNO and [(11)C]raclopride. The second was a double-blind, placebo-controlled experiment to compare the effect of pramipexole (a D(3) receptor-preferring agonist) vs placebo on the increased [(11)C]-(+)-PHNO signal observed in the globus pallidus of patients. Positron Emission Tomography Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. Twenty-three patients with schizophrenia and 23 healthy controls. Antipsychotic occupancies as measured with [(11)C]-(+)-PHNO and [(11)C]raclopride. The antipsychotic-treated patients showed high occupancies with both [(11)C]-(+)-PHNO and [(11)C]raclopride in the dorsal striatum, with [(11)C]raclopride occupancies about 20% higher. Most strikingly, patients did not show any occupancy with [(11)C]-(+)-PHNO in the globus pallidus as compared with normal controls or with their own scans using [(11)C]raclopride. This unblocked [(11)C]-(+)-PHNO signal was displaced by a single dose of pramipexole. Antipsychotics block both the high- and low-affinity states of the D(2) receptors across the brain, but antipsychotic treatment does not block the [(11)C]-(+)-PHNO signal in the D(3) receptor-rich regions, despite the ongoing D(2) receptor blockade. This [(11)C]-(+)-PHNO signal in regions such as the globus pallidus seems increased despite antipsychotic treatment and is displaceable by a D(3) receptor-preferring agonist. The radiotracer [(11)C]-(+)-PHNO and the data open up new avenues for exploring the potential therapeutic significance of the D(3) receptor in schizophrenia.
Publisher: Elsevier BV
Date: 11-1996
DOI: 10.1016/S0926-6410(96)00058-4
Abstract: The purpose of this study was to identify the brain regions invoked when subjects attempt to learn verbal materials for a subsequent memory test. Twelve healthy subjects undertook two different tasks: reading and encoding of word pairs, while they were being scanned using [15O]H2O positron emission tomography (PET). As expected, the encoding pairs were remembered much better (recall 39% vs. 8% P < 0.001) than reading pairs in a subsequent memory test. The encoding scans, as compared to reading scans, showed activation of the left prefrontal cortex, the anterior cingulate cortex and the left medial temporal cortex. The left prefrontal activations were in two discrete regions: (i) a left anterior and inferior left prefrontal (Brodmann's areas 45, 46) which we attribute to semantic processing and (ii) a left posterior mid-frontal region (BA 6, 44) which may reflect rote rehearsal. We interpret the data to suggest that when subjects use cognitive strategies of semantic processing and rote-rehearsal to learn words, they invoke discrete regions of the left prefrontal cortex. And this activation of the left prefrontal cortex along with the medial temporal region leads to a neurophysiological memory trace which can be used to guide subsequent memory retrieval.
Publisher: Springer Science and Business Media LLC
Date: 13-07-2002
DOI: 10.1007/S00213-002-1166-3
Abstract: Bupropion is thought to treat major depression by blocking the dopamine transporter (DAT) because bupropion appears to have a selective affinity for the DAT. The validity of this mechanism has been questioned because the affinity of bupropion for the DAT is quite low. To determine the occupancy of bupropion for the DAT during clinical treatment of patients with depression. Positron emission tomography with [(11)C]-RTI32 was used to determine the striatal DAT binding potential (BP) of eight depressed patients before and during treatment with bupropion. BP is proportional to available receptor density (receptors not blocked by drug). Occupancy is the percent change in BP. Eight healthy subjects were similarly studied in a test-retest design. No significant difference in DAT BP was found after bupropion treatment in comparison to the test-retest data. The occupancy after bupropion treatment was 14% (confidence interval 6-22%) as compared to 7% in the test-retest condition. Bupropion treatment occupies less than 22% of DAT sites. This raises the question as to whether a DAT occupancy of less than 22% is therapeutic or whether there is another mechanism involved during treatment with bupropion.
Publisher: Springer Science and Business Media LLC
Date: 04-04-2007
Abstract: Imaging the competition between D(2/3) radioligands and endogenous dopamine is so far the only way to measure dopamine release in the living human brain. The dopamine D(2) receptor exists in a high (D(2)(high)) and a low-affinity state for dopamine. Under physiological conditions, dopamine is expected to bind to D(2)(high) only. [(11)C]-(+)-4-propyl-9-hydroxynaphthoxazine ((+)-PHNO) is the first D(2/3) agonist radioligand for positron emission tomography (PET) imaging in humans. Since [(11)C]-(+)-PHNO is expected to bind preferentially to D(2)(high), it should be particularly vulnerable to competition with endogenous dopamine. Nine healthy subjects participated in two PET scans, one after administration of d- hetamine and one after placebo. [(11)C]-(+)-PHNO PET test re-test variability was determined in 11 healthy subjects. Binding potentials (BPs) were calculated for caudate, putamen, ventral striatum, and globus pallidus. d-Amphetamine led to a significant decrease of [(11)C]-(+)-PHNO BPs in caudate (-13.2%), putamen (-20.8%), and ventral striatum (-24.9%), but not in globus pallidus (-6.5%). d-Amphetamine-induced displacement correlated with serum d- hetamine levels in all regions but caudate. This is the first report on competition between endogenous dopamine and a D(2/3) agonist radioligand in humans. [(11)C]-(+)-PHNO PET might be a superior measure for release of endogenous dopamine than PET employing conventional D(2/3) antagonist radioligands.
Publisher: Wiley
Date: 08-2009
DOI: 10.1002/SYN.20646
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2001
DOI: 10.1097/00001756-200112210-00052
Abstract: Previous studies suggest that there is a dopamine lowering process during major depressive episodes (MDE). To investigate this, we measured the dopamine transporter binding potential (DAT BP) in the striatum of depressed and healthy subjects using [(11)C]RTI-32 PET. The DAT, a predominantly presynaptic receptor, decreases in density after chronic dopamine depletion and the BP is proportional to receptor density. In all striatal regions, subjects with MDE had significantly lower DAT BP. Low striatal DAT BP in MDE is consistent with a downregulation of DAT in response to a dopamine lowering process. There was also a strong, highly significant, inverse correlation between striatal DAT BP and neuropsychological tests of dopamine-implicated symptoms in patients (i.e. patients with lower DAT BP performed better). Lower DAT BP itself reduces extracellular clearance of dopamine. Patients who did not decrease their striatal DAT BP failed to compensate for low dopamine and showed greater impairment on dopamine related tests.
Publisher: American Psychiatric Association Publishing
Date: 2001
DOI: 10.1176/APPI.AJP.158.1.78
Abstract: In the cortex of animals, serotonin (5-HT) levels increase after several weeks of treatment with selective serotonin reuptake inhibitors (SSRIs). Studies using an intrasubject design to examine the effects of SSRI treatment on 5-HT(2A) receptors in the cortex of drug-free depressed patients are needed. In theory, agonist stimulation of 5-HT(2A) receptors could be relevant to SSRI treatment by promoting neuronal growth and survival as well as direct elevation of mood. The objective of this study was to evaluate the effect of 6 weeks of paroxetine treatment on 5-HT(2A) receptors in depressed patients. After a medication-free period of at least 3 months, 19 depressed patients were treated for 6 weeks with paroxetine, 20 mg/day. The authors used [(18)F]setoperone and positron emission tomography to assess 5-HT(2A) receptor binding potential in the patients before and after treatment and in 19 age-matched healthy subjects. 5-HT(2A) binding potential declined with age in all cortical regions in the depressed and healthy subjects. There was a significant interaction between age and treatment effect on 5-HT(2A) binding potential in all cortical regions. Subjects aged 20 to 30 years had a 10% decrease in 5-HT(2A) binding potential after treatment, whereas subjects aged 30 to 40 had no change. No regional differences in 5-HT(2A) binding potential between depressed and healthy subjects were found. 5-HT(2A) receptors down-regulate in young depressed subjects after treatment with paroxetine, but this down-regulation attenuates with age. This suggests that over 6 weeks paroxetine treatment increases 5-HT agonism on 5-HT(2A) receptors in the cortex of young patients with depression.
Publisher: Wiley
Date: 05-04-2006
DOI: 10.1111/J.1471-4159.2006.03840.X
Abstract: [11C]-(+)-PHNO (4-propyl-9-hydroxynaphthoxazine) is a new agonist radioligand that provides a unique opportunity to measure the high-affinity states of the D2 receptors (D2-high) using positron emission tomography (PET). Here we report on the distribution, displaceablity, specificity and modeling of [11C]-(+)-PHNO and compare it with the well characterized antagonist D2 radioligand, [11C]raclopride, in cat. [11C]-(+)-PHNO displayed high uptake in striatum with a mean striatal binding potential (BP) of 3.95 +/- 0.85. Pre-treatment with specific D1 (SCH23390), D2 (raclopride, haloperidol) and D3 receptor (SB-277011) antagonists indicated that [11C]-(+)-PHNO binding in striatum is specific to D2 receptors. Within-subject comparisons showed that [11C]-(+)-PHNO BP in striatum was almost 2.5-fold higher than that measured with [11C]-(-)-NPA ([11C]-(-)-N-propyl-norapomorphine). Comparison of the dose-effect of hetamine (0.1, 0.5 and 2 mg/kg i.v.) showed that [11C]-(+)-PHNO was more sensitive to the dopamine releasing effect of hetamine than [11C]raclopride. Amphetamine induced up to 83 +/- 4% inhibition of [11C]-(+)-PHNO BP and only up to 56 +/- 8% inhibition of [11C]raclopride BP. Scatchard analyses of [11C]-(+)-PHNO and [11C]raclopride bindings in two cats showed that the Bmax obtained with the agonist (29.6 and 32.9 pmol/mL) equalled that obtained with the antagonist (30.6 and 33.4 pmol/mL). The high penetration of [11C]-(+)-PHNO in brain, its high signal-to-noise ratio, its favorable in vivo kinetics and its high sensitivity to hetamine shows that [11C]-(+)-PHNO has highly suitable characteristics for probing the D2-high with PET.
Publisher: Oxford University Press (OUP)
Date: 15-09-2010
Publisher: Elsevier BV
Date: 09-2011
DOI: 10.1016/J.SCHRES.2011.05.005
Abstract: Most antipsychotics are thought to have an effect on D(2) and D(3) receptors, although their D(3), versus D(2) binding has not been clearly established in vivo in humans. However, the development of [(11)C]-(+)-PHNO now permits the differentiation of antipsychotic activity on these two receptor subtypes. In this study we examined the effects of antipsychotics on D(2) and D(3) receptors by comparing [(11)C]-(+)-PHNO in D(2)-rich (caudate, CAU and putamen, PUT), mixed (ventral striatum) and D(3)-rich (globus-pallidus, GP and substantia nigra, SN) regions before and after the initiation of antipsychotic medication. The investigation therefore represents a longitudinal within-subject follow-up design wherein antipsychotic-naive patients with schizophrenia spectrum disorders were first scanned in a drug-naïve state and then again after ~2.5 weeks of antipsychotic treatment (risperidone or olanzapine). Binding potential (non displaceable or BP(ND)) was obtained to derive estimates of drug occupancy in the identified brain regions. Antipsychotic treatment was associated with the expected occupancies in the D(2)-rich regions unexpectedly though, patients showed a higher, rather than the expected lower, [(11)C]-(+)-PHNO BP(ND) in the GP and SN despite simultaneous evidence for ongoing D(2) blockade in the other regions (CAU and PUT). In conclusion, patients treated with atypical antipsychotics demonstrated no evidence of D(3) receptor occupancy, but instead possible D(3) up-regulation following short-term treatment. The present findings add to a very limited body of evidence related to D(3) binding in vivo. [(11)C]-(+)-PHNO offer new opportunities for exploring the potential therapeutic significance of the D(3) receptor in schizophrenia and the action of antipsychotics.
Publisher: Oxford University Press (OUP)
Date: 19-01-2009
DOI: 10.1093/BRAIN/AWN337
Abstract: The D(3) dopamine (DA) receptor is a member of the D(2)-like DA receptor family. While the D(2) receptor is abundant especially in motor-regions of the striatum, the D(3) receptor shows a relative abundance in limbic regions and globus pallidus. This receptor is of current interest in neurology because of its potential involvement in psychiatric and motor complications in Parkinson's disease and the possibility that dopamine D(3)-preferring agonist therapy might delay progression of the disorder. Preclinical data indicate that striatal levels of the D(3) (but not the D(2)) DA receptor are decreased following lesion of nigrostriatal DA neurons at present, there are no in vivo data on this receptor subtype in Parkinson's disease. The objective of this positron emission tomography study was to compare [(11)C]-(+)-PHNO (D(3) versus D(2) preferring) and [(11)C]raclopride (D(3) = D(2)) binding in brain of non-depressed, non-demented, dopaminergic drug-naïve patients with early-stage Parkinson's disease (n = 10), relative to matched-controls (n = 9). Parkinson's disease was associated with a trend for bilaterally decreased [(11)C]-(+)-PHNO (but not [(11)C]raclopride) binding in the D(3)-rich ventral striatum (-11%, P = 0.07) and significantly decreased binding in globus pallidus (-42%, P = 0.02). In contrast, in the primarily D(2)-populated putamen, both [(11)C]-(+)-PHNO (25%, P = 0.02) and [(11)C]raclopride (25%, P < 0.01) binding were similarly increased, especially on the side contra-lateral to the symptoms. In the midbrain, presumably containing D(3) receptors localized to the substantia nigra, [(11)C]-(+)-PHNO binding was normal. Decreased [(11)C]-(+)-PHNO to [(11)C]raclopride ratio correlated with motor deficits and lowered-mood (P < 0.02). Our imaging data suggest that brain DA neuron loss in the human causes region-specific differential changes in DA D(2) and D(3) receptors with D(3) receptor 'downregulation' possibly related to some motor and mood problems in Parkinson disease. D(3) receptor levels might be a determinant vulnerability factor underlying side-effects associated with treatment hence, these initial findings provide valuable baseline information to understand the role of D(3) receptors in response to Parkinson's disease medication.
Publisher: Elsevier BV
Date: 05-1994
DOI: 10.1016/0006-8993(94)90091-4
Abstract: This study investigates the effect of a serotonergic agent, fenfluramine, on neuronal activity, as measured using [18F]fluorodeoxyglucose (FDG) uptake with positron emission tomography (PET) in humans. Eleven subjects each received oral fenfluramine and placebo, on two different occasions, followed by FDG PET scans. Our study shows that fenfluramine modulates ongoing neuronal activity in a regionally specific fashion with a relative increase in metabolism in the prefrontal cortex and a relative decrease in the occipital-temporal regions.
Publisher: Elsevier BV
Date: 05-1998
Abstract: Positron emission tomography was used to identify brain regions that showed general increase or decrease in regional cerebral blood flow (rCBF) across time that was task-independent. Twelve male subjects were scanned eight times: the first and last scans were taken while subjects performed a baseline fixation task and the middle six scans were taken while subjects performed a visuomotor activation task. To determine whether there was a consistency across different studies in the regions that showed this time-related change in rCBF two additional datasets were analyzed. There were similarities across all three studies in the regions that showed a monotonic task-independent change in activity. In all three studies there was a general bilateral decrease in rCBF of occipital and temporal areas across scans that might be related to habituation in the visual domain. Increases in rCBF were found in anterior cingulate, postcentral gyrus, and precentral gyrus across studies. It is likely that these changes reflect motor learning and motor program retrieval. This implies that, unless the experimenter controls for time-dependent changes in brain activity, the interpretation of task-related changes in rCBF may be confounded by these monotonic changes in rCBF. We present analytic strategies to identify experimental effects that are independent of nonspecific time effects, which can be used when it is not possible to control these effects through counterbalancing the experimental design. Nonspecific confounds are particularly relevant in functional MRI studies in which the number of scans acquired per study is much larger.
Publisher: Elsevier BV
Date: 07-1994
DOI: 10.1016/0304-3940(94)90861-3
Abstract: The purpose of this study was to investigate the functional effects of apomorphine, a non-selective dopamine agonist, on regional neuronal activity using regional cerebral blood flow, measured using [15O]H2O and positron emission tomography (PET), as an index. Eight normal volunteers were scanned twice before and twice after receiving 10 micrograms/kg subcutaneous apomorphine. Apomorphine produced the expected side-effects and endocrine response. Analysis of the PET scans revealed that apomorphine increased regional cerebral blood flow (rCBF), presumably reflecting a change in neuronal activity, in the anterior cingulate, ventral motor cortex and the dorsolateral prefrontal cortex along with a decrease in rCBF in the retrosplenial cingulate region. These regions form a functional network of brain regions modulated by the dopaminergic system.
Publisher: Elsevier BV
Date: 07-1995
DOI: 10.1016/0024-3205(95)02037-J
Abstract: Risperidone is a recently introduced neuroleptic distinguished by a decreased incidence of extrapyramidal side effects (EPS). The mechanism of its low EPS is unclear. Since it has been shown that EPS is related to the level of D2 receptor occupancy, we studied nine patients receiving 2-6 mg/day of risperidone using [11C]-raclopride PET scans in order to determine the in vivo D2 receptor binding characteristics of risperidone. The mean level of receptor occupancy was 66% at 2 mg 73% at 4 mg and 79% at 6 mg. Three patients, those with the highest receptor occupancies, exhibited mild EPS, though none required anitparkinsonian medications. Our results suggest that at doses of 4-6 mg the in vivo D2 receptor occupancy of risperidone is similar to that of typical neuroleptics and higher than that of clozapine. This would suggest that the EPS benefits of risperidone cannot be explained by a low D2 binding but may be related to its high 5-HT2 affinity. However, the emergence of EPS at higher levels of D2 receptor occupancy, in this study and in previous clinical trials, would suggest that risperidone's high 5-HT2 affinity provides only a relative protection from EPS. And once the D2 occupancy exceeds a certain threshold this 'relative' 5-HT2-mediated protection from EPS may be lost.
Publisher: Springer Science and Business Media LLC
Date: 20-05-1997
Abstract: The purpose of this study was to determine the relationship between dopamine D2 receptor occupancy and plasma haloperidol. Twelve patients treated with 1-5 mg/day of haloperidol had their D2 occupancy measured using [11C]-raclopride and positron emission tomography and haloperidol plasma levels measured using gas chromatograph mass spectrophotometer. The patients exhibited haloperidol plasma levels ranging from 0.5 to 5.8 ng/ml and D2 occupancy from 53 to 88%. The D2 occupancy was related to the plasma level as a saturating rectangular hyperbola relationship (r2 = 0.84) and it showed that, on average, 50% D2 occupancy was achieved with 0.51 ng/ml and 80% D2 occupancy with 2.0 ng/ml. Our findings demonstrate that 2-5 mg/day of haloperidol, which usually leads to plasma levels of 1-2 ng/ml, would be expected to induce 60-80% dopamine D2 receptor occupancy. If, as has been claimed, 70% D2 occupancy is adequate for typical neuroleptic response, then the conventional use of > 10 mg/day may have been too high, since 70% occupancy can be achieved in most patients by 2-5 mg/day. On the other hand, if as others have suggested, 8-12 ng/ml of haloperidol is the correct therapeutic window for plasma levels, then the required therapeutic D2 occupancy is closer to 90%, not 70%. The implications of the D2 occupancy findings for the optimal dosing of neuroleptics are discussed.
Publisher: Elsevier BV
Date: 03-2006
DOI: 10.1016/J.BIOPSYCH.2005.09.017
Abstract: The high-affinity states of dopamine D2-receptors (D2(high)) are postulated to be functionally responsible for signal transduction. At present, no useful in vivo method exists to selectively measure D2(high) in humans, as current D2 radioligands for positron emission tomography (PET) are either not D2-selective or do not differentiate between D2 high- and low-affinity states. The D2-agonist (+)-PHNO [(+)4-propyl-9-hydroxynaphthoxazine] was labeled with carbon-11 and studied with PET. Eight [11C]-(+)-PHNO scans were acquired in four healthy volunteers. We observed greatest [11C]-(+)-PHNO accumulation in caudate, putamen, and globus pallidus [binding potentials (BPs): 3.00 +/- .4, 3.10 +/- .2, and 4.17 +/- 1.2]. Small but detectable binding was identified in the substantia nigra/ventral tegmental area. Preliminary test-retest data in two subjects suggests BP-estimates to be reliable. Pre-treatment with haloperidol reduced BPs in regions showing specific binding with no detectable changes in cerebellum. Parallel imaging with [11C]-raclopride showed substantial differences in the globus pallidus. [11C]-(+)-PHNO proved to be a D2/3-receptor agonist-radioligand with good brain uptake and favorable kinetics for PET in humans. [11C]-(+)-PHNO delineated D2/3-receptor rich brain regions with high signal-to-noise ratio. This is the first demonstration of a viable agonist-radioligand for D2 receptors in humans and opens the door for investigating D2(high) in health and disease.
Publisher: American Chemical Society (ACS)
Date: 19-05-2005
DOI: 10.1021/JM050155N
Abstract: In vivo imaging of dopamine D2 receptors with agonist (as opposed to the more commonly employed antagonist) radiotracers could provide important information on the high-affinity (functional) state of the D2 receptor in illnesses such as schizophrenia, movement disorders, and addictions. We report here the radiosynthesis and evaluation of the potent D2 agonist (+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol, (+)-3, labeled with carbon-11, as a potential radiotracer for imaging the high-affinity state of dopamine D2 receptors with positron emission tomography (PET). [(11)C]-(+)-3 was reliably synthesized in the quantities and at the specific activities and radiochemical purities required for human PET studies. Ex vivo biodistribution studies in rat brain demonstrated that [(11)C]-(+)-3 crossed the blood-brain barrier readily and had an appropriate regional brain distribution for a radiotracer that maps dopamine D2 receptors. The binding of [(11)C]-(+)-3 was saturable and demonstrated an excellent signal-to-noise ratio as measured by its striatum-to-cerebellum ratio of 5.6, 60 min postinjection. The binding was highly stereospecific, and blocking and displacement studies were consistent with selective and specific binding to the dopamine D2 receptors. Further, [(11)C]-(+)-3 showed marked and appropriate sensitivity to both increases and decreases in the levels of endogenous dopamine. Brain radioactive metabolite and physicochemical measurements are in full accord with the desired properties of a neuroreceptor imaging agent for PET. All of the above, coupled with the documented full D2 agonistic properties of (+)-3, strongly indicate that [(11)C]-(+)-3 is a leading candidate radiotracer for the imaging of the dopamine D2 high-affinity state using PET in human subjects.
Publisher: Wiley
Date: 1996
DOI: 10.1002/(SICI)1097-0193(1996)4:1<1::AID-HBM1>3.0.CO;2-7
Publisher: Oxford University Press (OUP)
Date: 05-01-2017
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.PSCYCHRESNS.2006.01.011
Abstract: Manual drawing of regions of interest (ROIs) on brain positron emission tomography (PET) images is labour intensive and subject to intra- and inter-in idual variations. To standardize analysis and improve the reproducibility of PET measures, we have developed image analysis software for automated quantification of PET data. The method is based on the in idualization of a set of standard ROIs using a magnetic resonance (MR) image co-registered with the PET image. To evaluate the performance of this automated method, the software-based quantification has been compared with conventional manual quantification of PET images obtained using three different PET radiotracers: [(11)C]-WAY 100635, [(11)C]-raclopride and [(11)C]-DASB. Our results show that binding potential estimates obtained using the automated method correlate highly with those obtained by trained raters using manual delineation of ROIs for frontal and temporal cortex, thalamus, and striatum (global intraclass correlation coefficient >0.8). For the three radioligands, the software yields time-activity data that are similar (within 8%) to those obtained by manual quantification, eliminates investigator-dependent variability, considerably shortens the time required for analysis and thus provides an alternative method for accurate quantification of PET data.
Publisher: Springer Science and Business Media LLC
Date: 12-1996
Publisher: Springer Science and Business Media LLC
Date: 06-10-2000
Abstract: Dopamine D2 receptor upregulation in the striatum is regularly seen in response to the administration of traditional antipsychotics in animal experiments. This is associated with hyperactivity and, for this reason, D2 receptor upregulation has long been postulated as central to tar e dyskinesia (TD). Using positron emission tomography (PET), the present study attempted to determine whether antipsychotic-induced D2 receptor up-regulation also occurs in humans. The long-term effects of traditional and novel antipsychotics on dopamine D2 receptors were investigated in nine subjects meeting DSM-IV criteria for schizophrenia who were deemed eligible for temporary treatment washout. Subjects had been treated with traditional antipsychotics (haloperidol n=3, perphenazine n=1) and novel antipsychotics (risperidone n=3, olanzapine n=2) in the moderate to high dosage range. Fourteen days after treatment withdrawal, the binding potentials (BPs) of dopamine D2 receptors were measured using 11[C] raclopride. The obtained BPs were compared to the BPs from antipsychotic-naive control subjects with schizophrenia. There was a significant increase in the D2 BP in both groups combined that reached 34%. The increases in the D2 BPs in the groups treated with conventional and novel antipsychotics were 37% and 31%, respectively. Significantly, the patients showing the highest degree of D2 receptor upregulation (98%) developed severe and persistent TD shortly after being started on a new antipsychotic with low affinity for D2 receptors. This study demonstrates for the first time, using in vivo neuroreceptor imaging, that dopamine D2 receptor binding is increased after long-term treatment with antipsychotics in humans. The data suggest that both traditional and novel antipsychotics with high affinity for dopamine D2 receptors are associated with a substantial increase in D2 receptor binding. The present data in humans agree well with animal data that implicate D2 receptor-mediated mechanisms in motor hyperactivity.
Publisher: SAGE Publications
Date: 11-10-2006
Abstract: The kinetic modeling of [ 11 C]-(+)-PHNO binding to the dopamine D 2/3 receptors in six human volunteers using positron emission tomography (PET) is described. [ 11 C]-(+)-PHNO is the first agonist radioligand for the D 2/3 in humans and as expected showed high uptake in caudate, putamen, globus pallidus (GP) and ventral striatum, and low uptake in cerebellum. A two-tissue compartment model (2CM) with four parameters was necessary to adequately fit time—activity data in all regions. Although a 2CM provided an excellent estimation of total distribution volumes, which were highly correlated with those obtained with the invasive Logan approach, it provided a poor identification of the k 3 / k 4 ratios. Coupling K 1 / k 2 between brain regions (Method C) or fixing K 1 / k 2 to the value obtained in cerebellum (Method D) enabled more stable estimates of k 3 / k 4 as compared with an unconstrained 2CM. The k 3 / k 4 obtained with Method D ranged from 0.12 ± 0.03 in cerebellum to 3.93 ± 0.77 in GP and were similar to those obtained when coupling K 1 / k 2 . Binding potentials (BPs) obtained using the simplified reference tissue model ( BP SRTM ) ranged from 2.08 ± 0.34 in caudate to 3.55 ± 0.78 in GP and were highly correlated with k 3 / k 4 estimates obtained with Method D ( r = 0.98). However, BP SRTM were 11% ± 5% lower than values obtained with Method D. BPs derived using the noninvasive Logan approach were slightly lower but not significantly different than BP SRTM . This study demonstrates that [ 11 C]-(+)-PHNO can be used for the quantitative measurement of D 2/3 densities and should enable further studies of potential D 2/3 dysregulation in several important psychiatric and neurologic illnesses.
Publisher: MIT Press - Journals
Date: 05-1998
Abstract: One of the important questions cognitive theories of reasoning must address is whether logical reasoning is inherently sentential or spatial. A sentential model would exploit nonspatial (linguistic) properties of representations whereas a spatial model would exploit spatial properties of representations. In general terms, the linguistic hypothesis predicts that the language processing regions underwrite human reasoning processes, and the spatial hypothesis suggests that the neural structures for perception and motor control contribute the basic representational building blocks used for high-level logical and linguistic reasoning. We carried out a [ 15 O] H 2 O PET imaging study to address this issue. Twelve normal volunteers performed three types of deductive reasoning tasks (categorical syllogisms, three-term spatial relational items, and three-term nonspatial relational items) while their regional cerebral blood flow pattern was recorded using [ 15 O] H 2 O PET imaging. In the control condition subjects semantically comprehended sets of three sentences. In the deductive reasoning conditions subjects determined whether the third sentence was entailed by the first two sentences. The areas of activation in each reasoning condition were confined to the left hemisphere and were similar to each other and to activation reported in previous studies. They included the left inferior frontal gyrus (Brodmann areas 45, 47), a portion of the left middle frontal gyrus (Brodmann area 46), the left middle temporal gyrus (Brodmann areas 21, 22), a region of the left lateral inferior temporal gyrus and superior temporal gyrus (Brodmann areas 22, 37), and a portion of the left cingulate gyrus (Brodmann areas 32, 24). There was no significant right- hemisphere or parietal activation. These results are consistent with previous neuroimaging studies and raise questions about the level of involvement of classic spatial regions in reasoning about linguistically presented spatial relations.
Publisher: Wiley
Date: 2004
DOI: 10.1002/SYN.20016
Abstract: Clinical effects of antipsychotic drugs are thought to be mediated primarily through antagonism of the dopamine D2 receptors. Recent studies have demonstrated increased aromatic decarboxylase activity following acute administration of dopamine D2 receptor antagonists both in vivo and ex vivo. However, this effect has never been demonstrated in human subjects. We studied the effect of acute antipsychotic administration on dopamine synthesis in rodents and healthy human subjects using 6-[18F]-L-m-tyrosine. In rats, we studied the effect of a single subcutaneous injection of haloperidol and risperidone on dopamine synthesis using 6-[18F]-L-m-tyrosine. In our human study, six healthy volunteers underwent two 6-[18F]-L-m-tyrosine PET scans, before and after 3 mg risperidone to measure the rate of accumulation of radioactivity in the striatum as an index of dopamine synthesis. The striatal/cerebellar radioactivity count ratio and the ratio of dopamine metabolites to dopamine concentration was significantly higher in all rodent treatment groups compared to controls. In the PET study we found no significant change in the rate of uptake in the striatum. Our results suggest that 6-[18F]-L-m-tyrosine PET may not be a useful tool in the study of the effect of antipsychotics on dopamine synthesis in human subjects.
Publisher: Oxford University Press (OUP)
Date: 15-04-2009
Publisher: American Psychiatric Association Publishing
Date: 09-2004
Publisher: Informa UK Limited
Date: 15-07-2010
DOI: 10.1080/17470911003589309
Abstract: Social behavior and desire for social relationships have been independently linked to the serotonergic system, the prefrontal cortex, especially the orbitofrontal cortex (OFC), and the anterior cingulate cortex (ACC). The goal of this study was to explore the role of serotonin 5HT(2A) receptors in these brain regions in forming and maintaining close interpersonal relationships. Twenty-four healthy subjects completed the Temperament and Character Inventory (TCI) prior to undergoing [(18)F]setoperone brain positron emission tomography (PET) to measure serotonin 5HT(2A) receptor availability within the OFC (BA 11 and 47) and ACC (BA 32). We explored the relationship between desire for social relationships, as measured by the TCI reward dependence (RD) scale, and 5HT(2A) receptor non-displaceable binding potential (BP(nd)) in these regions. Scores of RD were negatively correlated with 5HT(2A) BP(nd) in the ACC (BA 32, r = -.528, p = .012) and OFC (BA 11, r = -.489, p = .021 BA 47, r = -.501, p = .017). These correlations were corroborated by a voxel-wise analysis. These results suggest that the serotonergic system may have a regulatory effect on the OFC and ACC for establishing and maintaining social relationships.
Publisher: Springer Science and Business Media LLC
Date: 06-08-2009
DOI: 10.1038/NPP.2008.116
Abstract: Long-term occupancy of dopamine D(2)-receptors, as achieved by chronic treatment with antipsychotics, leads to D(2)-receptor upregulation, and this upregulation is thought to be responsible for loss of efficacy and development of tar e dyskinesia. However, little is known about the parameters of D(2)-receptor blockade (duration and percentage of blockade) that lead to upregulation. In this study, we investigated the effects of different degrees (60 vs >80%) and durations (a transient peak vs 24 h/day) of D(2)-receptor blockade on inducing this upregulation. These different patterns of D(2)-receptor occupancy kinetics were produced in cats using bolus vs constant infusion of haloperidol for 4 weeks. D(2)-receptors were measured using positron emission tomography and Scatchard analyses of [(11)C]raclopride binding, before and after withdrawal of treatment. Continuously high (80% for 24 h/day) D(2)-receptor blockade led to a robust upregulation of striatal D(2)-receptors that was maximal at 1-week withdrawal (35+/-5%) and still detectable at 2-week withdrawal (20+/-3%). This pattern of D(2)-receptor blockade also induced behavioral tolerance to the effect of haloperidol on spontaneous locomotor activity. Continuously moderate (60% for 24 h/day) or transiently high (80% for a few hours/day) D(2)-receptor blockade did not produce any of these effects. The long-term effect of haloperidol on D(2)-receptor density and behavioral tolerance thus appears to be dependent not only on a critical threshold of D(2)-receptor blockade but also on the daily duration of D(2)-receptors blockade. This suggests that as far as antipsychotics are concerned, not only dose but disbursment throughout the day have an impact on eventual pharmacodynamic and behavioral outcomes.
Publisher: Wiley
Date: 2004
DOI: 10.1002/SYN.20010
Abstract: In this study, we evaluated the potential of using a new beta-sensitive microprobe system for in vivo quantification of [11C]raclopride binding and for in vivo determination of drug-induced receptor occupancy in the rat striatum. To validate this system, an ex vivo tissue dissection method was used to corroborate in vivo beta-microprobe measurements. Our data showed that the beta-microprobe-derived [11C]raclopride binding kinetics in striatum could be quantified using a tissue compartmental model with a cerebellar reference region. Haloperidol (0.001-0.1 mg/kg i.v.) induced a dose-dependent decrease in [11C]raclopride binding in striatum as measured using the beta-microprobe with an ED50 value of 0.013 mg/kg. Highly significant relationships (P < 0.0001) were observed, within the same animals, between in vivo and ex vivo measures of haloperidol-induced D2-receptor occupancy (r = 0.98) as well as between in vivo and ex vivo measures of [11C]raclopride binding potentials (r = 0.99). Results from pretreatment and displacement studies with unlabeled raclopride and hetamine conformed to the effect of these drugs as observed in humans using [11C]raclopride and PET and allowed estimation of the in vivo k(off) value of raclopride to 0.025 +/- 0.004 min(-1). However, allowing the system to stabilize before measurements and shielding the photomultiplier tubes were critical for obtaining these consistent results. This study demonstrates that the beta-microprobe provides reliable measurements of [11C]raclopride binding kinetics in rodents, allows for quantitative in vivo measurements of antipsychotic drug action in brain, and represents a valid and cost-effective alternative to positron emission tomography imaging in small animals.
Publisher: Wiley
Date: 1996
DOI: 10.1002/(SICI)1522-7162(1996)4:2<81::AID-DEPR8>3.0.CO;2-I
Abstract: Although tricuspid regurgitation (TR) is a general medical issue with growing prevalence and socioeconomic burden, most clinicians have not paid much attention to TR in the past. Several problems of TR have been pointed out in clinical practice, which include: ambiguous clinical manifestations and the difficulty in initial detection, limitations in generally used diagnostic tools, the absence of objective criterion for therapeutic intervention, high operative morbidity and mortality, and lack of long-term clinical data after the intervention for TR. Therefore, patients with TR usually visit clinicians at a much-advanced state, and this delay gives a major dilemma in clinical decision-making in a routine clinical practice. To improve the clinical outcome of TR, we need more knowledge about TR for solving the current problems and making strategies for better clinical practice. With this background, we have discussed in the present article about the pathophysiology of TR and the problems frequently experienced by clinical physicians in the diagnosis and treatment of TR. Furthermore, we have discussed the future strategy to improve the treatment of TR.
Publisher: Elsevier BV
Date: 03-1996
DOI: 10.1016/0304-3940(96)12479-4
Abstract: This study assessed the modulatory effect of a serotonergic agonist, d-fenfluramine, on localized neuronal firing as indexed by changes in regional cerebral blood flow (rCBF). Previously, we reported the effect of oral d, l-fenfluramine on neuronal activity as measured by change in [18F]fluorodeoxyglucose uptake. Improvements in the current study include: a more specific serotonin agonist, d-fenfluramine a more reliable administration route, intravenous and a one session paradigm made possible with the radiotracer [15O]H2O. Changes in relative rCBF (P < 0.001) were observed: increases within the frontal cortex bilaterally and decreases within the temporal cortex bilaterally, and left thalamus. Other significant findings were elevated cortisol and growth hormone increased euphoria and panic symptoms and decreased tiredness. These results support further investigation with intravenous d-fenfluramine to study the net functional effects of serotonergic stimulation in health and illness.
Publisher: Wiley
Date: 23-02-2011
DOI: 10.1002/GPS.2682
Abstract: We explored whether prior findings of reduction in serotonin 2A receptor (5-HT(2A) R) binding with age could be replicated and whether high resolution research tomography (HRRT) for positron emission tomography could compensate for partial volume effects in the presence of age-related brain atrophy, which has been a traditional concern for radioligand PET studies in the elderly. We derived 5-HT(2A) R nondisplaceable binding potentials (BP(ND) ) in frontal, temporal, anterior-cingulate, insula, caudate and putamen volumes of interest (VOIs) for 28 healthy subjects (mean ± SD age = 43.9 ± 17.0 years, range: 19-78 years) using HRRT. Partial volume correction (PVC) was performed in the VOI analysis. The 5-HT(2A) R BP(ND) s decreased with age, a relationship best described by an exponential-decay regression. The BP(ND) s were found to be consistent before and after PVC, with an intra-class correlation coefficient of 0.84 and 95% confidence interval = 0.78-0.88. These new findings update current knowledge, in that the aging process is not always uniform across the life span and suggest that PVC may not be necessary with HRRT in healthy subjects.
Publisher: Wiley
Date: 2006
DOI: 10.1002/SYN.20290
Abstract: This study reports on the binding kinetics and pharmacological characterization of [11C]-(+)-PHNO ((+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol), a promising agonist radiotracer for in vivo evaluation of the D2-receptor. Its in vivo kinetics were monitored in rat striatum and cerebellum using a beta-sensitive Microprobe system. Control studies showed that [11C]-(+)-PHNO binding was reversible and reached a peak time equilibrium of specific binding in striatum 30 min after radiotracer injection. The binding potential (BP) calculated by the simplified reference tissue model was 3-fold higher than that measured with [11C]-(-)-NPA (2.14 +/- 0.50 vs. 0.66 +/- 0.01, respectively). In contrast, the methyl analog of (+)-PHNO, [11C]-(+)-MHNO, which displayed promising D2-agonist properties in vitro, showed no specific binding in the striatum in vivo. [11C]-(+)-PHNO binding was totally blocked by raclopride (1 mg/kg i.v.) and 97% displaced by NPA (2 mg/kg i.v.) suggesting that [11C]-(+)-PHNO was specific for the high affinity states of D2/D3-receptors. However, (+)-PHNO (1 mg/kg i.v.) totally blocked and displaced [11C]-raclopride binding in striatum. Thus, (+)-PHNO at high concentrations might be able to bind to the low affinity states of D2/D3-receptors. After an hetamine pretreatment (2 mg/kg i.v.), a 69% decrease in BP value (P < 0.05) was observed for [11C]-(+)-PHNO indicating that its binding was highly sensitive to variations of endogenous DA. These results substantiate the use of [11C]-(+)-PHNO as an agonist radiotracer for D2-imaging. The sensitivity of its binding to competition with endogenous DA suggests an association with the subset of high affinity state D2-receptors.
Publisher: Elsevier BV
Date: 04-1997
Abstract: Determining the areas of brain activity associated with cognitive processing has typically relied on the use of a subtraction paradigm, which is based on the premise that the neural processes underlying behavior are additive. If the additivity assumption is valid then brain regions associated with a semantic processing task should be the same regardless of how participants make a response. To investigate this proposition, participants underwent six PET scans, in which they made semantic or letter word judgments, responding "yes" or "no" in three different modes: mouse-clicking, spoken response, or silent thought. Analyses showed an increase in regional cerebral blood flow associated with semantic processing in the left inferior frontal cortex, anterior cingulate, and right cerebellum for all three response conditions. However, there was a significant interaction: the greatest increase was observed in the mouse-click condition and the weakest change seen with silent thought. Moreover, other areas of the brain were uniquely activated for each response mode. The results indicate that different areas of the brain were recruited for semantic processing depending on how participants had to organize their responses. Implications for the additivity assumption and methods of analysis to be used in conjunction with the subtraction technique are discussed.
No related grants have been discovered for Sylvain Houle.