PET imaging of dopamine-D2 receptor internalization in schizophrenia.

Recent genetic, molecular and post-mortem studies suggest impaired dopamine (DA)-D2 receptor (D2R) trafficking in patients with schizophrenia (SZ). Imaging and preclinical studies have shown agonist-induced D2R internalization can be imaged with positron emission tomography (PET) using D2R radiotracers combined with psychostimulant challenge. This is feasible if radiotracer binding is measured when postchallenge DA levels have returned to baseline, following the initial competition phase between DA and radiotracer for binding to D2R. Here we used 'late-phase' imaging after challenge to test the hypothesis that impaired D2R internalization in SZ leads to blunted late-phase displacement, or a faster return to baseline, in patients compared with healthy controls (HCs). We imaged 10 patients with SZ and 9 HCs with PET and [11C]raclopride at baseline and two times (3-5 and 6-10 h) following 0.5 mg kg-1 dextroamphetamine. We measured binding potential relative to non-displaceable compartment (BPND) and derived percent reduction from baseline (ΔBPND) for each postamphetamine scan. To test the hypothesis that time course of return of striatal BPND to baseline differed between SZ and HCs, we implemented a linear model with ΔBPND as dependent variable, time after amphetamine as repeated measure and time after amphetamine and diagnostic group as fixed effects. Neither diagnostic group nor interaction of diagnostic group-by-time after amphetamine significantly affected striatal ΔBPND (F=1.38, P=0.26; F=0.51, P=0.61). These results show similar pattern of return of BPND to baseline as a function of time in patients with SZ and HC, suggesting that striatal D2R internalization as measured by our imaging paradigm is normal in patients with SZ.

PET imaging of dopamine-D2 receptor internalization in schizophrenia.

This corrects the article DOI: 10.1038/mp.2017.107.

Unexpectedly high affinity of a novel histamine H(3) receptor antagonist, GSK239512, in vivo in human brain, determined using PET.

BACKGROUND AND PURPOSE: This study aimed to investigate the relationship between the plasma concentration (PK) of the novel histamine H3 receptor antagonist, GSK239512, and the brain occupancy of H(3) receptors (RO) in healthy human volunteers. EXPERIMENTAL APPROACH: PET scans were obtained after i.v. administration of the H(3) -specific radioligand [(11) C]GSK189254. Each subject was scanned before and after single oral doses of GSK239512, at 4 and 24 h after dose. PET data were analysed by compartmental analysis, and regional RO estimates were obtained by graphical analysis of changes in the total volumes of distribution of the radioligand, followed by a correction for occupancy by the high affinity radioligand. The PK/RO relationship was analysed by a population-modelling approach, using the average PK of GSK239512 during each scan. KEY RESULTS: Following administration of GSK239512, there was a reduction in the brain uptake of [(11) C]GSK189254 in all regions, including cerebellum. RO at 4 h was higher than at 24 h, and the PK/RO model estimated a PK associated with 50% of RO of 0.0068 ng·mL(-1) . This corresponds to a free concentration of 4.50 × 10(-12 ) M (pK = 11.3). CONCLUSIONS AND IMPLICATIONS: The affinity of GSK239512 for brain H3 receptors in humans in vivo is much higher than that expected from studies in vitro, and higher than that observed in PET studies in pigs. The study illustrates the utility of carrying out PET studies in humans early in drug development, providing accurate quantification of GSK239512 RO in vivo as a function of time and dose.

Relationship between glycine transporter 1 inhibition as measured with positron emission tomography and changes in cognitive performances in nonhuman primates.

Several lines of evidence suggest that schizophrenia is associated with deficits in glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptors. Glycine is a NMDA receptor co-agonist, and extracellular levels of glycine are regulated in the forebrain by the glycine type-1 transporters (GlyT-1). GlyT-1 inhibitors elevate extracellular glycine and thus potentiate NMDA transmission. This mechanism represents a promising new avenue for the treatment of schizophrenia. Here, the recently introduced positron emission tomography radiotracer [11C]GSK931145 was used to quantify the relationship between occupancy of GlyT-1 by a GlyT-1 inhibitor, Org 25935, and its impact on spatial working memory performances in rhesus monkeys. The effect of Org 25935 on working memory was assessed both in control conditions and during a state of relative NMDA hypofunction induced by ketamine administration, at a dose selected for each animal to reduce task performance by about 50%. Under control conditions, Org 25935 had no effect on working memory at GlyT-1 occupancies lower than 75% and significantly impaired working memory at occupancies higher than 75%. Under ketamine conditions, Org 25935 reversed the deficit in working memory induced by ketamine and did so optimally in the 40-70% GlyT-1 occupancy range. The results confirm the efficacy of this mechanism to correct working memory deficits associated with NMDA hypofunction. These data also suggest the existence of an inverted-U dose-response curve in the potential therapeutic effect of this class of compounds.

Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD.

BACKGROUND: Atomoxetine (ATX), a drug for treatment of depression and ADHD, has a high affinity for the norepinephrine transporter (NET); however, our previous study showed it had a blocking effect similar to fluoxetine on binding of [(11)C]DASB, a selective serotonin transporter (SERT) ligand. Whether the therapeutic effects of ATX are due to inhibition of either or both transporters is not known. Here we report our comparative PET imaging studies with [(11)C]MRB (a NET ligand) and [(11)C]AFM (a SERT ligand) to evaluate in vivo IC50 values of ATX in monkeys. METHODS: Rhesus monkeys were scanned up to four times with each tracer with up to four doses of ATX. ATX or saline (placebo) infusion began 2h before each PET scan, lasting until the end of the 2-h scan. The final infusion rates were 0.01-0.12mg/kg/h and 0.045-1.054mg/kg/h for the NET and SERT studies, respectively. ATX plasma levels and metabolite-corrected arterial input functions were measured. Distribution volumes (VT) and IC50 values were estimated. RESULTS: ATX displayed dose-dependent occupancy on both NET and SERT, with a higher occupancy on NET: IC50 of 31±10 and 99±21ng/mL plasma for NET and SERT, respectively. At a clinically relevant dose (1.0-1.8mg/kg, approx. 300-600ng/mL plasma), ATX would occupy >90% of NET and >85% of SERT. This extrapolation assumes comparable free fraction of ATX in humans and non-human primates. CONCLUSION: Our data suggests that ATX at clinically relevant doses greatly occupies both NET and SERT. Thus, therapeutic modes of ATX action for treatment of depression and ADHD may be more complex than selective blockade of NET.

D-dimer cut-off adjusted to age performs better for exclusion of pulmonary embolism in patients over 75 years.

INTRODUCTION: A D-dimer (DD) test improves the diagnosis of PE (PE) when combined with clinical scores. However, as DD levels increase physiologically with age, this testing has less specificity in older patients. Douma et al. (1). proposed the use of an age adjusted DD cut-off to increase the specificity of this test. METHODS: We performed chart reviews of patients, older than 75 years, hospitalized for suspicion of PE in 2010-2011 (n = 165). PE was assessed with either pulmonary scintigraphy (PS, n = 64) and/or pulmonary computed tomography (PC, n = 101). We compared the specificity, sensitivity and false negatives rates of an age adjusted DD cut-off level ("ADC" = (patient's age x 0.01) microg/ml) with those of the conventional cut off level ("CDC" = 0.5 microg/ml). RESULTS: PE was confirmed in 45 cases. In the 120 patients with no PE (negative PS or PC), 7 cases had CDC below cut-off levels, while 28 cases had an ADC below cutoff level. The use of the ADC thus increased the specificity (ADC: 23% vs CDC: 6%, p = 0.0001), and this was obtained without significant loss of sensitivity (ADC: 96% vs CDC: 98%, ns). Patients were clinically assessed with the revised Geneva scores. In the negative PE group, the number of patients classified with low, moderate or high clinical probability of PE were 31, 81 and 8, respectively. The percentage of patients with DD values below cut-off values was 4%, 0.8% and 0.8%, respectively using the CDC and 9%, 12% and 2.5% using the ADC. CONCLUSIONS: In this age group, the specificity of ADC was found superior to that of the CDC. The clinical use of the ADC might be associated with less useless diagnosis procedures, without significant increase in rate of diagnosis failure.

Computerized cognitive remediation training for schizophrenia: an open label, multi-site, multinational methodology study.

A recent single-site study (Fisher et al., 2009. Am J Psychiatry. 166 (7) 805-11) showed that repeated training with the Brain Fitness Program (BFP) improved performance on a battery of neuropsychological tasks. If replicated these data suggest an important non-pharmacological method for ameliorating cognitive impairment in schizophrenia. Our study evaluated the BFP training effects in an open-label, multi-site, multinational clinical trial. Fifty-five stable adult patients with schizophrenia on regular antipsychotic medication completed ≥ 32 BFP training sessions over 8-10 weeks. Training effects on cognitive performance and functional capacity outcome measures were measured using CogState® schizophrenia battery, UCSD Performance based Skills Assessment (UPSA-2) and Cognitive Assessment Interview (CAI). BFP training showed a large and significant treatment effect on a training exercise task (auditory processing speed), however this effect did not generalize to improved performance on independent CogState® assessment. There were no significant effects on UPSA-2 or CAI scores. Our study demonstrated the feasibility of implementing BFP training in a multi-site study. However, BFP training did not show significant treatment effects on cognitive performance or functional capacity outcome measures despite showing large and significant effects on a training exercise.

Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C] DASB binding in the living human brain.

Studies in vitro suggest that the expression of the serotonin transporter (5-HTT) is regulated by polymorphic variation in the promoter region of the 5-HTT gene (5-HTTLPR); however, results from human brain imaging studies examining the relation between 5-HTT genotype and 5-HTT radioligand binding in vivo have been inconsistent. This inconsistency could reflect small participant numbers or the use of sub-optimal radiotracer for measuring the 5-HTT. We used positron emission tomography in conjunction with the selective 5-HTT ligand [(11)C] DASB to examine the availability of the 5-HTT in seven brain regions in 63 healthy European caucasian volunteers who were genotyped for short (S) and long (L) variants (SLC6A4 and rs25531) of the 5-HTTLPR. [(11)C] DASB binding potential was not influenced by the allelic status of participants whether classified on a biallelic or triallelic basis in any of the regions studied. Our PET findings, in a relatively large sample with a near optimal radiotracer, suggest that 5-HTTLPR polymorphic variation does not affect the availability of 5-HTT to [(11)C] DASB binding in adult human brain. The reported impact of 5-HTTLPR polymorphic variation on emotional processing and vulnerability to depression are more likely therefore to be expressed through effects exerted during neurodevelopment.

Identification and evaluation of [11C]GSK931145 as a novel ligand for imaging the type 1 glycine transporter with positron emission tomography.

The type-1 glycine transporter (GlyT1) is an important target for the development of new medications for schizophrenia. A specific and selective positron emission tomography (PET) GlyT1 ligand would facilitate drug development studies to determine whether a drug reaches this target and help establish suitable doses for clinical trials. This article describes the evaluation of three candidate GlyT1 PET radioligands (GSK931145, GSK565710, and GSK991022) selected from a library of compounds based on favorable physicochemical and pharmacological properties. Each candidate was successfully labeled using [(11)C]methyl iodide or [(11)C]methyl triflate and administered to a pig pre- and postadministration with a pharmacological dose of a GlyT1 inhibitor to determine their suitability as PET ligands in the porcine brain in vivo. All three candidate ligands were analyzed quantitatively with compartment analyses employing a plasma input function. [(11)C]GSK931145 showed good brain penetration and a heterogeneous distribution in agreement with reported GlyT1 localization. Following pretreatment with GSK565710, uptake of [(11)C]GSK931145 was reduced to homogeneous levels. Although [(11)C]GSK565710 also showed good brain penetration and a heterogeneous distribution, the apparent level of specific binding was reduced compared to [(11)C]GSK931145. In contrast, [(11)C]GSK991022 showed a much lower brain penetration and resultant signal following pretreatment with GSK565710. Based on these findings [(11)C]GSK931145 was identified as the most promising ligand for imaging GlyT1 in the porcine brain, possessing good brain penetration, specific signal, and reversible kinetics. [(11)C]GSK931145 is now being progressed into higher species.

Impact of scatter correction on D2 receptor occupancy measurements using 123I-IBZM SPECT: comparison to 11C-Raclopride PET.

Reported values of D(2) receptor occupancy (RO) achieved by antipsychotic drugs tend to be lower when measured with (123)I-IBZM SPECT than with (11)C-Raclopride PET. Image degrading factors such as attenuation, distance-dependent collimator response and scatter could account for this difference. While attenuation correction is routinely applied to SPECT images, the other degradations are not usually accounted for. The aim of this work was to assess the impact of scatter correction on D(2) RO quantification with (123)I-IBZM SPECT, and to compare the results of both corrected and un-corrected SPECT values with (11)C-Raclopride PET measurements. Phantom experiments as well as within-subject human data from a previous study were used for this purpose. SPECT images were reconstructed using filtered back-projection including attenuation correction (FBP(A)), ordered subsets expectation maximization including attenuation and point spread function corrections (OSEM(A+PSF)) and ordered subsets expectation maximization including attenuation, point spread function and scatter corrections (OSEM(A+PSF+SCT)). PET images were reconstructed using the FBP algorithm and corrected for attenuation, scatter, random coincidences and dead time. Quantification of receptor availability was performed using the tissue ratio at pseudoequilibrium for SPECT, and the simplified reference tissue model (SRTM) for PET. Analysis was performed using both occipital cortex (occ) and cerebellum (cer) as reference regions for both modalities. When images were reconstructed using FBP(A), SPECT D(2) RO values were significantly lower as compared with PET leading to a D(2) RO difference of -20% (CI(95%): -13, -27%) (occ) and -23% (CI(95%): -14, -31%) (cer). When images were reconstructed using OSEM(A+PSF), SPECT D(2) RO values were also lower as compared with PET leading to a D(2) RO difference of -21% (CI(95%): -14, -27%) (occ) and -24% (CI(95%): -18, -30%) (cer). When images were reconstructed using OSEM(A+PSF+SCT), the D(2) RO bias was reduced to -6% (CI(95%): 0, -13%) (occ) and -11% (CI(95%): -4, -18%) (cer). These data suggest that the scatter correction plays a major role in explaining the differences between D(2) RO measurements using (123)I-IBZM SPECT and (11)C-Raclopride PET.

COMT genotype predicts cortical-limbic D1 receptor availability measured with [11C]NNC112 and PET.

A common polymorphism (val158met) in the gene encoding catechol-O-methyltransferase (COMT) has been shown to affect dopamine (DA) tone in cortex and cortical functioning. D1 receptors are the main DA receptors in the cortex, and studies have shown that decreased levels of cortical DA are associated with upregulation of D1 receptor availability, as measured with the positron-emission tomography (PET) radiotracer [11C]NNC112. We compared [11C]NNC 112 binding in healthy volunteers homozygous for the Val allele compared with Met carriers. Subjects were otherwise matched for parameters known to affect [11C]NNC 112 binding. Subjects with Val/Val alleles had significantly higher cortical [11C]NNC 112 binding compared with Met carriers, but did not differ in striatal binding. These results confirm the prominent role of COMT in regulating DA transmission in cortex but not striatum, and the reliability of [11C]NNC 112 as a marker for low DA tone as previously suggested by studies in patients with schizophrenia.

Occupancy of dopamine D2 receptors by the atypical antipsychotic drugs risperidone and olanzapine: theoretical implications.

RATIONALE: To examine the D2 occupancy of two commonly used antipsychotic medications and relate this to the D2 occupancy by endogenous dopamine in schizophrenia. OBJECTIVES: The aim of this study is to compare the occupancy of striatal D2 receptors by the atypical antipsychotic medications risperidone and olanzapine at fixed dosages and to estimate the effect on D2 occupancy by dopamine as a result of these treatments. METHODS: Seven patients with schizophrenia taking risperidone 6 mg/day and nine patients with schizophrenia taking olanzapine 10 mg/day underwent an [123I]IBZM SPECT scan after 3 weeks of treatment. The specific to non-specific equilibrium partition coefficient (V3") after bolus plus constant infusion of the tracer was calculated as [(striatal activity)/(cerebellar activity)]-1. D2 receptor occupancy was calculated by comparing V3" measured in treated patients to an age-corrected V3" value derived from a group of untreated patients with schizophrenia, previously published, according to the following formula: OCC=1-(V3" treated/V3" drug free). RESULTS: V3" was significantly lower in risperidone treated patients compared with olanzapine treated patients (0.23+/-0.06 versus 0.34+/-0.08, P=-0.01), which translated to a significantly larger occupancy in schizophrenic patients treated with risperidone compared to olanzapine (69+/-8% versus 55 +/-11%, P=0.01). Data from our previous study were used to calculate the occupancy of striatal D2 receptors by antipsychotic medications required to reduce the occupancy of these receptors by endogenous dopamine to control values. In medication-free patients with schizophrenia, the occupancy of striatal D2 receptors by endogenous dopamine is estimated at 15.8%. In healthy controls, the occupancy of striatal D2 receptors by dopamine is estimated at 8.8%. In order to reduce the dopamine occupancy of striatal D2 receptors in patients with schizophrenia to control values, 48% receptor occupancy by antipsychotic medications is required. CONCLUSIONS: These data indicate that the dosage of these medications, found to be effective in the treatment of schizophrenia, reduces DA stimulation of D2 receptors to levels slightly lower than those found in unmedicated healthy subjects.

In vivo evaluation of [11C]-3-[2-[(3-methoxyphenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2-carboxylic acid ([11C]3MPICA) as a PET radiotracer for the glycine site of the NMDA ion channel.

Alterations in normal NMDA receptor composition, densities and function have been implicated in the pathophysiology of certain neurological and neuropsychiatric disorders such as Parkinson's Disease, Huntington's Chorea, schizophrenia, alcoholism and stroke. In our first effort to provide PET ligands for the NMDA/glycine site, we reported the synthesis of a novel high affinity glycine site ligand, 3-[2-[(3-methoxyphenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2-carboxylic acid ((3MPICA), Ki = 4.8 +/- 0.9 nM) and the corresponding carbon-11 labeled PET ligand, [11C]3MPICA. We report here the in vivo evaluation of [11C]3MPICA in rats. Biodistribution analysis revealed that [11C]3MPICA exhibited low degree of brain penetration and high blood concentration. The average uptake at two minutes was highest in the cerebellum (0.19 +/- 0.04 %ID/g) and thalamus (0.18 +/- 0.05 %ID/g) and lower in the hippocampus (0.13 +/- 0.03) and frontal cortex (0.11 +/- 0.04 %ID/g). The radioactivity cleared quickly from all brain regions examined. Administration of unlabeled 3MPICA (1 mg/kg, i.v.) revealed at 60 minutes a small general reduction in regional brain radioactivity concentrations in treated animals versus controls, however, the blood radioactivity concentration was also lowered, confounding the assessment of the degree of saturable binding. Warfarin co-administration (100 mg/kg, i.v.) significantly lowered blood activity at 5 minutes post-injection (-27%, P < 0.01) but failed to significantly increase the brain uptake of the radiotracer. In view of these results, and especially considering the low brain penetration of this tracer, [11C]3MPICA does not appear to be a promising PET radiotracer for in vivo use.

Imaging neurochemical endophenotypes: promises and pitfalls.

A large number of polymorphisms in genes coding for neurotransmitter receptors and transporters have been associated with neuropsychiatric conditions, although few of these associations have been consistently replicated. These proteins are critical targets of psychoactive drugs and the clarification of the functional significance of these polymorphisms might offer important leads for drug development and therapeutic applications. Brain imaging techniques such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) provide the means to monitor the expression and function of many of these proteins in the living human brain. This paper reviews brain imaging studies designed to evaluate the significance of polymorphisms in genes coding for important drug targets (e.g., the serotonin transporter [SERT], the dopamine transporter [DAT] and the dopamine D(2) receptor) in terms of expression or function. These studies illustrate the unique opportunities, as well as the pitfalls, generated by combining genetic analysis with brain imaging studies.

Dopamine D(2) receptor availability and amphetamine-induced dopamine release in unipolar depression.

BACKGROUND: Reduced dopaminergic transmission has been implicated in the pathophysiology of major depression. The aim of the present study was to measure striatal D(2) receptor availability and amphetamine-induced dopamine release in nonpsychotic, unmedicated, unipolar patients during an episode of major depression. METHODS: The striatal equilibrium specific to nonspecific partition coefficient (V(3)") of the D(2) receptor antagonist [(123)I]IBZM was measured with single photon emission computerized tomography before and after amphetamine administration in 9 depressed subjects and 10 matched healthy control subjects. RESULTS: No significant differences were observed in preamphetamine D(2) receptor availability between depressed patients (0.73 +/- 0.08) and control subjects (0.78 +/- 0.10, p =.23). Amphetamine-induced reduction in [(123)I]IBZM V(3)" (DeltaV(3)") was similar in depressed patients (-9.8 +/- 5.5%) and control subjects (-7.8 +/- 2.5%, p =.32). Amphetamine induced a transient improvement in symptomatology in depressed patients, but this improvement did not correlate with [(123)I]IBZM DeltaV(3)". CONCLUSIONS: This study did not replicate previously reported alterations in striatal D(2) receptor density in depressed patients and suggests that stimulant-induced dopamine release is not altered in major depression.

Models and methods for derivation of in vivo neuroreceptor parameters with PET and SPECT reversible radiotracers.

The science of quantitative analysis of PET and SPECT neuroreceptor imaging studies has grown considerably over the past decade. A number of methods have been proposed in which receptor parameter estimation results from fitting data to a model of the underlying kinetics of ligand uptake in the brain. These approaches have come to be collectively known as model-based methods and several have received widespread use. Here, we briefly review the most frequently used methods and examine their strengths and weaknesses. Kinetic modeling is the most direct implementation of the compartment models, but with some tracers accurate input function measurement and good compartment configuration identification can be difficult to obtain. Other methods were designed to overcome some particular vulnerability to error of classical kinetic modeling, but introduced new vulnerabilities in the process. Reference region methods obviate the need for arterial plasma measurement, but are not as robust to violations of the underlying modeling assumptions as methods using the arterial input function. Graphical methods give estimates of V(T) without the requirement of compartment model specification, but provide a biased estimator in the presence of statistical noise. True equilibrium methods are quite robust, but their use is limited to experiments with tracers that are suitable for constant infusion. In conclusion, there is no universally "best" method that is applicable to all neuroreceptor imaging studies, and carefully evaluation of model-based methods is required for each radiotracer.

Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum.

Dopamine transmission in the ventral striatum (VST), a structure which includes the nucleus accumbens, ventral caudate, and ventral putamen, plays a critical role in the pathophysiology of psychotic states and in the reinforcing effects of virtually all drugs of abuse. The aim of this study was to assess the accuracy and precision of measurements of D(2) receptor availability in the VST obtained with positron emission tomography on the high-resolution ECAT EXACT HR+ scanner (Siemens Medical Systems, Knoxville, TN, U.S.A.). A method was developed for identification of the boundaries of the VST on coregistered high-resolution magnetic resonance imaging scans. Specific-to-nonspecific partition coefficient (V(3)") and binding potential (BP) of [(11)C]raclopride were measured twice in 10 subjects, using the bolus plus constant infusion method. [(11)C]Raclopride V(3)" in the VST (1.86 +/- 0.29) was significantly lower than in the dorsal caudate (DCA, 2.33 +/- 0.28) and dorsal putamen (DPU, 2.99 +/- 0.26), an observation consistent with postmortem studies. The reproducibility of V(3)" and BP were appropriate and similar in VST (V(3)" test-retest variability of 8.2% +/- 6.2%, intraclass correlation coefficient = 0.83), DCA (7.7% +/- 5.1%, 0.77), DPU (6.0% +/- 4.1%, 0.71), and striatum as a whole (6.3% +/- 4.1%, 0.78). Partial volume effects analysis revealed that activities in the VST were significantly contaminated by counts spilling over from the adjacent DCA and DPU: 70% +/- 5% of the specific binding measured in the VST originated from D(2) receptors located in the VST, whereas 12% +/- 3% and 18% +/- 3% were contributed by D(2) receptors in the DCA and DPU, respectively. Thus, accuracy of D(2) receptor measurement is improved by correction for partial voluming effects. The demonstration of an appropriate accuracy and precision of D(2) receptor measurement with [(11)C]raclopride in the VST is the first critical step toward the use of this ligand in the study of synaptic dopamine transmission at D(2) receptors in the VST using endogenous competition techniques.

Vulnerability of positron emission tomography radiotracers to endogenous competition. New insights.

PET and SPECT neuroreceptor imaging techniques combined with pharmacological challenges have been introduced to measure acute fluctuations of synaptic dopamine (DA) concentrations in the living human brain. Changes in the in vivo binding of radioligands following manipulation of transmitter levels are generally believed to be driven by binding competition between the radioligand and neurotransmitter. This imaging modalityhas been very successful in the study of DA transmission at D2 receptors. Yet, the extension of this technique to the study of other neurotransmitter systems has proven difficult. This paper reviews recent evidencesuggesting that simple binding competition might not be the only phenomenon regulating transmitter-radioligand interactions in vivo, and examines emerging data indicating that receptor trafficking might also be involved. A better understanding of the mechanisms underlying these interactions should facilitate the development of PET and SPECT radiotracers suitable for the reporting of synaptic transmitter levels.

Synthesis of potent and selective dopamine D(4) antagonists as candidate radioligands.

A series of dopamine D(4) antagonists was synthesized and evaluated as potential candidates for development as positron emission tomography (PET) radioligands. All new compounds display high affinity and selectivity for the D(4) receptors and compounds 5b, 5d, and 5e were identified as candidates for radioligand development.

How does pindolol improve antidepressant action?

Since 1994, the beta-adrenoceptor and 5-HT(1A/1B) receptor ligand pindolol has been used to accelerate or enhance the clinical effects of antidepressant drugs, such as the selective 5-HT reuptake inhibitors (SSRIs), that act primarily on 5-HT-containing neurones. Pindolol was initially thought to act by preventing the inhibition of 5-HT release, elicited by SSRIs and other 5-HT-acting drugs, as a result of its ability to antagonize the action of 5-HT at midbrain raphe 5-HT(1A) autoreceptors that control the activity of ascending 5-HT-mediated pathways. However, the partial agonist properties of pindolol at 5-HT(1A) receptors and beta-adrenoceptors suggest that other explanations for its action are also possible. In this article, recent controversial data on the mechanism of action of pindolol, which are crucial for the development of more rapid and efficient antidepressant therapies, will be discussed.