Altered Serotonin 1B Receptor Binding After Escitalopram for Depression Is Correlated With Treatment Effect.

BACKGROUND: Major depressive disorder (MDD) is commonly treated with selective serotonin reuptake inhibitors (SSRIs). SSRIs inhibit the serotonin transporter (5-HTT), but the downstream antidepressant mechanism of action of these drugs is poorly understood. The serotonin 1B (5-HT1B) receptor is functionally linked to 5-HTT and 5-HT1B receptor binding and 5-HT1B receptor mRNA is reduced in the raphe nuclei after SSRI administration in primates and rodents, respectively. The effect of SSRI treatment on 5-HT1B receptor binding in patients with MDD has not been examined previously. This positron emission tomography (PET) study aimed to quantify brain 5-HT1B receptor binding changes in vivo after SSRI treatment for MDD in relation to treatment effect. METHODS: Eight unmedicated patients with moderate to severe MDD underwent PET with the 5-HT1B receptor radioligand [11C]AZ10419369 before and after 3 to 4 weeks of treatment with the SSRI escitalopram 10 mg daily. Depression severity was assessed at time of PET and after 6 to 7 weeks of treatment with the Montgomery-Åsberg Depression Rating Scale. RESULTS: We observed a significant reduction in [11C]AZ10419369 binding in a dorsal brainstem (DBS) region containing the median and dorsal raphe nuclei after escitalopram treatment (P = .036). Change in DBS [11C]AZ10419369 binding correlated with Montgomery-Åsberg Depression Rating Scale reduction after 3-4 (r = 0.78, P = .021) and 6-7 (r = 0.94, P < .001) weeks' treatment. CONCLUSIONS: Our findings align with the previously reported reduction of 5-HT1B receptor binding in the raphe nuclei after SSRI administration and support future studies testing change in DBS 5-HT1B receptor binding as an SSRI treatment response marker.

Disease activity in rheumatoid arthritis is inversely related to cerebral TSPO binding assessed by [11C]PBR28 positron emission tomography.

Reumatoid Arthritis (RA) is an autoimmune disorder characterized by peripheral joint inflammation. Recently, an engagement of the brain immune system has been proposed. The aim with the current investigation was to study the glial cell activation marker translocator protein (TSPO) in a well characterized cohort of RA patients and to relate it to disease activity, peripheral markers of inflammation and autonomic activity. Fifteen RA patients and fifteen healthy controls matched for age, sex and TSPO genotype (rs6971) were included in the study. TSPO was measured using Positron emission tomography (PET) and the radioligand [11C]PBR28. The outcome measure was total distribution volume (VT) estimated using Logan graphical analysis, with grey matter (GM) as the primary region of interest. Additional regions of interest analyses as well as voxel-wise analyses were also performed. Clinical evaluation of disease activity, symptom assessments, serum analyses of cytokines and heart rate variability (HRV) analysis of 24 h ambulatory ECG were performed in all subjects. There were no statistically significant group differences in TSPO binding, either when using the primary outcome VT or when normalizing VT to the lateral occipital cortex (p > 0.05). RA patients had numerically lower VT values than healthy controls (Cohen's D for GM = -0.21). In the RA group, there was a strong negative correlation between [11C]PBR28 VT in GM and disease activity (DAS28)(r = -0.745, p = 0.002, corrected for rs6971 genotype). Higher serum levels of IFNγ and TNF-α were found in RA patients compared to controls (p < 0.05) and several measures of autonomic activity showed significant differences between RA and controls (p < 0.05). However, no associations between markers of systemic inflammation or autonomic activity and cerebral TSPO binding were found. In conclusion, no statistically significant group differences in TSPO binding as measured with [11C]PBR28 PET were detected. Within the RA group, lower cerebral TSPO binding was associated with higher disease activity, suggesting that cerebral TSPO expression may be related to disease modifying mechanisms in RA. In light of the earlier confirmed neuro-immune features of RA, these results warrant further investigations regarding neuro-immune joint-to-CNS signalling to open up for potentially new treatment strategies.

Increased number of monocytes and plasma levels of MCP-1 and YKL-40 in first-episode psychosis.

OBJECTIVE: Accumulating evidence implicates immune activation in the development of schizophrenia. Here, monocyte numbers, monocyte chemoattractant protein-1 (MCP-1) and chitinase-3-like protein 1 (YKL-40) were investigated in plasma and cerebrospinal fluid (CSF) in first-episode psychosis (FEP) patients. METHOD: CSF and blood were sampled from 42 first-episode psychosis (FEP) patients and 22 healthy controls. The levels of YKL-40 and MCP-1 were measured using electrochemiluminescence assay, and blood monocytes were counted using an XN-9000-hematology analyzer. RESULTS: We found higher plasma levels of MCP-1 and YKL-40 in FEP patients compared with healthy controls, a condition that was unrelated to antipsychotic and/or anxiolytic medication. This was combined with an increased number of blood monocytes and a borderline significant increase in YKL-40 levels in the CSF of tobacco-free FEP patients. Plasma or CSF chemokines or blood monocytes did not correlate with the severity of symptoms or the level of functioning. CONCLUSION: These data demonstrate activation of monocytes in FEP and strengthens the idea of an immune dysfunction of psychotic disorders. Further studies are required to perceive a role of YKL-40 and MCP-1 in the initiation and progression of schizophrenia.

Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [11C]PBR28.

Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [11C]PBR28. Gray matter (GM) volume of distribution (VT) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [11C]PBR28 binding, and gender. There was a significant reduction of [11C]PBR28 VT in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM VT and clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia.

Mapping the distribution of serotonin transporter in the human brainstem with high-resolution PET: Validation using postmortem autoradiography data.

The human brainstem is a complex structure with several small nuclei and neural pathways of interest in the pathophysiology of central nervous system (CNS) disorders. In common with other monoaminergic systems, serotoninergic neurons originate from a group of nuclei located in the brainstem. The present study was designed to validate a user-independent approach for a detailed in vivo quantification of serotonin transporter (5-HTT) availability in the human brainstem using a template-based approach that consisted of three steps. First, 3T-MR images and parametric binding potential (BPND) [(11)C]MADAM images of ten healthy subjects were used to generate a PET template of 5-HTT availability. In the second step, volumes of interest (VOIs) for different brainstem nuclei were obtained using a method in which VOIs are initially delineated on MRI images using anatomical landmarks and then are finally tailored on the distribution of 5-HTT binding using a thresholding approach applied to the 5-HTT template. In the final step, the VOIs were transformed and applied individually to BPND images of 16 healthy subjects (14M/2F, 20-64years). The in vivo distribution of BPND values obtained with the template-based method were in good agreement with an individual-based approach taken as gold standard. Results were also in agreement with 5-HTT quantification using in vitro binding data obtained with autoradiography (ARG) studies using [(3)H]MADAM. The proposed template-based method can be applied to PET data acquired in several CNS disorders in which serotonin neurons in the brainstem might be affected.

Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain.

The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about the regulation of receptor and transporter density levels. This lack of knowledge obscures interpretation of differences in protein availability reported in psychiatric patients. In this study, we used positron emission tomography (PET) in a twin design to estimate the relative contribution of genetic and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [(11)C]raclopride binding to the D2- and D3-dopamine receptor and [(11)C]WAY100635 binding to the serotonin 5-HT1A receptor. Heritability, shared environmental effects and individual-specific non-shared effects were estimated for regional D2/3 and 5-HT1A receptor availability in projection areas. We found a major contribution of genetic factors (0.67) on individual variability in striatal D2/3 receptor binding and a major contribution of environmental factors (pairwise shared and unique individual; 0.70-0.75) on neocortical 5-HT1A receptor binding. Our findings indicate that individual variation in neuroreceptor availability in the adult brain is the end point of a nature-nurture interplay, and call for increased efforts to identify not only the genetic but also the environmental factors that influence neurotransmission in health and disease.

Test-retest reproducibility of [(11)C]PBR28 binding to TSPO in healthy control subjects.

PURPOSE: The PET radioligand [(11)C]PBR28 binds to the translocator protein (TSPO), a marker of brain immune activation. We examined the reproducibility of [(11)C]PBR28 binding in healthy subjects with quantification on a regional and voxel-by-voxel basis. In addition, we performed a preliminary analysis of diurnal changes in TSPO availability. METHODS: Twelve subjects were examined using a high-resolution research tomograph and [(11)C]PBR28, six in the morning and afternoon of the same day, and six in the morning on two separate days. Regional volumes of distribution (V T) were derived using a region-of-interest based two-tissue compartmental analysis (2TCM), as well as a parametric approach. Metabolite-corrected arterial plasma was used as input function. RESULTS: For the whole sample, the mean absolute variability in V T in the grey matter (GM) was 18.3 ± 12.7 %. Intraclass correlation coefficients in GM regions ranged from 0.90 to 0.94. Reducing the time of analysis from 91 to 63 min yielded a variability of 16.9 ± 14.9 %. There was a strong correlation between the parametric and 2TCM-derived GM values (r = 0.99). A significant increase in GM V T was observed between the morning and afternoon examinations when using secondary methods of quantification (p = 0.028). In the subjects examined at the same time of the day, the absolute variability was 15.9 ± 12.2 % for the 91-min 2TCM data. CONCLUSION: V T of [(11)C]PBR28 binding showed medium reproducibility and high reliability in GM regions. Our findings support the use of parametric approaches for determining [(11)C]PBR28 V T values, and indicate that the acquisition time could be shortened. Diurnal changes in TSPO binding in the brain may be a potential confounder in clinical studies and should be investigated further.

The dopamine D1 receptor agonist (S)-[¹¹C]N-methyl-NNC 01-0259 is not sensitive to changes in dopamine concentration--a positron emission tomography examination in the monkey brain.

Dopamine D2 receptor positron emission tomography (PET) radioligands have proven useful for indirect assessment of the endogenous dopamine concentration in the living brain. On the contrary, dopamine D1 receptor antagonist radioligands have shown no sensitivity to changes in the dopamine concentration. A recent approach to enhance the sensitivity of radioligands to the dopamine concentration has been the development of dopamine D2 receptor agonist radioligands. The aim of this study was to evaluate the dopamine sensitivity of a dopamine D1 receptor agonist radioligand. For this purpose, we developed (S)-[¹¹C]N-methyl-NNC 01-0259 ((S)-[¹¹C]1) and characterized the receptor binding of (S)-[¹¹C]1 using in vitro receptor binding assays and in vivo PET measurements in monkeys. In vitro, both enantiomers of 1 were partial dopamine D1 receptor agonists, with (S)-1 having a 10-50 times higher affinity than (R)-1. PET studies in monkey confirmed the stereoselectivity of [¹¹C]1 in vivo. In monkey, administration of the dopamine D1-like receptor antagonist (R)-(+)-SCH 23390 decreased the striatal binding potential of (S)-[¹¹C]1 by 97%, but administration of the dopamine concentration enhancer d-amphetamine did not affect (S)-[¹¹C]1 binding. We conclude that the agonist (S)-[¹¹C]1 provides specific binding to dopamine D1-like receptors, possibly representing binding to the high-affinity state of the receptors. The partial dopamine D1 receptor agonist radioligand has, however, no enhanced sensitivity to endogenous dopamine concentrations in comparison with antagonist radioligands.

Fenfluramine-induced serotonin release decreases [11C]AZ10419369 binding to 5-HT1B-receptors in the primate brain.

The need for positron emission tomography (PET)-radioligands that are sensitive to changes in endogenous serotonin (5-HT) levels in brain is recognized in experimental and clinical psychiatric research. We recently developed the novel PET radioligand [(11)C]AZ10419369 that is highly selective for the 5-HT(1B) receptor. In this PET-study in three cynomolgus monkeys, we examined the sensitivity of [(11)C]AZ10419369 to altered endogenous 5-HT levels. Fenfluramine-induced 5-HT release decreased radioligand binding in a dose-dependent fashion with a regional average of 27% after 1 mg/kg and 50% after 5 mg/kg. This preliminary study supports that [(11)C]AZ10419369 is sensitive to endogenous 5-HT levels in vivo and may serve as a tool to examine the pathophysiology and treatment of major psychiatric disorders.

Age-related reduction in dopamine D1 receptors in the human brain: from late childhood to adulthood, a positron emission tomography study.

Age-dependent decrease in dopamine receptor density throughout adulthood is well described, meanwhile less is known about development of dopamine system in humans and in vivo it has not been investigated. We examined dopamine D1 receptor (D1DR) binding in the cerebral cortex and striatum of 12 adolescents (mean age 13.5+/-1.8 years) and 18 young adults (25+/-2.3 years) using positron emission tomography (PET) and radioligand [(11)C]SCH23390. Over the age span of 10-30 years [(11)C]SCH23390 binding (binding potential, BP) declined in all brain regions. The rate of BP decline was age-segment and brain region dependent. Most pronounced decline in BP was observed in the cortical regions during adolescence (mean BP in adults lower by 14-26% as compared to adolescents, P<0.0001). Significantly slower rate of decline in BP was observed in two cortical regions (orbitofrontal and posterior cingulate cortices) and striatal regions. The present PET-study provides new evidence on the development of D1DR in humans in vivo which is of critical importance for understanding of the biology of neurodevelopmental disorders.

Age-related loss of olfactory sensitivity: association to dopamine transporter binding in putamen.

The relationship between age-related reductions in the binding potential for the striatal dopamine transporter (DAT) and age-related deficits in olfactory sensitivity was examined in 12 subjects ranging from 36 to 82 years of age. Positron emission tomography (PET) and the radioligand [(11)C]beta-CIT-FE were used to determine DAT binding in two striatal regions, the caudate and the putamen. The results showed age-related losses of DAT binding from early to late adulthood of similar size for caudate and putamen, and there was a pronounced age deterioration in olfactory sensitivity. Importantly, the age-related olfactory deficit was associated with reductions in DAT binding in putamen, but not caudate. Also, DAT binding in putamen added systematic variance in odor threshold after controlling for age. The findings indicate that DAT binding in putamen is related to age-related olfactory deficits, as well as to odor sensitivity independently of age.

Transcription factor AP-2beta genotype, striatal dopamine D2 receptor density and cerebrospinal fluid monoamine metabolite concentrations in humans.

Transcription factor AP-2beta has been suggested to influence brain monoaminergic systems by regulating target genes. In order to explore a possible functional role, AP-2beta genotype was analysed in relation to striatal dopamine D2 receptor density determined in vivo by positron emission tomography in human subjects (n = 52). The AP-2beta genotype was also analysed in relation to cerebrospinal fluid (CSF) concentrations of homovanillic acid (HVA), 3-methoxy-4-hydroxy-phenylglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA) in healthy human subjects (n = 90). There was no association between the AP-2beta genotype and measures of dopamine receptor density, or CSF 5-HIAA concentrations. However, AP-2beta genotype was associated with CSF-levels of HVA (in women) and MHPG. These data may suggest a functional involvement of AP-2beta in the dopaminergic system, but should be interpreted with caution until replicated.

Limbic reductions of 5-HT1A receptor binding in human temporal lobe epilepsy.

OBJECTIVE: To test the hypothesis that in mesial temporal lobe epilepsy (MTLE) there is involvement outside of mesial structures and that this involvement affects serotonin systems, thus suggesting a mechanism for affective symptoms in this population. METHODS: Serotonin 5-HT1A receptor binding was studied with PET and [Carbonyl-11C]WAY-100 635 in 14 patients (6 with left-, 8 with right-sided mesial temporal lobe focus) and 14 controls. The 5-HT1A receptor binding potential was calculated for hippocampus, amygdala, orbitofrontal, insular, lateral temporal, and anterior cingulate cortex, in raphe nuclei, and in two regions presumably uninvolved in the epileptogenic process (parietal, and dorsolateral frontal neocortex). RESULTS: The binding potential was reduced in the epileptogenic hippocampus (p = 0.0001) and amygdala (p = 0.0001) in all patients, including the six with normal [18F]FDG PET and MRI. It was also reduced in the anterior cingulate (p = 0.002), insular (p = 0.015), and lateral temporal cortex (p = 0.029) ipsilaterally to the focus, in contralateral hippocampus (p = 0.025), and in the raphe nuclei (p = 0.016). CONCLUSION: Patients with severe MTLE show reduced 5-HT1A receptor binding potential in the EEG-focus, and its limbic connections. [(11)C]WAY-100 635 PET may provide additional information to EEG, [18F]FDG PET, and MRI when evaluating patients with intractable seizures. Reductions in 5-HT1A binding in the insula and cingulate suggest a mechanism by which affective symptoms in MTLE may result.

PET studies on the brain uptake and regional distribution of [11C]vinpocetine in human subjects.

OBJECTIVES: Vinpocetine is a compound widely used in the prevention and treatment of cerebrovascular diseases. It is still not clear whether the drug has a direct and specific effect on neurotransmission or its effects are due to extracerebral actions, such as changes in cerebral blood flow. The main objective of the present investigation was to determine the global uptake and regional distribution of radiolabelled vinpocetine in the human brain in order to explore whether it may have direct central nervous system effects. MATERIAL AND METHODS: Three healthy subjects were examined with positron emission tomography and [11C]vinpocetine. The regional uptake was determined in anatomically defined volumes-of-interest. The fractions of [11C]vinpocetine and labelled metabolites in plasma were determined using high pressure liquid chromatography. RESULTS: The uptake of [11C]vinpocetine in brain was rapid and 3.7% (mean; n = 4) of the total radioactivity injected was in brain 2 min after radioligand administration. The uptake was heterogeneously distributed among brain regions. When compared with the cerebellum, an a priori reference region, the highest regional uptake was in the thalamus, upper brain stem, striatum and cortex. Following an initial peak, the total concentration of radioactivity in blood was relatively stable with time, whereas the concentration of the unchanged compound decreased with time in an exponential manner. CONCLUSION: Vinpocetine, administered intravenously in humans, readily passes the blood-brain barrier and enters the brain. Its regional uptake and distribution in the brain is heterogeneous, indicating binding to specific sites. The brain regions showing increased uptake in the human brain correspond to those in which vinpocetine has been shown to induce elevated metabolism and blood flow. These observations support the hypothesis that vinpocetine has direct neuronal actions in the human brain.

Autoradiographic evaluation of [11C]vinpocetine binding in the human postmortem brain.

The main objective ofthe study was to evaluate with autoradiographic technique whether or not [11C]vinpocetine, a compound widely used in the prevention and treatment of cerebrovascular diseases (Cavinton, Gedeon Richter Ltd., Budapest), binds to specific sites in the human brain in post mortem human brain sections. Binding was assessed under four conditions: the incubation was performed using Tris-HCl buffer with or without the addition of salts (0.1% (weight/vol) ascorbic acid, 120 mM NaCl, 5 mM KCl, 2 mM CaCl2 and 1 mM MgCl2), with or without the addition of excess (10 microM) unlabelled vinpocetine. Measurements on digitized autoradiograms indicated that [11C]vinpocetine labelled all grey matter areas in the human brain to a similar extent and no significantly heterogeneous binding could be demonstrated among cortical or subcortical regions. The addition of excess unlabelled vinpocetine lowered the binding slightly in all regions. Although these results indicate that [11C]vinpocetine does not bind to human brain transmitter receptors or transporters with a high affinity (Ki < 10 nM), it cannot be ruled out that the compound binds to receptors and/or transporters with lower affinity.

Reproducibility of [11 C]FLB 457 binding in extrastriatal regions.

Extrastriatal D2 dopamine receptors represent an important target of research into the pathophysiology and pharmacotherapy of psychiatric disorders. The high affinity radioligand [11C]FLB 457 makes possible the measurement of low concentrations of D2 receptors in extrastriatal regions using positron emission tomography (PET). The aim of this study was to assess the test/retest variability and reliability of [11C]FLB 457 binding using a reference tissue model. Eight healthy male subjects (aged 20-33 years) underwent two [11C]FLB 457 PET examinations. Radioactivity in the cerebellum was used as the reference. The binding potentials (BPs) for five cortical regions of interest (ROIs) were calculated using the reference tissue model. The BP was also calculated for each pixel in the form of parametric images. Reproducibility was assessed both for the ROI method and for the parametric images. The test/retest reproducibility for [11C]FLB 457 binding was good, with a mean variability ranging from 4.5% for the thalamus to 15.5% for the hippocampus. The parametric images also demonstrated good reproducibility. These results support the suitability of using [11C]FLB 457 for the quantitative evaluation of extrastriatal D2 receptors and for protocols requiring repeated measurements in the same individual.

Potentials and pitfalls using high affinity radioligands in PET and SPET determinations on regional drug induced D2 receptor occupancy--a simulation study based on experimental data.

The D2 dopamine receptor density ranges from 0.2 to 40 nM among human brain regions. For high density regions radioligands like [(11)C]raclopride provide accurate and reliable estimates of the receptor density. In research on neuropsychiatric disorders there is, however, a growing need for quantitative approaches that accurately measure D2 dopamine receptor occupancy induced by drugs or endogenous dopamine in regions with low receptor density. The new high affinity radioligands [(11)C]FLB 457 and [(123)I]epidepride have been shown to provide a signal for extrasriatal D2 dopamine receptor populations in the human brain in vivo. Initial observations indicate, however, that the time required to reach equilibrium is dependent on receptor density. Ratio analyses may thus not be readily used for comparisons among different brain regions. The aim of the present simulation study was to examine commonly used approaches for calculation of drug induced D2 dopamine receptor occupancy among regions with widely different receptor density. The input functions and the rate constants of [(11)C]FLB 457 and the reference ligand [(11)C]raclopride were first used in a simulation estimating the effect of receptor density on equilibrium time. In a second step we examined how errors produced by inaccurate determination of the binding potential parameter propagate to calculations of drug induced receptor occupancy. The simulations showed a marked effect of receptor density on equilibrium time for [(11)C]FLB 457, but not for [(11)C]raclopride. For [(11)C]FLB 457, a receptor density above about 7 nM caused the time of equilibrium to fall beyond time of data acquisition (1 h). The use of preequilibrium data caused the peak equilibrium and the end time ratio approaches but not the simplified reference tissue model (SRTM) approach to underestimate the binding potential and thus also the drug occupancy calculated for high-density regions. The study supports the use of ratio and SRTM analyses in extrastriatal low-density receptor regions for which the high affinity ligand [(11)C]FLB 457 was developed. However, in high-density regions such as the human striatum simple ratio approaches cannot be validly applied, whereas the SRTM approach has higher potential to provide valid estimates. Interestingly, the results suggest that published data on a proposed extrastriatal selectivity for the antipsychotic drugs clozapine and olanzapine may be due to erroneous estimations of the binding potential when using ratio approaches.

Dopamine and cognitive functioning: brain imaging findings in Huntington's disease and normal aging.

Recent brain imaging studies in Huntington's disease (HD) and normal aging suggest a relationship between central dopaminergic neurotransmission and cognitive performance. Results demonstrate substantial losses in dopamine (DA) function in both HD and aging. Moreover, HD patients and older adults show deficits across multiple cognitive domains, including episodic memory, speed of processing, and executive functioning. Although few studies are available at present, there is converging evidence that multiple measures of pre- and postsynaptic DA biochemistry are (a) highly interrelated, and (b) strongly associated with the cognitive deficits that accompany HD and aging. There is also emerging evidence that DA neurotransmission influences cognitive performance independent of HD or age. In general, the research reviewed in this article indicates that the nigrostriatal DA system is an important component of a frontostriatal circuitry that is critically involved in cognitive functioning.

Brain radioligands--state of the art and new trends.

Non-invasive radioligand imaging methods for brain receptor studies use either short-lived positron-emitting radionuclides such as 11C and 18F for positron emission tomography (PET) or single photon-emitting radionuclides such as 123I for single photon emission computed tomography (SPECT). PET and SPECT use radioligands which are injected intravenously into experimental animals, human volunteers or patients. The main applications of radioligands in brain research concern human neuropsychopharmacology and the discovery and development of novel drugs to be used in thetherapy of neurological and psychiatric disorders. A basic problem in PET and SPECT brain receptor studies is the lack of useful radioligands with appropriate binding characteristics. Prerequisite criteria need to be satisfied for a radioligand to reveal target binding sites in vivo. This section will discuss these important criteria and also review recent examples in neuroreceptor radioligand development such as selective radioligands for brain monoamine transporters.