Synthesis and in†vivo Evaluation of Fluorine-18 and Iodine-123 Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine Derivatives as PET and SPECT Radiotracers for Mapping A2A Receptors.

Imaging agents that target adenosine type 2A (A2A ) receptors play an important role in evaluating new pharmaceuticals targeting these receptors, such as those currently being developed for the treatment of movement disorders like Parkinson's disease. They are also useful for monitoring progression and treatment efficacy by providing a noninvasive tool to map changes in A2A receptor density and function in neurodegenerative diseases. We previously described the successful evaluation of two A2A -specific radiotracers in both nonhuman primates and in subsequent human clinical trials: [(123) I]MNI-420 and [(18) F]MNI-444. Herein we describe the development of both of these radiotracers by selection from a series of A2A ligands, based on the pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine core of preladenant. Each of this series of 16 ligands was found to bind to recombinant human A2A receptor in the low nanomolar range, and of these 16, six were radiolabeled with either fluorine-18 or iodine-123 and evaluated in nonhuman primates. These initial in vivo results resulted in the identification of 7-(2-(4-(4-(2-[(18) F]fluoroethoxy)phenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine ([(18) F]MNI-444) and 7-(2-(4-(2-fluoro-4-[(123) I]iodophenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-amine ([(123) I]MNI-420) as PET and SPECT radiopharmaceuticals for mapping A2A receptors in brain.

Identification and in vivo evaluation of a fluorine-18 rolipram analogue, [(18) F]MNI-617, as a radioligand for PDE4 imaging in mammalian brain.

Phosphodiesterase (PDE) 4 is the most prevalent PDE in the central nervous system (CNS) and catalyzes hydrolysis of intracellular cAMP, a secondary messenger. By therapeutic inhibition of PDE4, intracellular cAMP levels can be stabilized, and the symptoms of psychiatric and neurodegenerative disorders including depression, memory loss and Parkinson's disease can be ameliorated. Radiotracers targeting PDE4 can be used to study PDE4 density and function, and evaluate new PDE4 therapeutics, in vivo in a non-invasive way, as has been shown using the carbon-11 labeled PDE4 inhibitor R-(-)-rolipram. Herein we describe a small series of rolipram analogs that contain fluoro- or iodo-substituents that could be used as fluorine-18 PET or iodine-123 SPECT PDE4 radiotracers. This series was evaluated with an in vitro binding assay and a 4-(fluoromethyl) derivative of rolipram, MNI-617, was identified, with a five-fold increase in affinity for PDE4 (Kd = 0.26 nM) over R-(-)-rolipram (Kd = 1.6 nM). A deutero-analogue d2 -[(18) F]MNI-617 was radiolabeled and produced in 23% yield with high (>5 Ci/µmol) specific activity and evaluated in non-human primate, where it rapidly entered the brain, with SUVs between 4 and 5, and with a distribution pattern consistent with that of PDE4.

Convenient synthesis of 18F-radiolabeled R-(-)-N-n-propyl-2-(3-fluoropropanoxy-11-hydroxynoraporphine.

Aporphines are attractive candidates for imaging D2 receptor function because, as agonists rather than antagonists, they are selective for the receptor in the high affinity state. In contrast, D2 antagonists do not distinguish between the high and low affinity states, and in vitro data suggests that this distinction may be important in studying diseases characterized by D2 dysregulation, such as schizophrenia and Parkinson's disease. Accordingly, MCL-536 (R-(-)-N-n-propyl-2-(3-[(18)F]fluoropropanoxy-11-hydroxynoraporphine) was selected for labeling with (18)F based on in vitro data obtained for the non-radioactive ((19)F) compound. Fluorine-18-labeled MCL-536 was synthesized in 70% radiochemical yield, >99% radiochemical purity, and specific activity of 167 GBq/µmol (4.5 Ci/µmol) using p-toluenesulfonyl (tosyl) both as a novel protecting group for the phenol and a leaving group for the radiofluorination.

Automated one-step radiosynthesis of the CB1 receptor imaging agent [(18) F]MK-9470.

The fluorine-18-labeled positron emission tomography (PET) radiotracer [(18) F]MK-9470 is a selective, high affinity inverse agonist that has been used to image the cannabinoid receptor type 1 in human brain in healthy and disease states. This report describes a simplified, one-step [(18) F]radiofluorination approach using a GE TRACERlab FXFN module for the routine production of this tracer. The one-step synthesis, by [(18) F]fluoride displacement of a primary tosylate precursor, gives a six-fold increase in yield over the previous two-step method employing O-alkylation of a phenol precursor with 1,2-[(18) F]fluorobromoethane. The average radiochemical yield of [(18) F]MK-9470 using the one-step method was 30.3 ± 11.7% (n = 12), with specific activity in excess of 6 Ci/µmol and radiochemical purity of 97.2 ± 1.5% (n = 12), in less than 60 min. This simplified, high yielding, automated process was validated for routine GMP production of [(18) F]MK-9470 for clinical studies.

Comparison of delayed matching-to-sample performance in monkeys and children.

Although research has consistently demonstrated that accuracy on a variety of memory tasks decreases as delay increases, relatively little research has been conducted to quantify this relationship across development in humans or directly compare rates of forgetting between humans and monkeys. This study utilized a delayed matching-to-sample (DMTS) task to compare the relative contributions of proactive interference and attention on the rate of forgetting in monkeys and children. The performance of 1125 children from four to fourteen years of age and 10 adult rhesus monkeys was compared. For this DMTS task, a shape was displayed on the center one of three press-plates. After a delay, the subjects were required to match the original shape with one of three choice shapes to receive a banana-flavored food pellet for monkeys, or a nickel for children. A modified power function provided an excellent fit for the data for monkeys and children. The forgetting rates in children decreased with age, and the forgetting rates for monkeys were most comparable to those of younger children. The data also suggest that proactive interference did not significantly contribute to the forgetting rates for monkeys or younger children. Further, the monkeys appeared to attend to the task at a level similar to that of younger children as evidenced by the similarities in response latencies. The results from this study indicate that the rate of forgetting in monkeys, as well as the mechanisms underlying this rate, appears to share more similarities with that of younger children than of older children.

Synthesis and biological evaluation of positron emission tomography radiotracers targeting serotonin 4 receptors in brain: [18F]MNI-698 and [18F]MNI-699.

Two new benzodioxane derivatives were synthesized as candidates to image the serotonin 4 receptors by positron emission tomography (PET) and radiolabeled with fluorine-18 via a two-step procedure. Competition binding assays demonstrated that MNI-698 and MNI-699 had sub-nanomolar binding affinities against rat striatal 5-HT4 receptors (Ki of 0.20 and 0.07 nM, respectively). PET imaging in rhesus monkey showed that the regional brain distribution of [(18)F]MNI-698 and [(18)F]MNI-699 were consistent with the known densities of 5-HT4 in brain. [(18)F]MNI-698 and [(18)F]MNI-699 are among the first fluorine-18 radiotracers developed for imaging the 5-HT4 receptors in vivo and are currently under preclinical investigation in primates for future human use.

Kinetic modeling, test-retest, and dosimetry of 123I-MNI-420 in humans.

UNLABELLED: In vivo imaging of adenosine 2A receptors (A2A) in the brain has attracted significant interest from the scientific community, because studies have shown that dysregulation of these receptors is implicated in a variety of neurodegenerative and psychiatric disorders, including Parkinson and Huntington diseases. This work aimed to describe the kinetic properties, test-retest results, and dosimetry estimates of (123)I-MNI-420, a SPECT radiotracer for the in vivo imaging of A2A in the brain. METHODS: Nine healthy human subjects were enrolled in this study; 7 completed (123)I-MNI-420 brain SPECT studies, and 2 participated in whole-body planar imaging evaluating (123)I-MNI-420 biodistribution and dosimetry. For 3 of the brain SPECT studies, arterial blood was collected for invasive modeling. Noninvasive models were also explored, including Logan graphical analysis and simplified reference tissue models. Test-retest reliability was assessed in 4 subjects. To evaluate radiotracer biodistribution and dosimetry, serial whole-body images were acquired immediately after injection and at selected time points after injection. Urine samples were collected over a period of 21 h to calculate urinary excretion. RESULTS: (123)I-MNI-420 rapidly entered the human brain and displayed uptake consistent with known A2A densities. At pseudoequilibrium (reached at 90 min after radiotracer injection), stable target-to-cerebellum ratios of around 1.4-2.0 were determined. Binding potentials around 0.8-1.2 were estimated using different kinetic models and the cerebellum as the reference region. Average test-retest variability in the striatum was 4.8%, 3.5%, and 6.5% for the simplified reference tissue model, Logan graphical analysis, and standardized uptake value ratio methods, respectively. The estimated radiation effective dose determined from whole-body studies was 0.036 mSv/MBq. CONCLUSION: The data indicate that (123)I-MNI-420 is a useful SPECT radiotracer for imaging A2A in the brain and has radiation doses that would allow for multiple scans in the same research subject each year. The availability of (123)I-MNI-420 offers the possibility of investigating A2A activity in specific conditions and evaluating drug occupancy for A2A candidate therapeutics.

A thalamocorticostriatal dopamine network for psychostimulant-enhanced human cognitive flexibility.

BACKGROUND: Everyday life demands continuous flexibility in thought and behavior. We examined whether individual differences in dopamine function are related to variability in the effects of amphetamine on one aspect of flexibility: task switching. METHODS: Forty healthy human participants performed a task-switching paradigm following placebo and oral amphetamine administration. [(18)F]fallypride was used to measure D2/D3 baseline receptor availability and amphetamine-stimulated dopamine release. RESULTS: The majority of the participants showed amphetamine-induced benefits through reductions in switch costs. However, such benefits were variable. Individuals with higher baseline thalamic and cortical receptor availability and striatal dopamine release showed greater reductions in switch costs following amphetamine than individuals with lower levels. The relationship between dopamine receptors and stimulant-enhanced flexibility was partially mediated by striatal dopamine release. CONCLUSIONS: These data indicate that the impact of the psychostimulant on cognitive flexibility is influenced by the status of dopamine within a thalamocorticostriatal network. Beyond demonstrating a link between this dopaminergic network and the enhancement in task switching, these neural measures accounted for unique variance in predicting the psychostimulant-induced cognitive enhancement. These results suggest that there may be measurable aspects of variability in the dopamine system that predispose certain individuals to benefit from and hence use psychostimulants for cognitive enhancement.

The metabotropic glutamate receptor 8 agonist (S)-3,4-DCPG reverses motor deficits in prolonged but not acute models of Parkinson's disease.

Metabotropic glutamate receptors (mGlus) are 7 Transmembrane Spanning Receptors (7TMs) that are differentially expressed throughout the brain and modulate synaptic transmission at both excitatory and inhibitory synapses. Recently, mGlus have been implicated as therapeutic targets for many disorders of the central nervous system, including Parkinson's disease (PD). Previous studies have shown that nonselective agonists of group III mGlus have antiparkinsonian effects in several animal models of PD, suggesting that these receptors represent promising targets for treating the motor symptoms of PD. However, the relative contributions of different group III mGlu subtypes to these effects have not been fully elucidated. Here we report that intracerebroventricular (icv) administration of the mGlu(8)-selective agonist (S)-3,4-dicarboxyphenylglycine (DCPG [ 2.5, 10, or 30 nmol]) does not alleviate motor deficits caused by acute (2 h) treatment with haloperidol or reserpine. However, following prolonged pretreatment with haloperidol (three doses evenly spaced over 18-20 h) or reserpine (18-20 h), DCPG robustly reverses haloperidol-induced catalepsy and reserpine-induced akinesia. Furthermore, DCPG (10 nmol, icv) reverses the long-lasting catalepsy induced by 20 h pretreatment with the decanoate salt of haloperidol. Finally, icv administration of DCPG ameliorates forelimb use asymmetry caused by unilateral 6-hydroxydopamine lesion of substantia nigra dopamine neurons. These findings suggest that mGlu(8) may partially mediate the antiparkinsonian effects of group III mGlu agonists in animal models of PD in which dopamine depletion or blockade of D(2)-like dopamine receptors is prolonged and indicate that selective activation of mGlu(8) may represent a novel therapeutic strategy for alleviating the motor symptoms of PD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

The use of an incremental repeated acquisition task to assess learning in children.

The development of valid animal models of learning is especially important since learning is critical for nearly all aspects of human behavior and identifying appropriate surrogates provides additional opportunity to study various aspects of learning. Examining the factors that affect learning is often complicated by the need to administer the same task repeatedly across experimental conditions. Incremental repeated acquisition (IRA) tasks have been used extensively in animal research because they circumvent this problem by requiring a subject to learn different response chains repeatedly across sessions. The present study examined the association of age, sex of the participant, and IQ on the performance of an incremental repeated acquisition task in 837 children, aged 5-13 years. This task required children to learn to press four response levers in a specific sequence that was randomly chosen. Illumination of colored indicator lights signaled position in the required response chain. Initially, for the first link, only one of the four levers was correct: a response to it resulted in the delivery of a monetary reinforcer (5 cents). After mastery of the first link (i.e. three correct presses), the children were presented with a two-link response chain: a different lever had to be pressed before pressing the previously correct lever. After mastery of the two-link chain, the response chain length was once again increased, and so on until a response chain consisting of six links was completed or until the task timed out. Older children and children with higher IQs mastered longer response chain lengths and were more accurate in performance of this learning task than younger children. In addition, older children and children with higher IQs had higher effective response rates and lower ineffective response rates. No significant effects of the sex of the participant were demonstrated for any of the variables on this task, except overall response rate. The results indicate that this test is sensitive to developmental variables in children, with the degree of sensitivity of certain dependent variables being age-dependent. Characterization of performance of this task by humans facilitates comparisons with animal models employing the same task, thus enhancing its translational utility.

Dopaminergic mechanisms of individual differences in human effort-based decision-making.

Preferences for different combinations of costs and benefits are a key source of variability in economic decision-making. However, the neurochemical basis of individual differences in these preferences is poorly understood. Studies in both animals and humans have demonstrated that direct manipulation of the neurotransmitter dopamine (DA) significantly impacts cost/benefit decision-making, but less is known about how naturally occurring variation in DA systems may relate to individual differences in economic behavior. In the present study, 25 healthy volunteers completed a dual-scan PET imaging protocol with [(18)F]fallypride and d-amphetamine to measure DA responsivity and separately completed the effort expenditure for rewards task, a behavioral measure of cost/benefit decision-making in humans. We found that individual differences in DA function in the left striatum and ventromedial prefrontal cortex were correlated with a willingness to expend greater effort for larger rewards, particularly when probability of reward receipt was low. Additionally, variability in DA responses in the bilateral insula was negatively correlated with willingness to expend effort for rewards, consistent with evidence implicating this region in the processing of response costs. These findings highlight the role of DA signaling in striatal, prefrontal, and insular regions as key neurochemical mechanisms underlying individual differences in cost/benefit decision-making.

Evidence for chronically altered serotonin function in the cerebral cortex of female 3,4-methylenedioxymethamphetamine polydrug users.

CONTEXT: MDMA (3,4-methylenedioxymethamphetamine, also popularly known as "ecstasy") is a popular recreational drug that produces loss of serotonin axons in animal models. Whether MDMA produces chronic reductions in serotonin signaling in humans remains controversial. OBJECTIVE: To determine whether MDMA use is associated with chronic reductions in serotonin signaling in the cerebral cortex of women as reflected by increased serotonin(2A) receptor levels. DESIGN: Cross-sectional case-control study comparing serotonin(2A) receptor levels in abstinent female MDMA polydrug users with those in women who did not use MDMA (within-group design assessing the association of lifetime MDMA use and serotonin(2A) receptors). Case participants were abstinent from MDMA use for at least 90 days as verified by analysis of hair samples. The serotonin(2A) receptor levels in the cerebral cortex were determined using serotonin(2A)-specific positron emission tomography with radioligand fluorine 18-labeled setoperone as the tracer. SETTING: Academic medical center research laboratory. PARTICIPANTS: A total of 14 female MDMA users and 10 women who did not use MDMA (controls). The main exclusion criteria were nondrug-related DSM-IV Axis I psychiatric disorders and general medical illness. MAIN OUTCOME MEASURES: Cortical serotonin(2A) receptor nondisplaceable binding potential (serotonin(2A)BP(ND)). RESULTS: MDMA users had increased serotonin(2A)BP(ND) in occipital-parietal (19.7%), temporal (20.5%), occipitotemporal-parietal (18.3%), frontal (16.6%), and frontoparietal (18.5%) regions (corrected P < .05). Lifetime MDMA use was positively associated with serotonin(2A)BP(ND) in frontoparietal (ß = 0.665; P = .007), occipitotemporal (ß = 0.798; P = .002), frontolimbic (ß = 0.634; P = .02), and frontal (ß = 0.691; P = .008) regions. In contrast, there were no regions in which MDMA use was inversely associated with receptor levels. There were no statistically significant effects of the duration of MDMA abstinence on serotonin(2A)BP(ND). CONCLUSIONS: The recreational use of MDMA is associated with long-lasting increases in serotonin(2A) receptor density. Serotonin(2A) receptor levels correlate positively with lifetime MDMA use and do not decrease with abstinence. These results suggest that MDMA use produces chronic serotonin neurotoxicity in humans. Given the broad role of serotonin in human brain function, the possibility for therapeutic MDMA use, and the widespread recreational popularity of this drug, these results have critical public health implications.

Multimodal image coregistration and inducible selective cell ablation to evaluate imaging ligands.

We combined multimodal imaging (bioluminescence, X-ray computed tomography, and PET), tomographic reconstruction of bioluminescent sources, and two unique, complementary models to evaluate three previously synthesized PET radiotracers thought to target pancreatic beta cells. The three radiotracers {[(18)F]fluoropropyl-(+)-dihydrotetrabenazine ([(18)F]FP-DTBZ), [(18)F](+)-2-oxiranyl-3-isobutyl-9-(3-fluoropropoxy)-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline ((18)F-AV-266), and (2S,3R,11bR)-9-(3-fluoropropoxy)-2-(hydroxymethyl)-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol ((18)F-AV-300)} bind vesicular monoamine transporter 2. Tomographic reconstruction of the bioluminescent signal in mice expressing luciferase only in pancreatic beta cells was used to delineate the pancreas and was coregistered with PET and X-ray computed tomography images. This strategy enabled unambiguous identification of the pancreas on PET images, permitting accurate quantification of the pancreatic PET signal. We show here that, after conditional, specific, and rapid mouse beta-cell ablation, beta-cell loss was detected by bioluminescence imaging but not by PET imaging, given that the pancreatic signal provided by three PET radiotracers was not altered. To determine whether these ligands bound human beta cells in vivo, we imaged mice transplanted with luciferase-expressing human islets. The human islets were imaged by bioluminescence but not with the PET ligands, indicating that these vesicular monoamine transporter 2-directed ligands did not specifically bind beta cells. These data demonstrate the utility of coregistered multimodal imaging as a platform for evaluation and validation of candidate ligands for imaging islets.

Potent mGluR5 antagonists: pyridyl and thiazolyl-ethynyl-3,5-disubstituted-phenyl series.

We report the synthesis of four series of 3,5-disubstituted-phenyl ligands targeting the metabotropic glutamate receptor subtype 5: (2-methylthiazol-4-yl)ethynyl (1a-j,), (6-methylpyridin-2-yl)ethynyl (2a-j), (5-methylpyridin-2-yl)ethynyl (3a-j,), and (pyridin-2-yl)ethynyl (4a-j,). The compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro assay. All compounds were found to be full antagonists and exhibited low nanomolar to subnanomolar activity.

Impact of isoflurane anesthesia on D2 receptor occupancy by [18F]fallypride measured by microPET with a modified Logan plot.

UNLABELLED: In the previous work, we reported a method that utilized imaging data collected from 60 to 120 min following [(18) F]fallypride administration to estimate the distribution volume ratio DVR' (DVR' ∝ DVR; DVR = 1 + BP(ND) , where BP(ND) is a measure of receptor density, DA D2 in this case). In this work, we use this method to assess the effects of isoflurane anesthesia on [(18) F]fallypride DVR'. METHODS: Rats were injected with [(18) F]fallypride either unconsciously under ∼1.5% isoflurane via the tail vein (Group 1) or consciously via a catheter inserted either in the jugular vein (Group 2) or the tail vein (Group 3). After about 1 h of free access to food and water the rats were anesthetized with 1.5% isoflurane and imaged in a microPET for 60 min. The rats that were injected consciously (Groups 2 and 3) were placed in a rat restrainer during [(18) F]fallypride injection. They were habituated in that restrainer for 3 days prior to the experiment day to minimize restraint-related stress. For comparison, a control group of rats was imaged for 120 min simultaneously with the administration of [(18) F]fallypride i.v. while under 1.5% isoflurane. The DVR' estimates from the 60 min acquisitions were compared with the DVR' from the last 60 min of the 120 min acquisitions (after neglecting the first 60 min). In addition, the striatal time-activity curves were fit with a 2-tissue + plasma compartment model using an arbitrary simulated plasma input function to obtain k(3) /k(4) (≈ BP(ND) ) for the 60 and 120 min acquisitions. RESULTS: Isoflurane anesthesia caused a significant reduction, up to 22%, in the DVR' estimates, which were 15.7 ± 0.3 (mean ± SE) for the controls, 17.7 ± 0.3 for Group 1, 19.2 ± 0.4 for Group 2, and 18.8 ± 0.7 for Group 3. The compartmental model fit produced similar results, ∼30% reduction in k(3) /k(4) for the 120-min acquisitions compared with the 60-min acquisitions (initial conscious uptake of the radiotracer). CONCLUSION: The results of this study demonstrate that isoflurane anesthesia significantly decreases striatal [(18) F]fallypride BP(ND) in rats. Of similar importance, this work demonstrates the effectiveness of delayed scans following radiotracer injection and the implication that different types of studies can be conducted simultaneously with this method, including studies of behavioral and environmental impact on brain receptors.

2-Arylimidazo[2,1-b]benzothiazoles: a new family of amyloid binding agents with potential for PET and SPECT imaging of Alzheimer's brain.

We designed and synthesized a small series of 2-aryl-imidazo[2,1-b]benzothiazole, representing a combination of motifs from the two most potent amyloid imaging agents, PIB and IMPY. The binding affinity of the new compounds ranged from 6 to 133 nM. Among the best compounds, 3b (K(i)=6 nM) can be labeled with (11)CH(3) for PET imaging whereas 3j (K(i)=10.9 nM) can be labeled with (123)I for SPECT imaging.

A novel in vitro assay to assess phosphorylation of 3'-[(18)F]fluoro-3'-deoxythymidine.

PURPOSE: 3'-[(18)F]fluoro-3'-deoxythymidine ([(18)F]FLT) is phosphorylated by thymidine kinase 1 (TK-1), a cell cycle regulated enzyme. Appropriate use of [(18)F]FLT tracer requires validation of the TK-1 activity. Here, we report development of a novel phosphoryl-transfer assay to assess phosphorylation of [(18)F]FLT both in tumor cell lysates and tumor cells. PROCEDURES: The intrinsic F-18 radioactivity was used to quantify both substrate and phosphorylated products using a rapid thin layer chromatography method. Phosphorylation kinetics of [(18)F]FLT in SW480 and DiFi tumor cell lysates and cellular uptake were measured. RESULTS: The apparent Michaelis-Menten kinetic parameters for [(18)F]FLT are K(m) = 4.8 ± 0.3 µM and V(max) = 7.4 pmol min(-1) per 1 × 10(6) cells with ~2-fold higher TK-1 activity in DiFi versus SW480 lysates. CONCLUSIONS: The apparent K (m) of [(18)F]FLT was comparable to the value reported with purified recombinant TK-1. The uptake of [(18)F]FLT by SW480 cells is inhibited by nitrobenzylthioinosine or dipyridamole indicating that uptake is mediated predominantly by the equilibrative nucleoside transporters in these tumor cells.

Sex differences in the relationship of regional dopamine release to affect and cognitive function in striatal and extrastriatal regions using positron emission tomography and [¹8F]fallypride.

The purpose of this study was to examine sex differences in the correlations of d-amphetamine (d-AMPH) induced displacements of [¹8F]fallypride in striatal and extrastriatal regions in relation to affect and cognition. Seven male and six female healthy subjects, whose mean age was 25.9 years, underwent positron emission tomography (PET) with [¹8F]fallypride at baseline and 3 h after a 0.43 mg/kg oral dose of d-AMPH. Percent displacements in striatal and extrastriatal regions were calculated using regions of interest (ROI) analysis and on a pixel-by-pixel basis. Subjects underwent neuropsychological testing prior to the baseline PET study and one hour after d-AMPH administration for the second PET. In order to examine the subjective effect of d-AMPH, subjects rated PANAS at baseline and after administration of amphetamine. Correlations of changes in cognition and affect with regional dopamine (DA) release revealed several significant sex related differences. The results of this study demonstrate in vivo sex related differences in the relationship of regional DA release to affect and cognitive function.

Correlation of individual differences in schizotypal personality traits with amphetamine-induced dopamine release in striatal and extrastriatal brain regions.

OBJECTIVE: Schizotypal personality traits are associated with schizophrenia spectrum disorders, and individuals with schizophrenia spectrum disorders demonstrate increased dopamine transmission in the striatum. The authors sought to determine whether individual differences in normal variation in schizotypal traits are correlated with dopamine transmission in the striatum and in extrastriatal brain regions. METHOD: Sixty-three healthy volunteers with no history of psychiatric illness completed the Schizotypal Personality Questionnaire and underwent positron emission tomography imaging with [(18)F]fallypride at baseline and after administration of oral d-amphetamine (0.43 mg/kg). Dopamine release, quantified by subtracting each participant's d-amphetamine scan from his or her baseline scan, was correlated with Schizotypal Personality Questionnaire total and factor scores using region-of-interest and voxel-wise analyses. RESULTS: Dopamine release in the striatum was positively correlated with overall schizotypal traits. The association was especially robust in the associative subdivision of the striatum. Voxel-wise analyses identified additional correlations between dopamine release and schizotypal traits in the left middle frontal gyrus and left supramarginal gyrus. Exploratory analyses of Schizotypal Personality Questionnaire factor scores revealed correlations between dopamine release and disorganized schizotypal traits in the striatum, thalamus, medial prefrontal cortex, temporal lobe, insula, and inferior frontal cortex. CONCLUSIONS: The association between dopamine signaling and psychosis phenotypes extends to individual differences in normal variation in schizotypal traits and involves dopamine transmission in both striatal and extrastriatal brain regions. Amphetamine-induced dopamine release may be a useful endophenotype for investigating the genetic basis of schizophrenia spectrum disorders.