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Background The rs1344706 single nucleotide polymorphism in the ZNF804A gene has been associated with risk for psychosis in multiple genome-wide association studies, yet mechanisms underlying this association are not known. Given preclinical work suggesting an impact of ZNF804A on dopamine receptor gene transcription and clinical studies establishing dopaminergic dysfunction in patients with schizophrenia, we hypothesized that the ZNF804A risk single nucleotide polymorphism would be associated with variation in dopamine receptor availability in the human brain. Methods In this study, 72 healthy individuals genotyped for rs1344706 completed both [18F]fallypride and [11C]NNC-112 positron emission tomography scans to measure D2/D3 and D1 receptor availability, respectively. Genetic effects on estimates of binding potential for each ligand were tested first with canonical subject-specific striatal regions of interest analyses, followed by exploratory whole-brain voxelwise analyses to test for more localized striatal signals and for extrastriatal effects. Results Region of interest analyses revealed significantly less D2/D3 receptor availability in risk-allele homozygotes (TT) compared with non-risk allele carriers (G-allele carrier group: TG and GG) in the associative striatum and sensorimotor striatum, but no significant differences in striatal D1 receptor availability. Conclusions These data suggest that ZNF804A genotype may be meaningfully linked to dopaminergic function in the human brain. The results also may provide information to guide future studies of ZNF804A-related mechanisms of schizophrenia risk.

The stop-signal task is a well-established assessment of response inhibition, and in humans, proficiency is linked to dorsal striatum D2receptor availability. Parkinson's disease (PD) is characterized by changes to efficiency of response inhibition. Here, we studied 17 PD patients (6 female and 11 male) using the stop-signal paradigm in a single-blindedd-amphetamine (dAMPH) study. Participants completed [18F]fallypride positron emission topography (PET) imaging in both placebo and dAMPH conditions. A voxel-wise analysis of the relationship between binding potential (BPND) and stop-signal reaction time (SSRT) revealed that faster SSRT is associated with greater D2-like BPNDin the amygdala and hippocampus (right clusterqFDR-corr= 0.026, left clusterqFDR-corr= 0.002). A region of interest (ROI) examination confirmed this association in both the amygdala (coefficient = −48.26,p= 0.005) and hippocampus (coefficient = −104.94,p= 0.007). As healthy dopaminergic systems in the dorsal striatum appear to regulate response inhibition, we interpret our findings in PD to indicate either nigrostriatal damage unmasking a mesolimbic contribution to response inhibition, or a compensatory adaptation from the limbic and mesial temporal dopamine systems. These novel results expand the conceptualization of action-control networks, whereby limbic and motor loops may be functionally connected.SIGNIFICANCE STATEMENTWhile Parkinson's disease (PD) is characteristically recognized for its motor symptoms, some patients develop impulsive and compulsive behaviors (ICBs), manifested as repetitive and excessive participation in reward-driven activities, including sex, gambling, shopping, eating, and hobbyism. Such cognitive alterations compel a consideration of response inhibition in PD. To investigate inhibitory control and assess the brain regions that may participate, we assessed PD patients using a single-blindedd-amphetamine (dAMPH) study, with [18F]fallypride positron emission topography (PET) imaging, and stop-signal task performance. We find a negative relationship between D2-like binding in the mesial temporal region and top-signal reaction time (SSRT), with greater BPNDassociated with a faster SSRT. These discoveries indicate a novel role for mesolimbic dopamine in response inhibition, and advocate for limbic regulation of action control in this clinical population.

Pridopidine is an investigational drug in late stage development for the treatment of Huntington disease and originally postulated to act as dopamine stabilizer by modulating dopamine-dependent motor behavior. However, preclinical studies show pridopidine has highest affinity to sigma-1 receptors. Importantly, mediated by sigma-1 receptors, pridopidine has neuroprotective properties and enhances neuronal plasticity. The aim of our study was to determine the in-vivo the target engagement (receptor occupancy) of pridopidine at clinically relevant doses in healthy volunteers and Huntington disease patients. We used sigma-1 receptor-specific (S)-(-)-[18F]Fluspidine and dopamine D2/D3 receptor-specific [18F]Fallypride PET imaging to quantify the sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine. Eleven male healthy volunteers (pridopidine 0.5 to 90 mg in six dose groups) and three male Huntington disease patients (pridopidine 90 mg) were studied twice before and 2h following single oral doses of pridopidine using S-(-)-[18F]Fluspidine PET (300 MBq, 0-90min p.i.). Distribution volume VT was quantified using kinetic modeling (One-tissue compartment model; metabolite correction). Four male healthy volunteers were studied twice using [18F]Fallpride PET (200 MBq, 0-210min p.i.) before and 2h after a single oral dose of pridopidine (90 mg). Binding potential BPND was assessed by the simplified reference model. Volume-of-interest analyses were performed. For each subject/tracer, the receptor occupancy was calculated by the Lassen plot analysis. In healthy volunteers, there was high sigma-1 receptor occupancy (87 to 91%) across all brain regions at doses ranging from 22.5 to 90 mg. The sigma-1 receptor occupancy was 43% at 1 mg pridopidine. In Huntington disease patients, very similar to healthy volunteers, at 90 mg pridopidine, there was high sigma-1 receptor occupancy (87±7%, n.s.). In contrast, in healthy volunteers, there was only negligible dopamine D2/D3 receptor occupancy (3±2%) at 90 mg pridopidine. We established a sigmoid-shaped dose/sigma-1 receptor occupancy relation (Hill equation) with Hill coefficient larger than 1 in healthy volunteers, suggesting a positive cooperative binding nature of the sigma-1 receptor. Using PET, we report for the first time in the living human brain that after a single dose of 90 mg, pridopidine acts as a selective sigma-1 receptor ligand showing near to complete sigma-1 receptor occupancy (~90%) but only minimal (~3%) dopamine D2/D3 receptor occupancy. Our findings provide significant clarification about pridopidine’s mechanism of action and support further use of the 45 mg bidaily dose to achieve full and selective targeting of the sigma-1 receptor in future clinical trials in Huntington disease and amyotrophic lateral sclerosis.

Background Significant developments in stem cell therapy for Parkinson’s disease (PD) have already been achieved; however, methods for reliable assessment of dopamine neuron maturation in vivo are lacking. Establishing the efficacy of new cellular therapies using non-invasive methodologies will be critical for future regulatory approval and application. The current study examines the utility of neuroimaging to characterise the in vivo maturation, innervation and functional dopamine release of transplanted human embryonic stem cell-derived midbrain dopaminergic neurons (hESC-mDAs) in a preclinical model of PD. Methods Female NIH RNu rats received a unilateral stereotaxic injection of 6-OHDA into the left medial forebrain bundle to create the PD lesion. hESC-mDA cell and sham transplantations were carried out 1 month post-lesion, with treated animals receiving approximately 4 × 105 cells per transplantation. Behavioural analysis, [18F]FBCTT and [18F]fallypride microPET/CT, was conducted at 1, 3 and 6 months post-transplantation and compared with histological characterisation at 6 months. Results PET imaging revealed transplant survival and maturation into functional dopaminergic neurons. [18F]FBCTT-PET/CT dopamine transporter (DAT) imaging demonstrated pre-synaptic restoration and [18F]fallypride-PET/CT indicated functional dopamine release, whilst amphetamine-induced rotation showed significant behavioural recovery. Moreover, histology revealed that the grafted cells matured differently in vivo producing high- and low-tyrosine hydroxylase (TH) expressing cohorts, and only [18F]FBCTT uptake was well correlated with differentiation. Conclusions This study provides further evidence for the value of in vivo functional imaging for the assessment of cell therapies and highlights the utility of DAT imaging for the determination of early post-transplant cell maturation and differentiation of hESC-mDAs.

The neurobiological traits that confer risk for addictions remain poorly understood. However, dopaminergic function throughout the prefrontal cortex, limbic system, and upper brainstem has been implicated in behavioral features that influence addiction vulnerability, including poor impulse control, and altered sensitivity to rewards and punishments (i.e., externalizing features). To test these associations in humans, we measured type-2/3 dopamine receptor (DA2/3R) availability in youth at high vs. low risk for substance use disorders (SUDs). In this study, N = 58 youth (18.5 ± 0.6 years) were recruited from cohorts that have been followed since birth. Participants with either high (high EXT; N = 27; 16 F/11 M) or low pre-existing externalizing traits (low EXT; N = 31; 20 F/11 M) underwent a 90-min positron emission tomography [18F]fallypride scan, and completed the Barratt Impulsiveness Scale (BIS-11), Substance Use Risk Profile scale (SURPS), and Sensitivity to Punishment (SP) and Sensitivity to Reward (SR) questionnaire. We found that high vs. low EXT trait participants reported elevated substance use, BIS-11, SR, and SURPS impulsivity scores, had a greater prevalence of psychiatric disorders, and exhibited higher [18F]fallypride binding potential (BPND) values in prefrontal, limbic and paralimbic regions, even when controlling for substance use. Group differences were not evident in midbrain dopamine cell body regions, but, across all participants, low midbrain BPND values were associated with low SP scores. Together, the results suggest that altered DA2/3R availability in terminal extra-striatal and dopamine cell body regions might constitute biological vulnerability traits, generating an EXT trajectory for addictions with and without co-occurring alterations in punishment sensitivity (i.e., an internalizing feature).

Microfluidics offers numerous advantages for the synthesis of short-lived radiolabeled imaging tracers: performing 18F-radiosyntheses in microliter-scale droplets has exhibited high efficiency, speed, and molar activity as well as low reagent consumption. However, most reports have been at the preclinical scale. In this study we integrate a [18F]fluoride concentrator and a microdroplet synthesizer to explore the possibility of synthesizing patient doses and multi-patient batches of clinically-acceptable tracers. In the integrated system, [18F]fluoride (up to 41 GBq [1.1 Ci]) in [18O]H2O (1 mL) was first concentrated ∼80-fold and then efficiently transferred to the 8 μL reaction chip as a series of small (∼0.5 μL) droplets. Each droplet rapidly dried at the reaction site of the pre-heated chip, resulting in localized accumulation of large amounts of radioactivity in the form of dried [18F]TBAF complex. The PET tracer [18F]fallypride was synthesized from this concentrated activity in an overall synthesis time of ∼50 min (including radioisotope concentration and transfer, droplet radiosynthesis, purification, and formulation), in amounts up to 7.2 GBq [0.19 Ci], sufficient for multiple clinical PET scans. The resulting batches of [18F]fallypride passed all QC tests needed to ensure safety for clinical injection. This integrated technology enabled for the first time the impact of a wide range of activity levels on droplet radiosynthesis to be studied. Furthermore, this substantial increase in scale expands the applications of droplet radiosynthesis to the production of clinically-relevant amounts of radiopharmaceuticals, and potentially even centralized production of clinical tracers in radiopharmacies. The overall system could be applied to fundamental studies of droplet-based radiochemical reactions, or to the production of radiopharmaceuticals labeled with a variety of isotopes used for imaging and/or targeted radiotherapeutics.

Commonly comorbid early onset psychiatric disorders might reflect the varying expression of overlapping risk factors. The mediating processes remain poorly understood, but three factors show some promise: adolescent externalizing traits, early life adversity, and midbrain dopamine autoreceptors. To investigate whether these features acquire greater predictive power when combined, a longitudinal study was conducted in youth who have been followed since birth. Cohort members were invited to participate based on externalizing scores between 11 to 16 years of age. At age 18 (age 18.5 ± 0.6 y.o.), 52 entry criteria meeting volunteers had a 90-min positron emission tomography scan with [(18)F]fallypride, completed the Childhood Trauma Questionnaire, and were assessed with the Structured Clinical Interview for DSM-5. The three-factor model identified those with a lifetime history of DSM-5 disorders with an overall accuracy of 90.4% (p = 2.4 × 10(−5)) and explained 91.5% of the area under the receiver operating characteristic curve [95% CI: .824, 1.000]. Targeting externalizing disorders specifically did not yield a more powerful model than targeting all disorders (p = 0.54). The model remained significant when including data from participants who developed their first disorders during a three-year follow-up period (p = 3.5 × 10(−5)). Together, these results raise the possibility that a combination of temperamental traits, childhood adversity, and poorly regulated dopamine transmission increases risk for diverse, commonly comorbid, early onset psychiatric problems, predicting this susceptibility prospectively.

The process by which the value of delayed rewards is discounted varies from person to person. It has been suggested that these individual differences in subjective valuation of delayed rewards are supported by mesolimbic dopamine D2-like receptors (D2Rs) in the ventral striatum. However, no study to date has documented an association between direct measures of dopamine receptors and neural representations of subjective value in humans. Here, we examined whether individual differences in D2R availability were related to neural subjective value signals during decision making. Human participants completed a monetary delay discounting task during an fMRI scan and on a separate visit completed a PET scan with the high affinity D2R tracer [18 F]fallypride. Region-of-interest analyses revealed that D2R availability in the ventral striatum was positively correlated with subjective value-related activity in the ventromedial prefrontal cortex and midbrain but not with choice behavior. Whole-brain analyses revealed a positive correlation between ventral striatum D2R availability and subjective value-related activity in the left inferior frontal gyrus and superior insula. These findings identify a link between a direct measure of mesolimbic dopamine function and subjective value representation in humans and suggest a mechanism by which individuals vary in neural representation of discounted subjective value.

The short-lived radiolabeled "tracers" needed for performing whole body imaging in animals or patients with positron-emission tomography (PET) are generally produced via automated "radiosynthesizers". Most current radiosynthesizers are designed for routine production of relatively large clinical batches and are very wasteful when only a small batch of a tracer is needed, such as is the case for preclinical in vivo PET imaging studies. To overcome the prohibitively high cost of producing small batches of PET tracers, we developed a droplet microreactor system that performs radiochemistry at the 1-10μL scale instead of the milliliter scale of conventional technologies. The overall yield for the droplet-based production of many PET tracers is comparable to conventional approaches, but 10-100× less reagents are consumed, the synthesis can be completed in much less time (

Research using rodent models has established a relationship between the steroid hormone estrogen and dopamine function, by revealing changes throughout the estrous cycle and by directly manipulating neuroendocrine signaling through ovariectomy and administration of estrogen. However, a direct link between estrogen levels and dopamine signaling had not been established in humans. The goal of this study, therefore, was to assess the relationship between circulating 17β-estradiol and dopamine signaling in the human brain by testing for a relationship between two proxies for these variables: peripheral 17β-estradiol and striatal dopamine D(2)-type receptor availability, measured with [(18)F]fallypride and positron emission tomography (PET). Sixteen (23–45 years of age) women were tested on 2 days of the menstrual cycle estimated prospectively to occur during (a) the early follicular phase, when estrogen levels are near their nadir, and (b) the periovulatory phase, when estrogen levels peak. PET scans with [(18)F]fallypride were performed on these 2 days, and serum 17β-estradiol was measured using radioimmunoassay. Dopamine D(2)-type receptor availability did not differ significantly in the whole striatum or the caudate, putamen, or accumbens subregions during the high-estrogen vs. the low-estrogen phases of the menstrual cycle. We conclude that circulating estrogen levels do not affect dopamine D(2)-type receptor availability in the human striatum although other indices of dopaminergic function may be affected.

Dopaminergic dysfunction and changes in white matter integrity are among the most replicated findings in schizophrenia. A modulating role of dopamine in myelin formation has been proposed in animal models and healthy human brain, but has not yet been systematically explored in schizophrenia. We used diffusion tensor imaging and 18F-fallypride positron emission tomography in 19 healthy and 25 schizophrenia subjects to assess the relationship between gray matter dopamine D2/D3 receptor density and white matter fractional anisotropy in each diagnostic group. AFNI regions of interest were acquired for 42 cortical Brodmann areas and subcortical gray matter structures as well as stereotaxically placed in representative white matter areas implicated in schizophrenia neuroimaging literature. Welch's t-test with permutation-based p value adjustment was used to compare means of z-transformed correlations between fractional anisotropy and 18F-fallypride binding potentials in hypothesis-driven regions of interest in the diagnostic groups. Healthy subjects displayed an extensive pattern of predominantly negative correlations between 18F-fallypride binding across a range of cortical and subcortical gray matter regions and fractional anisotropy in rostral white matter regions (internal capsule, frontal lobe, anterior corpus callosum). These patterns were disrupted in subjects with schizophrenia, who displayed significantly weaker overall correlations as well as comparatively scant numbers of significant correlations with the internal capsule and frontal (but not temporal) white matter, especially for dopamine receptor density in thalamic nuclei. Dopamine D2/D3 receptor density and white matter integrity appear to be interrelated, and their decreases in schizophrenia may stem from hyperdopaminergia with dysregulation of dopaminergic impact on axonal myelination.

[18F]Fallypride and [18F]Fluortriopride (FTP) are two different PET radiotracers that bind with sub-nanomolar affinity to the dopamine D3 receptor (D3R). In spite of their similar D3 affinities, the two PET ligands display very different properties for labeling the D3R in vivo: [18F]Fallypride is capable of binding to D3R under “baseline” conditions, whereas [18F]FTP requires the depletion of synaptic dopamine in order to image the receptor in vivo. These data suggest that [18F]Fallypride is able to compete with synaptic dopamine for binding to the D3R, whereas [18F]FTP is not. The goal of this study was to conduct a series of docking and molecular dynamic simulation studies to identify differences in the ability of each molecule to interact with the D3R that could explain these differences with respect to competition with synaptic dopamine. Competition studies measuring the ability of each ligand to compete with dopamine in the β-arrestin assay were also conducted. The results of the in silico studies indicate that FTP has a weaker interaction with the orthosteric binding site of the D3R versus that of Fallypride. The results of the in silico studies were also consistent with the IC50 values of each compound in the dopamine β-arrestin competition assays. The results of this study indicate that in silico methods may be able to predict the ability of a small molecule to compete with synaptic dopamine for binding to the D3R.

D2-like dopamine receptors in animals and humans have been shown to be linked to impulsive behaviors that are highly relevant for several psychiatric disorders. Here, we investigate the relationship between the fronto-striatal D2/D3 dopamine receptor availability and response inhibition in a selected population of healthy OPRM1 G-allele carriers. Twenty-two participants successively underwent blood-oxygen level dependent functional magnetic resonance imaging (fMRI) while performing a stop-signal task and a separate positron emission tomography (PET) scan. Striatal and extrastriatal D2/D3 dopamine receptor availability was measured using the radiotracer [18F]fallypride. Caudate D2/D3 dopamine receptor availability positively correlated with stopping-related fronto-striatal fMRI activation. In addition, right prefrontal D2/D3 dopamine receptor availability correlated positively with stopping-related striatal fMRI BOLD signal. Our study partially replicates previous findings on correlations between striatal D2/D3 dopamine receptor availability and response inhibition in a population selected for its genetic determination of dopamine response to alcohol and as a modulator of impulse control via the endogenous opioid system. We confirm the important role of D2/D3 dopamine receptor availability in the fronto-striatal neural circuit for response inhibition. Moreover, we extend previous findings suggesting that dopamine receptor availability in the right inferior frontal cortex, a crucial region of the stopping network, is also strongly associated with stopping-related striatal fMRI activity in healthy OPRM1 G-allele carriers.

Background Positron emission tomography (PET) is a molecular imaging technique that can be used to investigate the in vivo pharmacology of drugs. Initial preclinical evaluation of PET tracers is often conducted in rodents due to the accessibility of disease models as well as economic considerations. Compared to larger species, rodents display a higher expression and/or activity of efflux transporters such as the P-glycoprotein (P-gp). Low brain uptake could, therefore, be species-specific and uptake in rodents not be predictive for that in humans. We hypothesized that a better prediction from rodent data could be achieved when a tracer is evaluated under P-gp inhibition. Consequently, we compared the performance of eight neuroreceptor tracers in rats with and without P-gp inhibition including a specific binding blockade. This data set was then used to predict the binding of these eight tracers in pigs. Methods PET tracers targeting serotonin 5-HT2A receptors ([18F]MH.MZ, [18F]Altanserin, [11C]Cimbi-36, [11C]Pimavanserin), serotonin 5-HT7 receptors ([11C]Cimbi-701, [11C]Cimbi-717 and [11C]BA-10) and dopamine D2/3 receptors ([18F]Fallypride) were used in the study. The brain uptake and target-specific binding of these PET radiotracers were evaluated in rats with and without inhibition of P-gp. Rat data were subsequently compared to the results obtained in pigs. Results Without P-gp inhibition, the amount of target-specific binding in the rat brain was sufficient to justify further translation for three out of eight evaluated tracers. With P-gp inhibition, results for five out of eight tracers justified further translation. The performance in pigs could correctly be predicted for six out of eight tracers when rat data obtained under P-gp inhibition were used, compared to four out of eight tracers without P-gp inhibition. Conclusions P-gp strongly affects the uptake of PET tracers in rodents, but false prediction outcomes can be reduced by evaluating a tracer under P-gp inhibition.

BackgroundThe 22q11.2 deletion syndrome (22q11DS) is caused by a deletion on chromosome 22 locus q11.2. This copy number variant results in haplo-insufficiency of the catechol-O-methyltransferase (COMT) gene, and is associated with a significant increase in the risk for developing cognitive impairments and psychosis. The COMT gene encodes an enzyme that primarily modulates clearance of dopamine (DA) from the synaptic cleft, especially in the prefrontal cortical areas. Consequently, extracellular DA levels may be increased in prefrontal brain areas in 22q11DS, which may underlie the well-documented susceptibility for cognitive impairments and psychosis in affected individuals. This study aims to examine DA D2/3receptor binding in frontal brain regions in adults with 22q11DS, as a proxy of frontal DA levels.MethodsThe study was performed in 14 non-psychotic, relatively high functioning adults with 22q11DS and 16 age- and gender-matched healthy controls (HCs), who underwent DA D2/3receptor [18F]fallypride PET imaging. Frontal binding potential (BPND) was used as the main outcome measure.ResultsBPNDwas significantly lower in adults with 22q11DS compared with HCs in the prefrontal cortex and the anterior cingulate gyrus. After Bonferroni correction significance remained for the anterior cingulate gyrus. There were no between-group differences in BPNDin the orbitofrontal cortex and anterior cingulate cortex.ConclusionsThis study is the first to demonstrate lower frontal D2/3receptor binding in adults with 22q11DS. It suggests that a 22q11.2 deletion affects frontal dopaminergic neurotransmission.

IntroductionRadio thin layer chromatography (radio-TLC) is commonly used to analyze purity of radiopharmaceuticals or to determine the reaction conversion when optimizing radiosynthesis processes. In applications where there are few radioactive species, radio-TLC is preferred over radio-high-performance liquid chromatography due to its simplicity and relatively quick analysis time. However, with current radio-TLC methods, it remains cumbersome to analyze a large number of samples during reaction optimization. In a couple of studies, Cerenkov luminescence imaging (CLI) has been used for reading radio-TLC plates spotted with a variety of isotopes. We show that this approach can be extended to develop a high-throughput approach for radio-TLC analysis of many samples.MethodsThe high-throughput radio-TLC analysis was carried out by performing parallel development of multiple radioactive samples spotted on a single TLC plate, followed by simultaneous readout of the separated samples using Cerenkov imaging. Using custom-written MATLAB software, images were processed and regions of interest (ROIs) were drawn to enclose the radioactive regions/spots. For each sample, the proportion of integrated signal in each ROI was computed. Various crude samples of [18F]fallypride, [18F]FET and [177Lu]Lu-PSMA-617 were prepared for demonstration of this new method.ResultsBenefiting from a parallel developing process and high resolution of CLI-based readout, total analysis time for eight [18F]fallypride samples was 7.5min (2.5min for parallel developing, 5min for parallel readout), which was significantly shorter than the 48min needed using conventional approaches (24min for sequential developing, 24min for sequential readout on a radio-TLC scanner). The greater separation resolution of CLI enabled the discovery of a low-abundance side product from a crude [18F]FET sample that was not discernable using the radio-TLC scanner. Using the CLI-based readout method, we also observed that high labeling efficiency (99%) of [177Lu]Lu-PSMA-617 can be achieved in just 10min, rather than the typical 30min timeframe used.ConclusionsCerenkov imaging in combination with parallel developing of multiple samples on a single TLC plate proved to be a practical method for rapid, high-throughput radio-TLC analysis.

RATIONALE: Sex differences in the dopaminergic response to psychostimulants could have implications for drug abuse risk and other psychopathology involving the dopamine system, but human data are limited and mixed. OBJECTIVES: Here, we sought to investigate sex differences in dopamine release after oral d-amphetamine administration. METHODS: We used [(18)F]fallypride Positron Emission Tomography (PET) to measure the change in dopamine D2/3 receptor availability (%ΔBP(ND), an index of dopamine release) between placebo and d-amphetamine sessions in two independent datasets containing a total of 39 females (either on hormonal birth control n=18, postmenopausal n=10, or studied in the first 10 days of their menstrual cycle n=11) and 37 males. RESULTS: Using both a priori anatomical regions of interest based on previous findings as well as voxelwise analyses, we failed to consistently detect broad sex differences in d-amphetamine-induced dopamine release. Nevertheless, there was limited evidence for greater right ventral striatal dopamine release in young adult males relative to similarly aged females, but this was not consistently observed across samples. Plasma estradiol did not correlate with dopamine release and this measure did not differ in females on and off hormonal birth control. CONCLUSIONS: While our finding in young adults from one dataset of greater %ΔBP(ND) in males is partially consistent with a previously published study on sex differences in d-amphetamine-induced dopamine release, our data do not support the presence of consistent widespread sex differences in this measure of dopamine release.

Wheel-running exercise in laboratory rodents (animal model useful to study the neurobiology of aerobic exercise) decreases behavioral markers of vulnerability to addictive properties of various drugs of abuse including cocaine. However, neurobiological mechanisms underpinning this protective effect are far from being fully characterized and understood. Here, 28-day-old female C57BL/6J mice were housed with (n=48) or without (n=48) a running wheel for 6 weeks before being tested for acute locomotor responsiveness and initiation of locomotor sensitization to intraperitoneal injections of 8 mg/kg cocaine. The long-term expression of sensitization took place 3 weeks after the last session. On the day after, all mice underwent a microPET imaging session with [18F]fallypride radiotracer (dopamine 2/3 receptor (D2/3R) antagonist). Exercised mice were less sensitive to acute and sensitized cocaine hyperlocomotor effects, such attenuation being particularly well-marked for long-term expression of sensitization (η2p = 0.262). Additionally, we found that chronic administrations of cocaine was associated with a clear-cut increase of [18F]fallypride binding potential in mouse striatum (η2p = 0.170), presumably reflecting an increase in postsynaptic D2/3R density in this region. Finally, we found evidence that wheel-running exercise was associated with a moderate decrease in D2/3R density in striatum (η2p = 0.075), a mechanism that might contribute to protective properties of such form of exercise against drugs of abuse vulnerability.

Positron emission tomography (PET) has great benefits for developing therapeutics and quantifying pathological markers in neuropsychiatric disorders. This study aimed to firstly demonstrate the feasibility of PET imaging for glucagon-like peptide-1 receptor (GLP-1R) in Alzheimer's disease (AD) and evaluate the GLP-1R expression. Besides, microglial activation, dopamine D2 receptor (D2R) expression, and glucose metabolism in the brain of APP/PS1/tau transgenic model of AD (3×Tg-AD) were also investigated by PET. [18F]FBEM-Cys39-exendin-4, [18F]DPA-714, [18F]fallypride, and [18F]FDG were prepared and PET imaging acquisitions for 3×Tg-AD mice and wild-type (WT) mice were performed at 15, 30, and 60 min post-injection. Fifteen regions of interest (ROIs) were selected and %ID/g was calculated. The results showed that the uptake of [18F]FBEM-Cys39-exendin-4 in 10 ROIs of 3×Tg-AD mice at 60 min post-injection was significantly lower than that of WT mice (p < 0.05). Besides, 3×Tg-AD mice showed significantly higher [18F]DPA-714 uptake in 7 ROIs and lower [18F]fallypride uptake in 4 ROIs compared to WT mice. [18F]FDG PET showed no significant differences in any ROIs between the two groups. A positive correlation between the uptake of [18F]fallypride and [18F]FBEM-Cys39-exendin-4 could be found in the whole brain. In summary, these results validated the feasibility of GLP-1R PET in AD and demonstrated the reduced GLP-1R and D2R expression as well as increased microglial activation caused by AD.

22q11.2 deletion syndrome (22q11DS) is a genetic disorder caused by a microdeletion on chromosome 22q11.2 and associated with an increased risk for developing psychosis. The catechol-O-methyltransferase (COMT) gene is located in the deleted region and involved in dopamine (DA) breakdown. Impaired reinforcement learning (RL) is a recurrent feature in psychosis and thought to be related to abnormal striatal DA function. This study aims to examine RL and the potential association with striatal DA-ergic neuromodulation in 22q11DS. Twelve non-psychotic adults with 22q11DS and 16 healthy controls (HC) were included. A dopamine D2/3 receptor [18F]fallypride positron emission tomography (PET) scan was acquired while participants performed a modified version of the probabilistic stimulus selection task. RL-task performance was significantly worse in 22q11DS compared to HC. There were no group difference in striatal nondisplaceable binding potential (BPND) and task-induced DA release. In HC, striatal task-induced DA release was positively associated with task performance, but no such relation was found in 22q11DS subjects. Moreover, higher caudate nucleus task-induced DA release was found in COMT Met hemizygotes relative to Val hemizygotes. This study is the first to show impairments in RL in 22q11DS. It suggests that potentially motivational impairments are not only present in psychosis, but also in this genetic high risk group. These deficits may be underlain by abnormal striatal task-induced DA release, perhaps as a consequence of COMT haplo-insufficiency. ispartof: EUROPEAN NEUROPSYCHOPHARMACOLOGY vol:28 issue:6 pages:732-742 ispartof: location:Netherlands status: published

Traditional radiosynthetic optimization faces the challenges of high radiation exposure, cost, and inability to perform serial reactions due to tracer decay. To accelerate tracer development, we have developed a strategy to simulate radioactive 18 F-syntheses by using tracer-level (nanomolar) non-radioactive 19 F-reagents and LC-MS/MS analysis. The methodology was validated with fallypride synthesis under tracer-level 19 F-conditions, which showed reproducible and comparable results with radiosynthesis, and proved the feasibility of this process. Using this approach, the synthesis of [18 F]MDL100907 was optimized under 19 F-conditions with greatly improved yield. The best conditions were successfully transferred to radiosynthesis. A radiochemical yield of 19% to 22% was achieved with the radiochemical purity >99% and the molar activity 38.8 to 53.6 GBq/ μmol (n = 3). The tracer-level 19 F-approach provides a high-throughput and cost-effective process to optimize radiosynthesis with reduced radiation exposure. This new method allows medicinal and synthetic chemists to optimize radiolabeling conditions without the need to use radioactivity.

High specific activity is often a significant requirement for radiopharmaceuticals. To achieve that with fluorine-18 (18 F)-labeled probes, it is mandatory to start from no-carrier-added fluoride and to reduce to a minimum the amount of precursor in order to decrease the presence of any pseudocarrier. In the present study, a feasible and efficient method for microscale one-pot radiosynthesis of 18 F-labeled probes is described. It allows a substantial reduction in precursor, solvent, and reagents, thus reducing also possible side reaction in the case of base-sensitive precursors. The method is based on the use of a small amount of Kryptofix 2.2.2/potassium [18 F]fluoride in MeOH (K.222/K[18 F]F-MeOH) obtained using Oasis MAX and MCX cartridges. Five methods, differing in terms of MeOH evaporation and precursor addition, for the radiosynthesis of [18 F]fallypride and [18 F]FET in ≤50-μL scale, were examined and evaluated. The method using the addition of DMSO to the K.222/K[18 F]F-MeOH solution prior to MeOH evaporation is proposed as a versatile procedure for feasible one-pot 10- to 20-μL scale radiosyntheses. This method was successfully applied also to the radiosynthesis of [18 F]FES, [18 F]FLT, and [18 F]FMISO, with radiochemical yields comparable with those reported in the literature. Purification of a crude product by an analytical HPLC column was also demonstrated.

The nigrostriatal and mesocorticolimbic dopamine networks regulate reward-driven behavior. Regional alterations to mesolimbic dopamine D2/3receptor expression are described in drug-seeking and addiction disorders. Parkinson's disease (PD) patients are frequently prescribed D2-like dopamine agonist (DAgonist) therapy for motor symptoms, yet a proportion develop clinically significant behavioral addictions characterized by impulsive and compulsive behaviors (ICBs). Until now, changes in D2/3receptor binding in both striatal and extrastriatal regions have not been concurrently quantified in this population. We identified 35 human PD patients (both male and female) receiving DAgonist therapy, with (n= 17) and without (n= 18) ICBs, matched for age, disease duration, disease severity, and dose of dopamine therapy. In the off-dopamine state, all completed PET imaging with [18F]fallypride, a high affinity D2-like receptor ligand that can measure striatal and extrastriatal D2/3nondisplaceable binding potential (BPND). Striatal differences between ICB+/ICB− patients localized to the ventral striatum and putamen, where ICB+ subjects had reduced BPND. In this group, self-reported severity of ICB symptoms positively correlated with midbrain D2/3receptor BPND. Group differences in regional D2/3BPNDrelationships were also notable: ICB+ (but not ICB−) patients expressed positive correlations between midbrain and caudate, putamen, globus pallidus, and amygdala BPNDs. These findings support the hypothesis that compulsive behaviors in PD are associated with reduced ventral and dorsal striatal D2/3expression, similar to changes in comparable behavioral disorders. The data also suggest that relatively preserved ventral midbrain dopaminergic projections throughout nigrostriatal and mesolimbic networks are characteristic of ICB+ patients, and may account for differential DAgonist therapeutic response.SIGNIFICANCE STATEMENTThe biologic determinants of compulsive reward-based behaviors have broad clinical relevance, from addiction to neurodegenerative disorders. Here, we address biomolecular distinctions in Parkinson's disease patients with impulsive compulsive behaviors (ICBs). This is the first study to image a large cohort of ICB+ patients using positron emission tomography with [18F]fallypride, allowing quantification of D2/3receptors throughout the mesocorticolimbic network. We demonstrate widespread differences in dopaminergic networks, including (1) D2-like receptor distinctions in the ventral striatum and putamen, and (2) a preservation of widespread dopaminergic projections emerging from the midbrain, which is associated with the severity of compulsive behaviors. This clearly illustrates the roles of D2/3receptors and medication effects in maladaptive behaviors, and localizes them specifically to nigrostriatal and extrastriatal regions.

Aims: The volatile general anesthetic sevofl urane is commonly used across all ages in the clinic. Sevofl urane-induced neurotoxic effects on the developing dopaminergic system are still unclear. The aim of this study was to evaluate the integrity of the D2/D3 receptor in developing rat brain utilizing molecular imaging techniques. Method: Positron Emission Tomography (PET) coupled with Computerized Tomography (CT) approaches were used to evaluate the effects of developmental sevofl urane exposure on D2/D3 receptors in rat pups. The PET radiotracer, [18F]-fallypride, was used to examine whether dopamine receptors were affected by prolonged sevofl urane-exposure during the brain growth spurt. Six postnatal day (PND) 7 rats in the experimental group were exposed to sevofl urane at the clinically-relevant concentration of 2.5% (v/v) for 8 hours, and an equal number of control animals were exposed to room air for 8 hours. MicroPET/CT scans were sequentially collected on PNDs 14, 21, 28, and 35. Results: No signifi cant differences in the retention of [18F]-fallypride in striatum were detected between sevofl urane-exposed and control animals at any of the scan times. D2/D3 receptors are not affected by prolonged sevofl urane-induced general anesthesia during development. Conclusions: Sevofl urane-induced neurotoxicity in the developing rodent brain was not associated with apparent derangements in dopamine D2/D3 receptors.

BackgroundAbnormalities in reward learning in psychotic disorders have been proposed to be linked to dysregulated subcortical dopaminergic (DA) neurotransmission, which in turn is a suspected mechanism for predisposition to psychosis. We therefore explored the striatal dopaminergic modulation of reward processing and its behavioral correlates in individuals at familial risk for psychosis.MethodsWe performed a DA D2/3 receptor [18F]fallypride positron emission tomography scan during a probabilistic reinforcement learning task in 16 healthy first-degree relatives of patients with psychosis and 16 healthy volunteers, followed by a 6-day ecological momentary assessment study capturing reward-oriented behavior in the everyday life.ResultsWe detected significant reward-induced DA release in bilateral caudate, putamen and ventral striatum of both groups, with no group differences in its magnitude nor spatial extent. In both groups alike, greater extent of reward-induced DA release in all regions of interest was associated with better performance in the task, as well as in greater tendency to be engaged in reward-oriented behavior in the daily life.ConclusionsThese findings suggest intact striatal dopaminergic modulation of reinforcement learning and reward-oriented behavior in individuals with familial predisposition to psychosis. Furthermore, this study points towards a key link between striatal reward-related DA release and pursuit of ecologically relevant rewards.

Parkinson's disease (PD) is characterized by widespread degeneration of monoaminergic (especially dopaminergic) networks, manifesting with a number of both motor and non-motor symptoms. Regional alterations to dopamine D2/3 receptors in PD patients are documented in striatal and some extrastriatal areas, and medications that target D2/3 receptors can improve motor and non-motor symptoms. However, data regarding the combined pattern of D2/3 receptor binding in both striatal and extrastriatal regions in PD are limited. We studied 35 PD patients off-medication and 31 age- and sex-matched healthy controls (HCs) using PET imaging with [18F]fallypride, a high affinity D2/3 receptor ligand, to measure striatal and extrastriatal D2/3 nondisplaceable binding potential (BPND). PD patients completed PET imaging in the off medication state, and motor severity was concurrently assessed. Voxel-wise evaluation between groups revealed significant BPND reductions in PD patients in striatal and several extrastriatal regions, including the locus coeruleus and mesotemporal cortex. A region-of-interest (ROI) based approach quantified differences in dopamine D2/3 receptors, where reduced BPND was noted in the globus pallidus, caudate, amygdala, hippocampus, ventral midbrain, and thalamus of PD patients relative to HC subjects. Motor severity positively correlated with D2/3 receptor density in the putamen and globus pallidus. These findings support the hypothesis that abnormal D2/3 expression occurs in regions related to both the motor and non-motor symptoms of PD, including areas richly invested with noradrenergic neurons. Keywords: Parkinson's disease, Dopamine, Positron emission tomography (PET), Neurodegeneration, Fallypride