Receptor Availability Research Articles

Striatal dopamine D2-type receptor availability and peripheral 17β-estradiol.

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 D2-type receptor availability, measured with [18F]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 [18F]fallypride were performed on these 2 days, and serum 17β-estradiol was measured using radioimmunoassay. Dopamine D2-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 D2-type receptor availability in the human striatum although other indices of dopaminergic function may be affected.

The neuroendocrine effects of dehydroepiandrosterone and 17β-estradiol in the in vitro preterm hyperoxia infant model

Preterm birth causes neurological deficits. Previously, we demonstrated that fetal zone steroids reduce hyperoxia-mediated cell death in vitro. In immature oligodendrocytes (OLN-93 cells), dehydroepiandrosterone + 17β-estradiol co-treatment had synergistic beneficial effects while signals were transduced through different receptors. In immature astrocytes (C6 cells), both hormones compete for the same receptor and no synergistic effects were observed. 17β-estradiol and progesterone drastically decrease while fetal zone steroids, mainly dehydroepiandrosterone, remain persistently high within preterm infants until term. Substitution of 17β-estradiol and progesterone does not improve neurological outcomes. We investigated the influence of dehydroepiandrosterone, 17β-estradiol or dehydroepiandrosterone + 17β-estradiol treatment in C6 or OLN-93 cells on steroid receptor availability and activation of intracellular signaling molecules in hyperoxic cell culture. We sought explanations of the observed synergistic effect in preliminary study. In C6 cells, the generated signaling of dehydroepiandrosterone + 17β-estradiol treatment has no synergistic effects. The combined effect on this particular pathway does not potentiate cell survival. In OLN-93 cells, we observed significant differences in the early generated signaling of 17β-estradiol + dehydroepiandrosterone treatment to either 17β-estradiol dehydroepiandrosterone alone but never to both at the same time. The latter finding needs, therefore, further investigation to explain synergistic effects. Nevertheless, we add insight into the receptor and signaling cascade alterations induced by 17β-estradiol, dehydroepiandrosterone or 17β-estradiol + dehydroepiandrosterone treatment of C6 and OLN-93 cells in hyperoxia.

Lower striatal dopamine D2/3receptor availability in obsessive-compulsive disorder: A meta-analysis of [11C]-raclopride and [123I]-IBZM studies

It is unclear whether striatal dopamine D2/3 receptor (D2/3R) availability is reduced in obsessive-compulsive disorder (OCD). We conducted a meta-analysis of substituted benzamide radiotracer studies to address this question (k = 4; N = 33 medication-free patients with OCD and N = 38 matched healthy controls). Our meta-analysis suggests that striatal D2/3R availability is lower in medication-free patients with OCD compared to healthy controls (Cohen's d = 0.97, 95% CI = 0.45–1.50, z = 3.65, I2 = 0, p < .0001). Previous studies have not been sufficiently powered to detect this observed effect-size. We recommend that future studies employ larger sample sizes (n ≥ 19 per group), composed of younger OCD patients with greater illness severity, to validate the findings of this meta-analysis. We hope these findings will help guide future dopamine imaging studies in OCD.

Novel Advances in Modifying BMPR2 Signaling in PAH.

Pulmonary Arterial Hypertension (PAH) is a disease of the pulmonary arteries, that is characterized by progressive narrowing of the pulmonary arterial lumen and increased pulmonary vascular resistance, ultimately leading to right ventricular dysfunction, heart failure and premature death. Current treatments mainly target pulmonary vasodilation and leave the progressive vascular remodeling unchecked resulting in persistent high morbidity and mortality in PAH even with treatment. Therefore, novel therapeutic strategies are urgently needed. Loss of function mutations of the Bone Morphogenetic Protein Receptor 2 (BMPR2) are the most common genetic factor in hereditary forms of PAH, suggesting that the BMPR2 pathway is fundamentally important in the pathogenesis. Dysfunctional BMPR2 signaling recapitulates the cellular abnormalities in PAH as well as the pathobiology in experimental pulmonary hypertension (PH). Approaches to restore BMPR2 signaling by increasing the expression of BMPR2 or its downstream signaling targets are currently actively explored as novel ways to prevent and improve experimental PH as well as PAH in patients. Here, we summarize existing as well as novel potential treatment strategies for PAH that activate the BMPR2 receptor pharmaceutically or genetically, increase the receptor availability at the cell surface, or reconstitute downstream BMPR2 signaling.

Seasonal Variation in the Brain μ-Opioid Receptor Availability.

Seasonal rhythms influence mood and sociability. The brain μ-opioid receptor (MOR) system modulates a multitude of seasonally varying socioemotional functions, but its seasonal variation remains elusive with no previously reported in vivo evidence. Here, we first conducted a cross-sectional study with previously acquired human [11C]carfentanil PET imaging data (132 male and 72 female healthy subjects) to test whether there is seasonal variation in MOR availability. We then investigated experimentally whether seasonal variation in daylength causally influences brain MOR availability in rats. Rats (six male and three female rats) underwent daylength cycle simulating seasonal changes; control animals (two male and one female rats) were kept under constant daylength. Animals were scanned repeatedly with [11C]carfentanil PET imaging. Seasonally varying daylength had an inverted U-shaped functional relationship with brain MOR availability in humans. Brain regions sensitive to daylength spanned the socioemotional brain circuits, where MOR availability peaked during spring. In rats, MOR availabilities in the brain neocortex, thalamus, and striatum peaked at intermediate daylength. Varying daylength also affected the weight gain and stress hormone levels. We conclude that cerebral MOR availability in humans and rats shows significant seasonal variation, which is predominately associated with seasonal photoperiodic variation. Given the intimate links between MOR signaling and socioemotional behavior, these results suggest that the MOR system might underlie seasonal variation in human mood and social behavior.SIGNIFICANCE STATEMENT Seasonal rhythms influence emotion and sociability. The central μ-opioid receptor (MOR) system modulates numerous seasonally varying socioemotional functions, but its seasonal variation remains elusive. Here we used positron emission tomography to show that MOR levels in both human and rat brains show daylength-dependent seasonal variation. The highest MOR availability was observed at intermediate daylengths. Given the intimate links between MOR signaling and socioemotional behavior, these results suggest that the MOR system might underlie seasonal variation in human mood and social behavior.

ADORA2A variation and adenosine A1 receptor availability in the human brain with a focus on anxiety-related brain regions: modulation by ADORA1 variation

Adenosine, its interacting A1 and A2A receptors, and particularly the variant rs5751876 in the A2A gene ADORA2A have been shown to modulate anxiety, arousal, and sleep. In a pilot positron emission tomography (PET) study in healthy male subjects, we suggested an effect of rs5751876 on in vivo brain A1 receptor (A1AR) availability. As female sex and adenosinergic/dopaminergic interaction partners might have an impact on this rs5751876 effect on A1AR availability, we aimed to (1) further investigate the pilot male-based findings in an independent, newly recruited cohort including women and (2) analyze potential modulation of this rs5751876 effect by additional adenosinergic/dopaminergic gene variation. Healthy volunteers (32/11 males/females) underwent phenotypic characterization including self-reported sleep and A1AR-specific quantitative PET. Rs5751876 and 31 gene variants of adenosine A1, A2A, A2B, and A3 receptors, adenosine deaminase, and dopamine D2 receptor were genotyped. Multivariate analysis revealed an rs5751876 effect on A1AR availability (P = 0.047), post hoc confirmed in 30 of 31 brain regions (false discovery rate (FDR) corrected P values < 0.05), but statistically stronger in anxiety-related regions (e.g., amygdala, hippocampus). Additional effects of ADORA1 rs1874142 were identified; under its influence rs5751876 and rs5751876 × sleep had strengthened effects on A1AR availability (Pboth < 0.02; post hoc FDR-corrected Ps < 0.05 for 29/30 regions, respectively). Our results support the relationship between rs5751876 and A1AR availability. Additional impact of rs1874142, together with rs5751876 and sleep, might be involved in regulating arousal and thus the development of mental disorders like anxiety disorders. The interplay of further detected suggestive ADORA2A × DRD2 interaction, however, necessitates larger future samples more comparable to magnetic resonance imaging (MRI)-based samples.

Quantification of the Cannabinoid Type 1 Receptor Availability in the Mouse Brain.

Introduction: The endocannabinoid system is involved in several diseases such as addictive disorders, schizophrenia, post-traumatic stress disorder, and eating disorders. As often mice are used as the preferred animal model in translational research, in particular when using genetically modified mice, this study aimed to provide a systematic analysis of in vivo cannabinoid type 1 (CB1) receptor ligand-binding capacity using positron emission tomography (PET) using the ligand [18F]MK-9470. We then compared the PET results with literature data from immunohistochemistry (IHC) to review the consistency between ex vivo protein expression and in vivo ligand binding.Methods: Six male C57BL/6J (6–9 weeks) mice were examined with the CB1 receptor ligand [18F]MK-9470 and small animal PET. Different brain regions were evaluated using the parameter %ID/ml. The PET results of the [18F]MK-9470 accumulation in the mouse brain were compared with immunohistochemical literature data.Results: The ligand [18F]MK-9470 was taken up into the mouse brain within 5 min after injection and exhibited slow kinetics. It accumulated highly in most parts of the brain. PET and IHC classifications were consistent for most parts of the telencephalon, while brain regions of the diencephalon, mesencephalon, and rhombencephalon were rated higher with PET than IHC.Conclusions: This preclinical [18F]MK-9470 study demonstrated the radioligand’s applicability for imaging the region-specific CB1 receptor availability in the healthy adult mouse brain and thus offers the potential to study CB1 receptor availability in pathological conditions.

Polycystic Ovary Syndrome and Brain: An Update on Structural and Functional Studies.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of women in reproductive age and is associated with reproductive, endocrine, metabolic, cardiovascular, and psychological outcomes. All these disorders are thought to be affected by central mechanisms which could be a major contributor in pathogenesis of PCOS. This mini-review discusses the relevance of central nervous system imaging modalities in understanding the neuroendocrine origins of PCOS as well as their relevance to understanding its comorbidities. Current data suggest that central nervous system plays a key role in development of PCOS. Decreased global and regional brain volumes and altered white matter microstructure in women with PCOS is shown by structural imaging modalities. Functional studies show diminished reward response in corticolimbic areas, brain glucose hypometabolism, and greater opioid receptor availability in reward-related regions in insulin-resistant patients with PCOS. These structural and functional disturbances are associated with nonhomeostatic eating, diminished appetitive responses, as well as cognitive dysfunction and mood disorders in women with PCOS. Structural and functional brain imaging is an emerging modality in understanding pathophysiology of metabolic disorders such as diabetes and obesity as well as PCOS. Neuroimaging can help researchers and clinicians for better understanding the pathophysiology of PCOS and related comorbidities as well as better phenotyping PCOS.

In vivo gamma-aminobutyric acid-A/benzodiazepine receptor availability and genetic liability in asymptomatic individuals with high genetic loading of schizophrenia: A [11C]flumazenil positron emission tomography study.

Whilst reduced signalling and gene expression related to gamma-aminobutyric acid (GABA) play a role in the presumed pathophysiology of schizophrenia, its origin is unclear. Studying asymptomatic individuals with high genetic liability to schizophrenia (AIs) would provide insights. Therefore, this study aimed to investigate the role of genetic liability in GABAergic dysfunction of schizophrenia by exploring in vivo GABA-A/benzodiazepine receptor (GABAR) availability in AIs. A total of 10 AIs with multiple relatives diagnosed as schizophrenia and 11 healthy controls underwent [11C]flumazenil positron emission tomography and neurocognitive function tests. There was no significant difference in [11C]flumazenil availability based on the groups. GABAR availability in caudate nuclei had positive correlations with genetic liability of AIs. GABAR availability in caudate nuclei and verbal memory measures of AIs revealed positive correlations. Only the correlation between right caudate and short-term verbal memory survived multiple-comparison correction (p = 0.030). This study, for the first time, reports correlations between the genetic liability of schizophrenia and GABAR availability. Correlations between [11C]flumazenil binding in caudate of individuals with high genetic liability to schizophrenia suggests that the GABAergic dysfunction may arise from shared genetic factors and also that it may be responsible for cognitive impairment of AIs.

Cortical thickness mediates the relationship between DRD2 C957T polymorphism and executive function across the adult lifespan.

Dopamine (DA) signaling is critical for optimal cognitive performance. Aging is accompanied by a change in the strength of this signaling, with a loss of striatal and extrastriatal D2 binding potential. The reduction in dopamine modulation with age negatively influences various aspects of cognition. DRD2 C957T (rs6277) impacts DA D2 receptor density and availability, with C homozygotes linked to lower striatal DA availability and reduced executive functioning (EF), but also high extrastriatal binding potential. Here, we investigated in 176 participants aged 20-94years whether: (1) DRD2 C carriers differ from T carriers in cortical thickness or subcortical volume in areas of high concentrations of D2 receptors that receive projections from mesocortical or nigrostriatal dopaminergic pathways; (2) whether the DRD2*COMT relationship has any synergistic effects on cortical thickness; (3) whether the effect of DRD2 on brain structure depends upon age; and (4) whether DRD2-related regional thinning affects executive function performance. We show that DRD2 impacts cortical thickness in the superior parietal lobule, precuneus, and anterior cingulate (marginal after FDR correction), while statistically controlling sex, age, and COMT genotype. Specifically, C homozygotes demonstrated thinner cortices than both heterozygotes and/or T homozygotes in an age-invariant manner. Additionally, DRD2 predicted executive function performance via cortical thickness. The results highlight that genetic influences on dopamine availability impact cognitive performance via the contribution of brain structure in cortical regions influenced by DRD2.

Differential associations of dopamine synthesis capacity with the dopamine transporter and D2 receptor availability as assessed by PET in the living human brain

BackgroundThe dopamine (DA) neurotransmission has been implicated in fundamental brain functions, exemplified by movement controls, reward-seeking, motivation, and cognition. Although dysregulation of DA neurotransmission in the striatum is known to be involved in diverse neuropsychiatric disorders, it is yet to be clarified whether components of the DA transmission, such as synthesis, receptors, and reuptake are coupled with each other to homeostatically maintain the DA neurotransmission. The purpose of this study was to investigate associations of the DA synthesis capacity with the availabilities of DA transporters and D2 receptors in the striatum of healthy subjects. MethodsFirst, we examined correlations between the DA synthesis capacity and DA transporter availability in the caudate and putamen using PET data with L-[β-11C]DOPA and [18F]FE-PE2I, respectively, acquired from our past dual-tracer studies. Next, we investigated relationships between the DA synthesis capacity and D2 receptor availability employing PET data with L-[β-11C]DOPA and [11C]raclopride, respectively, obtained from other previous dual-tracer assays. ResultsWe found a significant positive correlation between the DA synthesis capacity and DA transporter availability in the putamen, while no significant correlations between the DA synthesis capacity and D2 receptor availability in the striatum. ConclusionThe intimate association of the DA synthesis rate with the presynaptic reuptake of DA indicates homeostatic maintenance of the baseline synaptic DA concentration. In contrast, the total abundance of D2 receptors, which consist of presynaptic autoreceptors and postsynaptic modulatory receptors, may not have an immediate relationship to this regulatory mechanism.

Dopamine D2/3 Receptor Availabilities and Evoked Dopamine Release in Striatum Differentially Predict Impulsivity and Novelty Preference in Roman High- and Low-Avoidance Rats.

BackgroundImpulsivity and novelty preference are both associated with an increased propensity to develop addiction-like behaviors, but their relationship and respective underlying dopamine (DA) underpinnings are not fully elucidated.MethodsWe evaluated a large cohort (n = 49) of Roman high- and low-avoidance rats using single photon emission computed tomography to concurrently measure in vivo striatal D2/3 receptor (D2/3R) availability and amphetamine (AMPH)-induced DA release in relation to impulsivity and novelty preference using a within-subject design. To further examine the DA-dependent processes related to these traits, midbrain D2/3-autoreceptor levels were measured using ex vivo autoradiography in the same animals.ResultsWe replicated a robust inverse relationship between impulsivity, as measured with the 5-choice serial reaction time task, and D2/3R availability in ventral striatum and extended this relationship to D2/3R levels measured in dorsal striatum. Novelty preference was positively related to impulsivity and showed inverse associations with D2/3R availability in dorsal striatum and ventral striatum. A high magnitude of AMPH-induced DA release in striatum predicted both impulsivity and novelty preference, perhaps owing to the diminished midbrain D2/3-autoreceptor availability measured in high-impulsive/novelty-preferring Roman high-avoidance animals that may amplify AMPH effect on DA transmission. Mediation analyses revealed that while D2/3R availability and AMPH-induced DA release in striatum are both significant predictors of impulsivity, the effect of striatal D2/3R availability on novelty preference is fully mediated by evoked striatal DA release.ConclusionsImpulsivity and novelty preference are related but mediated by overlapping, yet dissociable, DA-dependent mechanisms in striatum that may interact to promote the emergence of an addiction-prone phenotype.

Adult Attachment System Links With Brain Mu Opioid Receptor Availability In Vivo

BackgroundSecure attachment is important in maintaining an individual’s health and well-being. Attachment disturbances increase the risk for developing psychiatric disorders such as affective disorders. Yet, the neurobiological correlates of human attachment are poorly understood at the neurotransmitter level. We investigated whether adult attachment style is linked to functioning of the opioid and serotonergic systems in the human brain. MethodsWe used positron emission tomography with radioligands [11C]carfentanil and [11C]MADAM to quantify mu opioid receptor (n = 39) and serotonin transporter (n = 37) availability in volunteers with no current psychiatric disorders. Attachment style was determined according to the Dynamic-Maturational Model of Attachment and Adaptation with the structured Adult Attachment Interview. ResultsSecure attachment was associated with higher mu opioid receptor availability in the hippocampus, amygdala, thalamus, and prefrontal cortex when compared with insecure (i.e., avoidant or ambivalent groups combined) attachment. In contrast, attachment style was not associated with serotonin transporter availability. ConclusionsOur results provide preliminary in vivo evidence that the opioid system may be involved in the neurocircuits associated with individual differences in adult attachment behavior. The results suggest that variation in mu opioid receptor availability may be linked with the individuals’ social relationships and psychosocial well-being and thus contributes to risk for psychiatric morbidity.

Association between cannabinoid 1 receptor availability and glutamate levels in healthy controls and drug-free patients with first episode psychosis: a multi-modal PET and 1H-MRS study

Cannabinoid 1 receptor and glutamatergic dysfunction have both been implicated in the pathophysiology of schizophrenia. However, it remains unclear if cannabinoid 1 receptor alterations shown in drug-naïve/free patients with first episode psychosis may be linked to glutamatergic alterations in the illness. We aimed to investigate glutamate levels and cannabinoid 1 receptor levels in the same region in patients with first episode psychosis. Forty volunteers (20 healthy volunteers, 20 drug-naïve/free patients with first episode psychosis diagnosed with schizophrenia/schizoaffective disorder) were included in the study. Glutamate levels were measured using proton magnetic resonance spectroscopy. CB1R availability was indexed using the distribution volume (VT (ml/cm3)) of [11C]MePPEP using arterial blood sampling. There were no significant associations between ACC CB1R levels and ACC glutamate levels in controls (R = − 0.24, p = 0.32) or patients (R = − 0.10, p = 0.25). However, ACC glutamate levels were negatively associated with CB1R availability in the striatum (R = − 0.50, p = 0.02) and hippocampus (R = − 0.50, p = 0.042) in controls, but these associations were not observed in patients (p > 0.05). Our findings extend our previous work in an overlapping sample to show, for the first time as far as we’re aware, that cannabinoid 1 receptor alterations in the anterior cingulate cortex are shown in the absence of glutamatergic dysfunction in the same region, and indicate potential interactions between glutamatergic signalling in the anterior cingulate cortex and the endocannabinoid system in the striatum and hippocampus.

Dopamine dysregulation in psychotic relapse after antipsychotic discontinuation: an [18F]DOPA and [11C]raclopride PET study in first-episode psychosis.

Although antipsychotic drugs are effective for relieving the psychotic symptoms of first-episode psychosis (FEP), psychotic relapse is common during the course of the illness. While some FEPs remain remitted even without medication, antipsychotic discontinuation is regarded as the most common risk factor for the relapse. Considering the actions of antipsychotic drugs on presynaptic and postsynaptic dopamine dysregulation, this study evaluated possible mechanisms underlying relapse after antipsychotic discontinuation. Twenty five FEPs who were clinically stable and 14 matched healthy controls were enrolled. Striatal dopamine activity was assessed as Kicer value using [18F]DOPA PET before and 6 weeks after antipsychotic discontinuation. The D2/3 receptor availability was measured as BPND using [11C]raclopride PET after antipsychotic discontinuation. Healthy controls also underwent PET scans according to the corresponding schedule of the patients. Patients were monitored for psychotic relapse during 12 weeks after antipsychotic discontinuation. 40% of the patients showed psychotic relapse after antipsychotic discontinuation. The change in Kicer value over time significantly differed between relapsed, non-relapsed patients and healthy controls (Week*Group: F = 4.827, df = 2,253.193, p = 0.009). In relapsed patients, a significant correlation was found between baseline striatal Kicer values and time to relapse after antipsychotic discontinuation (R2 = 0.518, p = 0.018). BPND were not significantly different between relapsed, non-relapsed patients and healthy controls (F = 1.402, df = 2,32.000, p = 0.261). These results suggest that dysfunctional dopamine autoregulation might precipitate psychotic relapse after antipsychotic discontinuation in FEP. This finding could be used for developing a strategy for the prevention of psychotic relapse related to antipsychotic discontinuation.

Longitudinal imaging of metabotropic glutamate 5 receptors during early and extended alcohol abstinence.

Chronic alcohol use has important effects on the glutamate system. The metabotropic glutamate 5 (mGlu5) receptor has shown promise in preclinical models as a target to reduce drinking-related behaviors and cue-induced reinstatement, motivating human studies of mGlu5 receptor negative allosteric modulators. The goal of this work was to measure levels of mGlu5 receptor availability with positron emission tomography (PET) imaging using the mGlu5 receptor-specific radiotracer [18F]FPEB during early and extended alcohol abstinence. Subjects who met DSM-5 criteria for alcohol use disorder (AUD; n = 17) were admitted inpatient for the study duration. [18F]FPEB PET scans were acquired first during early abstinence (6 ± 4 days after last drink) and a second time during extended abstinence (n = 13; 27 ± 6 days after last drink). A single scan was acquired in healthy controls matched for sex and smoking status (n = 20). [18F]FPEB total volumes of distribution (VT) corrected for partial volume effects were measured using equilibrium analysis throughout the brain. A linear mixed model controlling for smoking status and sex identified significantly higher [18F]FPEB VT in AUD subjects at early abstinence compared to controls (F(1,32) = 7.23, p = 0.011). Post-hoc analyses revealed this effect to occur in cortical brain regions. No evidence for significant changes in [18F]FPEB VT over time were established. These findings provide human evidence consistent with a robust preclinical literature supporting mGlu5 receptor drugs as pharmacotherapies for AUD.

A phase 1b study evaluating the effect of elacestrant treatment on estrogen receptor availability and estradiol binding to the estrogen receptor in metastatic breast cancer lesions using 18F-FES PET/CT imaging

BackgroundElacestrant is an oral selective estrogen receptor (ER) degrader. This phase 1b open-label, non-randomized study (RAD1901-106) was initiated to determine the effect of elacestrant on the availability of ER in lesions from postmenopausal women with ER+ advanced breast cancer (ABC) using 16α-18F-fluoro-17β-estradiol positron emission tomography with low-dose computed tomography (FES-PET/CT).MethodsEligible patients were postmenopausal women with ER+, HER2− ABC; tumor progression after ≥ 6 months of 1–3 lines of endocrine treatment for ABC; and measurable or evaluable disease. Two 8-patient cohorts were enrolled: one treated with 400 mg elacestrant once daily (QD) and one treated with 200 mg elacestrant QD with dose escalation to 400 mg QD after 14 days. Elacestrant was dosed continuously until progressive disease, toxicity, or withdrawal. FES-PET/CT was performed pre-dose at baseline and 4 h post-dose on day 14. The primary endpoint was the percentage difference in FES uptake in tumor lesions (maximum 20) after 14 days of treatment compared to baseline. Overall response was investigator-assessed by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1.ResultsPatients (n = 16; median age, 53.5 years) had ABC with a median 2.5 prior lines of endocrine therapy. Median reduction in tumor FES uptake from baseline to day 14 was 89.1% (Q1, Q3: 75.1%, 94.1%) and was similar in both cohorts (89.1% [Q1, Q3: 67.4%, 94.2%], 200/400 mg and 88.7% [Q1, Q3: 79.5%, 94.1%], 400 mg). Residual ER availability (> 25% persistence in FES uptake) on day 14 was observed in 3 patients receiving 200/400 mg (3/78, 37.5%) and 1 patient receiving 400 mg (1/8, 12.5%). The overall response rate (ORR) was 11.1% (1 partial response), and clinical benefit rate (CBR) was 30.8%. Median percentage change in FES uptake did not correlate with ORR or CBR. Adverse events occurring in > 20% of the patients were nausea (68.8%), fatigue (50.0%), dyspepsia (43.8%), vomiting (37.5%), and decreased appetite, dysphagia, and hot flush (31.3% each). Most events were grade 2 in severity.ConclusionElacestrant 200 mg and 400 mg QD greatly reduced ER availability measured by FES-PET/CT. In a heavily pretreated population, elacestrant was associated with antitumor activity.Trial registrationClinicalTrials.gov, NCT02650817. Registered on 08 January 2016

Retraction Note: Cannabinoid type 1 receptor availability in the amygdala mediates threat processing in trauma survivors.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Abstract 803: Visualizing bicalutamide effect on androgen receptor availability in patients with metastatic breast cancer

Abstract BACKGROUND: The androgen receptor (AR) is a potential new therapeutic target in metastatic breast cancer, but it is likely that only patients with tumors overexpressing AR can benefit. To non-invasively assess AR expression in all metastatic lesions, whole-body imaging techniques such as 16β-18F-fluoro-5α-dihydrotestosterone positron emission tomography (18F-FDHT-PET), can be used. 18F-FDHT uptake reduction during treatment with an AR antagonist may indicate effective targeting of AR, and therefore might be predictive for response to treatment. This study assessed the feasibility of 18F-FDHT-PET to detect changes in 18F-FDHT uptake during treatment with AR antagonist bicalutamide, and evaluated whether these changes were related to bicalutamide response. PATIENTS AND METHODS: Postmenopausal women with AR positive (&amp;gt;10% staining on primary tumor or metastasis biopsy), human epidermal growth factor receptor 2-negative metastatic breast cancer, regardless of estrogen receptor status, were eligible. At baseline, patients underwent a bone scintigraphy, and contrast-enhanced computed tomography, as part of standard staging. Metastatic lesions were identified on both imaging modalities. All patients received an 18F-FDHT-PET at baseline and after 4 to 6 weeks bicalutamide 150mg daily. Baseline 18F-FDHT uptake was expressed as maximum standardized uptake value (SUVmax). Change between baseline and repeated 18F-FDHT uptake was assessed as (difference of) SUVmax corrected for physiological background activity (SUVcor and ΔSUVcor), per patient and per lesion. Response evaluation was performed by radiological imaging according to RECIST 1.1 and/or clinical assessment. Clinical benefit was defined as absence of disease progression for at least 24 weeks. RESULTS: Twenty-one patients (mean age 65 years) with in total 536 metastatic lesions were included. Baseline 18F-FDHT-PET detected 341 of 515 lesions found with standard imaging, and 21 new lesions. Baseline 18F-FDHT uptake varied widely between patients (median SUVmax 2.62; range 1.58 - 5.58) and lesions (3.07; 0.64 - 20.24). Repeated 18F-FDHT-PET was evaluable in 17 patients with 349 metastatic lesions. Repeated 18F-FDHT uptake showed median SUVcor decrease from 1.30 to 0.72 per patient, and 1.26 to 0.69 per lesion (P &amp;lt; 0.001). Median ΔSUVcor per patient was −45% (range −72% to −7%), and per lesion −39% (−95% to +100%). In patients with clinical benefit on bicalutamide (n = 3), median ΔSUVcor was −49% versus −39% in patients without benefit (n = 14; P = 0.801). CONCLUSION: In this feasibility study, bicalutamide induced 18F-FDHT uptake change could be detected by repeated 18F-FDHT-PET in patients with AR positive metastatic breast cancer. However, in this small study, this change was not significantly related to bicalutamide response per patient. (NCT02697032) Funding by UMCG Healthy Ageing Pilots and de Cock-Hadders Foundation Citation Format: Jorianne Boers, Clasina M. Venema, Erik FJ de Vries, Geke AP Hospers, Hendrikus H. Boersma, Bart Rikhof, Christine Dorbritz, Andor WJM Glaudemans, Carolina P. Schröder. Visualizing bicalutamide effect on androgen receptor availability in patients with metastatic breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 803.

The circadian phase of antenatal glucocorticoid treatment affects the risk of behavioral disorders

During pregnancy, maternal endocrine signals drive fetal development and program the offspring’s physiology. A disruption of maternal glucocorticoid (GC) homeostasis increases the child’s risk of developing psychiatric disorders later in life. We here show in mice, that the time of day of antenatal GC exposure predicts the behavioral phenotype of the adult offspring. Offspring of mothers receiving GCs out-of-phase compared to their endogenous circadian GC rhythm show elevated anxiety, impaired stress coping, and dysfunctional stress-axis regulation. The fetal circadian clock determines the vulnerability of the stress axis to GC treatment by controlling GC receptor (GR) availability in the hypothalamus. Similarly, a retrospective observational study indicates poorer stress compensatory capacity in 5-year old preterm infants whose mothers received antenatal GCs towards the evening. Our findings offer insights into the circadian physiology of feto-maternal crosstalk and assign a role to the fetal clock as a temporal gatekeeper of GC sensitivity.