5-Hydroxytryptamine (5-HT2A) receptors play an important role in several psychiatric disorders. In order to investigate the serotonin (5-HT) receptor in vivo, reliable syntheses are required for positron emission tomography (PET) 5-HT radioligands. Owing to the excellent in vivo properties of [18F]MDL100907 for PET, there has been great interest to develop a novel synthetic route for [18F]MDL100907. Here, we report a highly efficient, scalable, and expedient synthesis for [18F]MDL100907. The radiofluorination was performed on a 18F-labeling boron pinacol ester precursor, which is synthesized using the Liebeskind–Srogl cross-coupling reaction as a key step. Our method is practically more suitable to employ late-stage Cu-mediated radiofluorination and facilitate the production of the [18F]MDL100907 radioligand in excellent decay-corrected RCY of 32 ± 10% (n = 7) within 60 min. We prepared [18F]MDL100907 in high molar activity (2.1 Ci/μmol) and compared it to [11C]MDL100907 in the brain of a nonhuman primate.

Anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid (18F-FACBC) is a synthetic amino acid analog PET radiotracer undergoing clinical trials for the evaluation of prostate and other cancers. We aimed to describe common physiologic uptake patterns, incidental findings, and variants in patients who had undergone 18F- FACBC PET. Methods: Sixteen clinical trials involving 611 18F-FACBC studies from 6 centers, which included dosimetry studies on 12 healthy volunteers, were reviewed. Qualitative observations of common physiologic patterns, incidental uptake, and variants that could simulate disease were recorded and compared with similar observations in studies of the healthy volunteers. Quantitative analysis of select data and review of prior published reports and observations were also made. Results: The liver and pancreas demonstrated the most intense uptake. Moderate salivary and pituitary uptake and variable mild to moderate bowel activity were commonly visualized. Moderate bone marrow and mild muscle activity were present on early images, with marrow activity decreasing andmuscle activity increasing with time. Brain and lungs demonstrated activity less than blood pool. Though 18F-FACBC exhibited little renal excretion or bladder uptake during the clinically useful early imaging time window, mild to moderate activity might accumulate in the bladder and interfere with evaluation of adjacent prostate bed and seminal vesicles in 5%-10% of patients. Uptake might also occur from benign processes such as infection, inflammation, prostatic hyperplasia, and metabolically active benign bone lesions such as osteoid osteoma. Conclusion: Common physiologic uptake patterns were similar to those noted in healthy volunteers. The activity in organs followed the presence of amino acid transport and metabolism described with other amino acid-based PET radiotracers. As with other PET radiotracers such as 18F-FDG, focal nonphysiologic uptake may represent incidental malignancy. Uptake due to benign etiologies distinct from physiologic background also occurred and could lead to misinterpretations if the reader is unaware of them.

Introduction: Fluorine-18 labeled 2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane ([18F]FECNT) binds reversibly to the dopamine transporter (DAT) with high selectivity. [18F]FECNT has been used extensively in the quantification of DAT occupancy in non-human primate brain and can distinguish between Parkinson's and healthy controls in humans. The purpose of this work was to develop a compartment model to characterize the kinetics of [18F]FECNT for quantification of DAT density in healthy human brain. Methods: Twelve healthy volunteers underwent 180min dynamic [18F]FECNT PET imaging including sampling of arterial blood. Regional time-activity curves were extracted from the caudate, putamen and midbrain including a reference region placed in the cerebellum. Binding potential, BPND, was calculated for all regions using kinetic parameters estimated from compartmental and Logan graphical model fits to the time-activity data. Simulations were performed to determine whether the compartment model could reliably fit time-activity data over a range of BPND values. Results: The kinetics of [18F]FECNT were well-described by the reversible 2-tissue arterial input and full reference tissue compartment models. Calculated binding potentials in the caudate, putamen and midbrain were in good agreement between the arterial input model, reference tissue model and the Logan graphical model. The distribution volume in the cerebellum did not reach a plateau over the duration of the study, which may be a result of non-specific binding in the cerebellum. Simulations that included non-specific binding show that the reference and arterial input models are able to estimate BPND for DAT densities well below that observed in normal volunteers. Conclusion: The kinetics of [18F]FECNT in human brain are well-described by arterial input and reference tissue compartment models. Measured and simulated data show that BPND calculated with reference tissue model is proportional to BPND calculated from the arterial input model. © 2014 Elsevier Inc.

The physiology of the oxytocin receptor has increasingly become a focus of scientific investigation due to its connection with social behavior and psychiatric disorders with impairments in social funciton. Experimental utilization of small molecule and peptide antagonists for the oxytocin receptor has played a role in deciphering these biological and social behavior connections in rodents. Described herein is the evaluation of a potent and selective oxytocin receptor antagonist, ALS-I-41, and details to consider for its use in nonhuman primate behavioral pharmacology experiments utilizing intranasal or intramuscular administration. The central nervous system penetration and rate of metabolism of ALS-I-41 was investigated via mass spectroscopy analysis of cerebrospinal fluid and plasma in the rhesus macaque after intranasal and intramuscular administration. Positron emission tomography was also utilized with [ 18 F] ALS-I-41 in a macaque to verify observed central nervous system (CNS) penetration and to further evaluate the effects of administration rate on CNS penetration of Sprague-Dawley rats in comparison to previous studies.

Purpose We explored the influence of FACBC (fluciclovine) PET/CT on the decision to offer radiotherapy and radiotherapy treatment field recommendations in postprostatectomy patients with recurrent prostate cancer. Patients and Methods After obtaining institutional review board approval and informed consent, 87 patients with detectable prostate-specific antigen (PSA) levels were recruited into a prospective clinical trial. After an initial provider-determined radiotherapy plan based on conventional imaging, 44 of 87 patients were randomized to additionally undergo fluciclovine PET/CT. Pre- and post-fluciclovine radiotherapy decisions were compared and changes were noted. Statistical significance of these decision changes was determined. Results Two of 44 patients in the experimental arm dropped out before fluciclovine scanning. Thirty-four (81.0%) of 42 had positive results on fluciclovine. Overall radiotherapy decision was changed in 17 (40.5%) of 42. Mean PSA, original Gleason score, and prostatectomy-PET interval did not differ significantly between patients with and without radiotherapy decision changes. Two (4.8%) of 42 had the decision for radiotherapy withdrawn due to positive extrapelvic findings. Radiotherapy field decision was changed in 15 (35.7%) of 42. Eleven (73.3%) of 15 had fields changed from prostate bed only to both prostate bed and pelvis, while 4 (26.7%) of 15 had fields changed from both prostate bed and pelvis to prostate bed only. Changes in overall radiotherapy decision and field were statistically significant (P < 0.0001). However, the change in the decision to offer radiotherapy or not was not statistically significant (P = 0.15). Conclusions Fluciclovine PET/CT significantly changed radiotherapy management decisions in postprostatectomy patients with recurrent prostate cancer. Further work in determining differences in PSA-free survival is ongoing.

Background Limited controlled data exist to guide treatment choices for clinicians caring for patients with major depressive disorder (MDD). Although many putative predictors of treatment response have been reported, most were identified through retrospective analyses of existing datasets and very few have been replicated in a manner that can impact clinical practice. One major confound in previous studies examining predictors of treatment response is the patient’s treatment history, which may affect both the predictor of interest and treatment outcomes. Moreover, prior treatment history provides an important source of selection bias, thereby limiting generalizability. Consequently, we initiated a randomized clinical trial designed to identify factors that moderate response to three treatments for MDD among patients never treated previously for the condition. Methods/design Treatment-naïve adults aged 18 to 65 years with moderate-to-severe, non-psychotic MDD are randomized equally to one of three 12-week treatment arms: (1) cognitive behavior therapy (CBT, 16 sessions); (2) duloxetine (30–60 mg/d); or (3) escitalopram (10–20 mg/d). Prior to randomization, patients undergo multiple assessments, including resting state functional magnetic resonance imaging (fMRI), immune markers, DNA and gene expression products, and dexamethasone-corticotropin-releasing hormone (Dex/CRH) testing. Prior to or shortly after randomization, patients also complete a comprehensive personality assessment. Repeat assessment of the biological measures (fMRI, immune markers, and gene expression products) occurs at an early time-point in treatment, and upon completion of 12-week treatment, when a second Dex/CRH test is also conducted. Patients remitting by the end of this acute treatment phase are then eligible to enter a 21-month follow-up phase, with quarterly visits to monitor for recurrence. Non-remitters are offered augmentation treatment for a second 12-week course of treatment, during which they receive a combination of CBT and antidepressant medication. Predictors of the primary outcome, remission, will be identified for overall and treatment-specific effects, and a statistical model incorporating multiple predictors will be developed to predict outcomes. Discussion The PReDICT study’s evaluation of biological, psychological, and clinical factors that may differentially impact treatment outcomes represents a sizeable step toward developing personalized treatments for MDD. Identified predictors should help guide the selection of initial treatments, and identify those patients most vulnerable to recurrence, who thus warrant maintenance or combination treatments to achieve and maintain wellness.

Background: Stereotactic radiosurgery (SRS) is often the primary treatment modality for patients with intracranial metastatic disease. Despite advances in magnetic resonance imaging, including use of perfusion and diffusion sequences and molecular imaging, distinguishing radiation necrosis from progressive tumor remains a diagnostic and clinical challenge. We investigated the sensitivity and specificity of 18F-fluciclovine PET to accurately distinguish radiation necrosis from recurrent intracranial metastatic disease in patients who had previously undergone SRS. Methods: Fluciclovine PET imaging was performed in 8 patients with a total of 15 lesions that had previously undergone SRS and had subsequent MRI and clinical features suspicious for recurrent disease. The SUVmax of each lesion and the contralateral normal brain parenchyma were summated and evaluated at four different time points (5 min, 10 min, 30 min, and 55 min). Lesions were characterized as either recurrent disease (11 of 15 lesions) or radiation necrosis (4 of 15 lesions) and confirmed with histopathological correlation (7 lesions) or through serial MRI studies (8 lesions). Results: Time activity curve analysis found statistically greater radiotracer accumulation for all lesions, including radiation necrosis, when compared to contralateral normal brain. While the mean and median SUVmax for recurrent disease were statistically greater than those of radiation necrosis at all time points, the difference was more significant at the earlier time points (p = 0.004 at 5 min–0.025 at 55 min). Using a SUVmax threshold of ≥ 1.3, fluciclovine PET demonstrated a 100% accuracy in distinguishing recurrent disease from radiation necrosis up to 30 min after injection and an accuracy of 87% (sensitivity = 0.91, specificity = 0.75) at the last time point of 55 min. However, tumor-to-background ratios (TBRmax) were not significantly different between recurrent disease and radiation necrosis at any time point due to variable levels of fluciclovine uptake in the background brain parenchyma. Conclusions: Fluciclovine PET may play an important role in distinguishing active intracranial metastatic lesions from radiation necrosis in patients previously treated with SRS but needs to be validated in larger studies.

Background: Oxidative stress and inflammation are proposed mechanisms of nonspecific kidney injury and progressive kidney failure. Higher dietary oxidative balance scores (OBS) are associated with lower prevalence of chronic kidney disease (CKD). Methods: We investigated the association between OBS and biomarkers of inflammation using data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Nutrient estimates from the Block Food Frequency Questionnaires were used to define tertiles of 11 pro- and antioxidant factors. Points for each OBS component were summed, with a higher score indicating predominance of antioxidant exposures. Multivariable linear regression models were used to estimate the association between OBS and biomarkers of inflammation (interleukin-6 [IL-6], interleukin-8 [IL-8], interleukin-10 [IL-10], fibrinogen, C-reactive protein [CRP], white blood cell count, and cystatin C). An interaction term was included to determine if associations between OBS and inflammatory markers differed between individuals with and without CKD. Results: Of 682 participants, 22.4% had CKD. In adjusted models, OBS was associated with CRP and IL-6. For every 5-unit increase in OBS, the CRP concentration was -15.3% lower (95% CI: -25.6, -3.6). The association of OBS with IL-6 differed by CKD status; for every 5-unit increase in OBS, IL-6 was -10.7% lower (95% CI: -16.3, -4.7) among those without CKD, but there was no association among those with CKD (p = 0.03). Conclusion: This study suggests that a higher OBS is associated with more favorable levels of IL-6 and CRP, and that the association of OBS and IL-6 may be modified by CKD status.

Persistent exposure to environmental stressors causes dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis and alters GABAA receptor (GABAAR) levels throughout the brain. Social subordination in socially housed female rhesus results in distinctive stress-related physiological and behavioral phenotypes that are dependent on the ovarian hormone estradiol (E2). In the present study, we utilized ovariectomized adult female rhesus monkeys undergoing hormone replacement with E2 to test the hypothesis that the chronic psychosocial stress of subordination alters GABAAR binding potential (GABAAR BPND) in limbic regions implicated in emotional processing including the prefrontal cortex, temporal lobe (amygdala and hippocampus), and hypothalamus. Furthermore, we tested the hypothesis that peripheral administration of a corticotropin-releasing hormone (CRH) receptor antagonist (astressin B) would reverse the alterations in GABAAR binding within these regions in subordinate females. After subjects received astressin B or saline for three consecutive days, GABAAR BPND was determined by positron emission tomography (PET) using 18F-flumazenil as a radioligand. T1-weighted structural magnetic resonance imaging scans were also acquired for PET scan co-registration, in order to perform a region of interest analysis using the pons as a reference region. Compared to socially dominant females, subordinate females exhibited increased GABAAR BPND in the prefrontal cortex but not in the temporal lobe or the hypothalamus. Administration of astressin B eliminated the status difference in GABAAR BPND in the prefrontal cortex, suggesting that the chronic stressor of social subordination modulates GABAergic tone via effects on CRH and the LHPA axis, at least in prefrontal regions.

Social subordination in female macaques represents a well-described model of chronic psychosocial stress. Additionally, a length polymorphism (5-HTTLPR) in the regulatory region of the serotonin (5-HT) transporter (5-HTT) gene (SLC6A4) is present in rhesus macaques, which has been linked to adverse outcomes similar to that described in humans with an analogous 5-HTTLPR polymorphism. The present study determined the effects of social status and the 5-HTTLPR genotype on 5-HT1A receptor binding potential (5-HT1A BPND) in brain regions implicated in emotional regulation and stress reactivity in ovariectomised female monkeys, and then assessed how these effects were altered by 17β-oestradiol (E2) treatment. Areas analysed included the prefrontal cortex [anterior cingulate (ACC); medial prefrontal cortex (mPFC); dorsolateral prefrontal cortex; orbitofrontal prefrontal cortex], amygdala, hippocampus, hypothalamus and raphe nucleui. Positron emission tomography using p-[18F]MPPF was performed to determine the levels of 5-HT1A BPND under a non-E2 and a 3-week E2 treatment condition. The short variant (s-variant) 5-HTTLPR genotype produced a significant reduction in 5-HT1A BPND in the mPFC regardless of social status, and subordinate s-variant females showed a reduction in 5-HT1A BPND within the ACC. Both these effects of 5-HTTLPR were unaffected by E2. Additionally, E2 reduced 5-HT1A BPND in the dorsal raphe of all females irrespective of psychosocial stress or 5-HTTLPR genotype. Hippocampal 5-HT1A BPND was attenuated in subordinate females regardless of 5-HTTLPR genotype during the non-E2 condition, an effect that was normalised with E2. Similarly, 5-HT1A BPND in the hypothalamus was significantly lower in subordinate females regardless of 5-HTTLPR genotype, an effect reversed with E2. Taken together, the data indicate that the effect of E2 on modulation of central 5HT1A BPND may only occur in brain regions that show no 5-HTTLPR genotype-linked control of 5-HT1A binding.