Scott Mason's research while affiliated with University of Pittsburgh and other places

Positron emission tomography (PET) imaging of tau aggregation in Alzheimer’s disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity 4-repeat (4R)-tau PET radiopharmaceutical for imaging non-AD tauopathies exists. Herein, the properties of analogues of a first-in-class 4R-tau lead, [ ¹⁸ F]OXD-2115, are described. Over 150 analogues of OXD-2115 were synthesized and screened for tau affinity in vitro against [ ³ H]OXD-2115, and in silico models were used to predict brain uptake. [ ¹⁸ F]OXD-2314 was identified as a selective, high-affinity non-AD tau PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primate and is being translated for first-in-human PET studies.

Background: Nociceptin, which binds to the nociceptin opioid peptide receptor (NOP), regulates stress and reward in addiction. In a previous [11C]NOP-1A positron emission tomography (PET) study, we found no differences in NOP in non-treatment-seeking individuals with alcohol use disorder (AUD) relative to healthy control subjects Here, we evaluated NOP in treatment-seeking individuals with AUD to document its relationship with relapse to alcohol. Methods: [11C]NOP-1A distribution volume (VT) was measured in recently abstinent individuals with AUD and healthy control subjects (n = 27/group) using an arterial input function-based kinetic analysis in brain regions that regulate reward and stress behaviors. Recent heavy drinking before PET was quantified using hair ethyl glucuronide (≥30 pg/mg was defined as heavy drinking). To document relapse, 22 subjects with AUD were followed with urine ethyl glucoronide tests (3/week) for 12 weeks after PET, where they were incentivized with money to abstain. Results: There were no differences in [11C]NOP-1A VT between individuals with AUD and healthy control subjects. Individuals with AUD who drank heavily before the study had significantly lower VT than those with no recent heavy drinking history. Significant negative correlations between VT and the number of drinking days and the number of drinks consumed per drinking day in the 30 days before enrollment were also present. Individuals with AUD who relapsed (and dropped out) had significantly lower VT than those who abstained for 12 weeks. Conclusions: Lower NOP VT in heavy drinking AUD predicted relapse to alcohol during a 12-week follow-up period. The results of this PET study support the need to investigate medications that act at NOP to prevent relapse in individuals with AUD.

Introduction Bone marrow-derived multipotent adult progenitor cells (MAPCs) are adult allogeneic adherent stem cells currently investigated clinically for use in acute respiratory distress syndrome (ARDS). To date, there is no agreement on which is the best method for stem cells delivery in ARDS. Here, we compared the efficacy of two different methods of administration and biodistribution of MAPC for the treatment of ARDS in a sheep model. Methods MAPC were labelled with [ ¹⁸ F] fluoro-29-deoxy-D-glucose and delivered by endobronchial (EB) or intravenous route 1 hour after lipopolysaccharide infusion in sheep mechanically ventilated. PET/CT images were acquired to determine the biodistribution and retention of the cells at 1 and 5 hours of administration. Results The distribution and retention of the MAPC was dependent on the method of cell administration. By EB route, PET images showed that MAPC remained at the site of administration and no changes were observed after 5 hours, whereas with intravenous route, the cells had broad biodistribution to different organs, being the lung the main organ of retention at 1 and 5 hours. MAPC demonstrated an equal effect on arterial oxygenation recovery by either route of administration. Conclusion The EB or intravenous routes of administration of MAPC are both effective for the treatment of ARDS in an acute sheep model, and the effect of MAPC therapy is not dependent of parenchymal integration or systemic biodistribution.

Phosphodiesterase‐10a (PDE10a) is located exclusively in medium spiny neurons (MSN). Rodent studies show an increase in striatal MSN spine density following exposure to cocaine. These increases in MSN spine density are suggested to underlie neurobiological changes which contribute to cocaine self‐administration. No postmortem or imaging studies have confirmed this finding in humans. Here, we hypothesized an increase in the MSN marker PDE10a in subjects with cocaine use disorder (“cocaine users”) compared to controls. PDE10a availability was measured with [¹¹C]IMA107 and PET in 15 cocaine users and 15 controls matched for age, gender, and nicotine status. Cocaine users with no comorbid psychiatric, medical, or drug abuse disorders were scanned following two weeks of outpatient‐monitored abstinence. [¹¹C]IMA107 binding potential relative to nondisplaceable uptake (BPND) in the regions of interest were derived with the simplified reference tissue method. No significant effect of diagnosis on BPND was demonstrated using linear mixed modeling with [¹¹C]IMA107 BPND as the dependent variable and regions of interest as a repeated measure. There were no significant relationships between BPND and clinical rating scales. To the extent that PDE10a is a valid proxy for MSN spine density, these results do not support its increase in recently abstinent cocaine users. This article is protected by copyright. All rights reserved.

Background The neuropeptide transmitter nociceptin, which binds to the nociceptin/orphanin FQ peptide (NOP) receptor, is a core component of the brain's anti-stress system. Nociceptin exerts its anti-stress effect by counteracting the functions of corticotropin releasing factor, the primary stress-mediating neuropeptide in the brain. Basic investigations support a role for medications that target nociceptin receptors in the treatment of alcohol use disorders. Thus, it is of high interest to measure the in vivo status of NOP receptors in individuals with alcohol use disorders. Methods Here, we used [¹¹C]NOP-1A and PET to measure the in vivo binding to NOP receptors in 15 DSM-IV alcohol-dependent humans and 15 healthy controls matched for age, gender, and smoking status. Alcohol-dependent individuals with no comorbid psychiatric, medical, or drug abuse disorders were scanned following two weeks of outpatient monitored abstinence (confirmed with 3x/week urine alcohol metabolite testing). [¹¹C]NOP-1A distribution volume (VT) in regions of interest (including the amygdala, hippocampus, midbrain, striatal, and prefrontal cortical subdivisions) were measured with kinetic analysis using the arterial input function. Results Regional [¹¹C]NOP-1A VT in alcohol-dependence was not significantly different compared to healthy controls. No relationship between [¹¹C]NOP-1A VT and other clinical measures (including duration and severity of alcohol abuse, craving, anxiety or depressive symptoms) were significant after correction for the multiple hypotheses tested. Conclusions The results of this study do not support alterations in the binding to NOP receptors in alcohol dependence. However, this finding does not necessarily rule out alterations in nociceptin transmission in alcohol dependence.