Synthesis and Characterization of a Positron Emission Tomography Imaging Probe Selectively Targeting the Second Bromodomain of Bromodomain Protein BRD4.

Two tandem bromodomains (BD1 and BD2) of bromodomain and extraterminal domain (BET) family proteins have shown distinct roles in mediating gene transcription and expression. Inhibitors that interact with a specific bromodomain may contribute to a specific therapeutic potential with fewer side effects. However, little is known about this disease-related target. Positron emission tomography (PET) imaging could allow us to achieve in-depth knowledge of the BD2 bromodomain. Herein we describe the radiosynthesis and evaluation of [11C]1 as a BRD4 BD2 bromodomain PET imaging radioligand. Our preliminary PET imaging results in rodents demonstrated that [11C]1 had suitable biodistribution in peripheral organs and tissues. Further blocking studies indicated that [11C]1 had good binding specificity toward the BD2 bromodomain. This study may pave the way for the development of a PET radioligand specifically targeting BD1/2 bromodomains as well as for the biological mechanism investigation of BD1/2 bromodomains.

Discovery of carbon-11 labeled sulfonamide derivative: A PET tracer for imaging brain NLRP3 inflammasome.

We report herein the discovery of a positron emission tomography (PET) tracer for the (NOD)-like receptor protein 3 (NLRP3). Our recent medicinal chemistry campaign on developing sulfonamide-based NLRP3 inhibitors led to an analog, 1, with a methoxy substituent amenable to labeling with carbon-11. PET/CT imaging studies indicated that [11C]1 exhibited rapid blood-brain barrier (BBB) penetration and moderate brain uptake, as well as blockable uptake in the brain. [11C]1, thus suggesting the potential to serve as a useful tool for imaging NLRP3 inflammasome in living brains.

A Survey of Demographics, Symptom Course, Family History, and Barriers to Treatment in Children with Pediatric Acute-Onset Neuropsychiatric Disorders and Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections.

Objective: Few large-scale studies of pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) have been conducted, and thus demographic data on these conditions are limited. The current study describes comorbid medical and psychiatric conditions in a self-referred cohort of children with PANS/PANDAS, along with treatment history, barriers to treatment, family medical and psychiatric history, and perceived caregiver burden in these conditions. Methods: A total of 441 primary caregivers of patients with infection-triggered PANS/PANDAS under the age of 18 were included in this online anonymous survey, reporting on a total of 490 children (due to some caregivers reporting multiple children in the family with PANS/PANDAS). Data were collected between July 2018 and May 2019. Primary caregivers completed questions pertaining to patient demographics, symptom presentation, disease course, family medical and psychiatric history, and severity of patients' obsessive-compulsive disorder (OCD) symptoms. Results: OCD was the most common psychiatric symptom reported in children at the onset of PANS/PANDAS (83.06%), along with a high percentage of medical and psychiatric comorbidities. Most psychiatric comorbidities began or worsened at the onset of PANS/PANDAS symptoms, while major depressive disorder was the most frequently reported psychiatric disorder to develop after PANS/PANDAS onset (10%). A high frequency of autoimmune and inflammatory conditions was reported in family members, with nearly 30% of mothers endorsing one or more autoimmune conditions (29.95%). Mean caregiver burden (Caregiver Burden Inventory; M = 44.0) fell above the "burnout" level, and standardized measures showed mildly elevated levels of depression, anxiety, and stress in caregivers (Depression, Anxiety, and Stress Scale-21; M = 11.85, 7.16, and 15.56, respectively). Conclusions: Primary caregivers of children with PANS/PANDAS reported a multitude of medical and psychiatric comorbidities in their children, along with a high frequency of autoimmune and psychiatric conditions in family members. Obsessive-compulsive symptoms were the most frequently reported psychiatric symptom. Caregivers of these patients experience elevated levels of burden, stress, anxiety, and depression. Further research is needed to better understand the varied disease course in PANS/PANDAS and to develop interventions to reduce caregiver burden in these disorders.

Design, Synthesis, and Evaluation of Thienodiazepine Derivatives as Positron Emission Tomography Imaging Probes for Bromodomain and Extra-Terminal Domain Family Proteins.

To better understand the role of bromodomain and extra-terminal domain (BET) proteins in epigenetic mechanisms, we developed a series of thienodiazepine-based derivatives and identified two compounds, 3a and 6a, as potent BET inhibitors. Further in vivo pharmacokinetic studies and analysis of in vitro metabolic stability of 6a revealed excellent brain penetration and reasonable metabolic stability. Compounds 3a and 6a were radiolabeled with fluorine-18 in two steps and utilized in positron emission tomography (PET) imaging studies in mice. Preliminary PET imaging results demonstrated that [18F]3a and [18F]6a have good brain uptake (with maximum SUV = 1.7 and 2, respectively) and binding specificity in mice brains. These results show that [18F]6a is a potential PET radiotracer that could be applied to imaging BET proteins in the brain. Further optimization and improvement of the metabolic stability of [18F]6a are still needed in order to create optimal PET imaging probes of BET family members.