[Brainmap]:Stal Shrestha, PhD-Novel PET radioligands show potential as a neuroinflammation biomarker and to monitor expression of designed receptors
Abstract:
Our group develops novel PET radiotracers to investigate neuropsychiatric disorders. Today’s talk will focus on two targets—1) the cyclooxygenase (COX) system, and DREADD (Designer Receptor Exclusively Activated by Designer Drug). The first target, COX, comprises of two primary isoforms, COX-1 and COX-2, which are key enzymes in neuroinflammation. We recently developed two PET radioligands: 11C-PS13 for COX-1 and 11C-MC1 for COX-2, and sought to demonstrate in vivo expression of COX-1 and COX-2 in rhesus monkeys. To induce transient neuroinflammation, LPS was injected into the right putamen of monkeys (n=3). In normal condition, 11C-PS13 but not 11C-MC1 showed specific uptake in spleen, gastrointestinal tract, and brain. After intracerebral injection of LPS, only 11C-MC1 uptake was significantly increased. Our results suggest that COX-1 is constitutively expressed in major organs while COX-2 is only induced by inflammation. Thus, 11C-PS13 and 11C-MC1 show promise as biomarkers for measuring inflammation in various disorders, as well as target engagement of therapeutic drugs. The second target, DREADD, used three activators of hM4Di to measure receptor occupancy. Six weeks after a unilateral injection of 150 μl of lentivirus, expressing hM4Di, we did PET imaging with 11C-clozapine to visualize in vivo binding, which showed strong uptake only in the injected hemisphere, suggesting hM4Di expression. Our result shows that the hM4Di DREADD can be monitored using PET imaging.
About the Speaker:
Stal Shrestha started his research career at Gary Strichartz’s group at Harvard. There, he studied behavioral and cellular mechanisms of postoperative pain (Shrestha et al., Journal of Pain,2009). In 2010, he matriculated to the joint NIH-Karolinska PhD graduate partnership program in Clinical Neuroscience, under the mentorship of Robert Innis, and Per Svenningsson. He conducted translational research using PET imaging and molecular techniques. In 2014, he successfully defended his PhD with eight publications—four were first-authored. Currently, Stal is a postdoctoral fellow at the NIH working on neuroinflammation and DREADDs under the mentorship of Victor Pike, Barry Richmond, and Robert Innis. His main project focuses on developing PET radiotracers for the COX system. Towards this end, Stal screened, evaluated, and developed a model of neuroinflammation. His findings show that these radiotracers can be used to measure COX-1 and COX-2 in neuroinflammation and to measure delivery to the brain of NSAIDs. He is also working on visualizing DREADD expression using 11C-Clozapine. DREADDs uses synthetic drugs, and can help modulate circuit activity with pharmacological interventions, and as such has the power to transform the field of clinical neuroscience and how we practice medicine.
