Event Details:
A novel PET radioligand to identify myeloid inflammation in neurological disorders
Katrin Andreasson
Professor of Neurology
Michelle James
Assistant Professor of Radiology and of Neurology
2015 Seed Grant: A novel PET radioligand to identify microglial inflammation in Alzheimer's disease
Lead Researchers: Katrin Andreasson, Michelle James, Sanjay Malhotra
Abstract
Triggering receptor expressed on myeloid cells 1 (TREM1) is a unique membrane receptor that acts as a potent amplifier of severe pro-inflammatory responses. Under physiologic conditions TREM1 levels are low, however with induction of pro-inflammatory responses, TREM1 expression is upregulated selectively in myeloid-lineage cells. Since TREM1 levels are strongly linked to maladaptive inflammatory processes, it is an attractive candidate imaging biomarker for detecting disease-promoting neuroinflammation in neurological disorders. Therefore, our goal was to validate the utility of detecting TREM1 is disease models, and then to develop a PET tracer that specifically targets TREM1 and assess its ability to non-invasively track maladaptive myeloid-driven immune responses in acute and chronic rodent neuroinflammatory disease models.
We generated a TREM1-specific PET tracer, by radiolabeling a selective anti-TREM1 antibody with copper-64 ([64Cu], t½ = 12.7 hours), and verified its specificity in HEK293 cells with and without TREM1 transfection. PET imaging of murine models of inflammation – including lipopolysaccharide (LPS)-induced systemic inflammation, ischemic stroke, and multiple sclerosis – was performed to evaluate in vivo specificity of our new PET tracer and simultaneously investigate the in vivo spatiotemporal dynamics of TREM1+ myeloid driven inflammation. We also obtained preliminary PET imaging data in transgenic AD model mice. In vivo PET imaging results demonstrated markedly higher binding of [64Cu]TREM1-mAb in regions containing inflammation in all mouse models investigated compared with control mice, and negligible uptake in TREM-1 knockout mice treated with LPS or following EAE active induction, corroborating the specificity of our new PET tracer for TREM1. We are presently performing fragment screening and in silico screening methods to identify a small molecule ligand specific for TREM1.