TREM2 Targeted 89Zr-ImmunoPET Visualizes Microglial Activation during the Inflammatory Response

Neuroinflammation is mainly mediated by activated immune cells such as microglia and astrocytes, and is a key driver of neurodegenerative and neurological diseases. Triggering receptor expressed on myeloid cells 2 (TREM2), which is selectively expressed on microglia in the central nervous system, has emerged as a promising target for assessing microglial activation. We developed an ⁸⁹ Zr-labeled bispecific anti-TREM2/anti-transferrin receptor antibody ( ⁸⁹ Zr-T2BA). TREM2 specificity was assessed in vitro in wild-type (WT) and TREM2-overexpressing (TREM2 OE) HEK293T cells. In vivo specificity and diagnostic performance were evaluated in healthy WT and TREM2 knockout (KO) mice, and in a systemic lipopolysaccharide (LPS)-induced neuroinflammation model. Microglial activation and peripheral immune infiltration were cross-validated by flow cytometry, Western blotting, and immunohistochemistry. ⁸⁹ Zr-T2BA showed selective uptake in TREM2 OE cells and clearly distinguished WT from KO mice. Importantly, ⁸⁹ Zr-T2BA detects LPS-induced neuroinflammation without confounding peripheral immune infiltration. These findings position TREM2-targeted ImmunoPET as a promising microglia-specific imaging strategy to detect the inflammatory response in the brain.