TREM2-Targeting peptide tracer for neuroinflammation PET imaging.

PURPOSE: Triggering receptor expressed on myeloid cells 2 (TREM2) has emerged as an important target in neurodegenerative diseases. However, noninvasive visualization of TREM2 expression in the central nervous system (CNS) remains challenging. This study aimed to develop and evaluate a novel peptide-based positron emission tomography (PET) tracer for imaging TREM2 in CNS. METHODS: A TREM2-targeting peptide was conjugated with DOTA and radiolabeled with gallium-68 to generate [68Ga]Ga-STZL730. Binding affinity, tracer stability, lipophilicity, and cellular uptake were evaluated. Dynamic PET imaging and blocking studies were performed in wild-type mice, TREM2 knockout mice, lipopolysaccharide (LPS)-induced neuroinflammation mice, and APP/PS1 Alzheimer's disease (AD) model mice. Autoradiography and immunofluorescence staining were conducted to validate tracer specificity and target expression. RESULTS: [68Ga]Ga-STZL730 was synthesized with high radiochemical purity (> 99%) and demonstrated excellent stability in vitro. The tracer exhibited specific binding to TREM2 with an affinity (KD) of 274 nM. In vivo PET imaging demonstrated that [68Ga]Ga-STZL730 could cross the blood-brain barrier, displaying moderate and sustained brain uptake. Notably, at 20-35 min post-injection, compared to wild-type controls, brain uptake was significantly reduced in TREM2 knockout mice (41.6% lower), whereas it was markedly increased in both LPS-treated mice (113.8% higher) and AD mice (86.0% higher). Blocking studies in AD mice demonstrated the specific binding of [68Ga]Ga-STZL730. In vitro autoradiography and immunohistochemical analyses further confirmed that elevated PET signals corresponded to increased TREM2 expression, which was spatially localized to activated microglia in APP/PS1 mice brain sections. CONCLUSION: [68Ga]Ga-STZL730 is a novel peptide-based PET tracer that enables specific, noninvasive imaging of TREM2 expression in the CNS. It provides a promising tool for investigating neuroinflammation and TREM2-associated pathology in neurodegenerative diseases.