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Purpose <p>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.</p> Methods <p>A TREM2-targeting peptide was conjugated with DOTA and radiolabeled with gallium-68 to generate [<sup>68</sup>Ga]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.</p> Results <p>[<sup>68</sup>Ga]Ga-STZL730 was synthesized with high radiochemical purity (&gt; 99%) and demonstrated excellent stability in vitro. The tracer exhibited specific binding to TREM2 with an affinity (K<sub>D</sub>) of 274 nM. In vivo PET imaging demonstrated that [<sup>68</sup>Ga]Ga-STZL730 could cross the blood-brain barrier, displaying moderate and sustained brain uptake. Notably, at 20–35&#xa0;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 [<sup>68</sup>Ga]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.</p> Conclusion <p>[<sup>68</sup>Ga]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.</p>

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TREM2-Targeting peptide tracer for neuroinflammation PET imaging

  • 期刊论文

  • 发表日期：

    2026年5月26日

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  • Xiaoyu Zhang,
  • Wenhao Liu,
  • Na Guo,
  • Xinyan Gao,
  • Suyun Pu,
  • Yabin Yang,
  • Xiaochuan Zha,
  • Kezhi Ding,
  • Dai Shi,
  • Jian Zhao,
  • Dengfeng Cheng,
  • Zonghua Luo

摘要

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.