Schaefer Rebecca, Kunze Lea H, Haertel Marlies, Zhu Yeqian, Schlepckow Kai, Willem Michael, Bartos Laura M, Palumbo Giovanna, Tomas Lukas, Schulz Christian, Massberg Steffen, Werner Rudolf A, Fischer Maximilian, Xia Dan, Monroe Kathryn M, Haass Christian, Brendel Matthias, Lindner Simon
Department of Nuclear Medicine, LMU University Hospital, LMU Munich, Munich, Germany.
Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital, LMU Munich, Munich, Germany.
J Nucl Med. 2025 Sep 2;66(9):1419-1424. doi: 10.2967/jnumed.125.269472.
The triggering receptor expressed on myeloid cells 2 (TREM2) plays a pivotal role in the activation of myeloid cells and is currently being investigated as a potential therapeutic target in several diseases. In this study, we established enhanced quantification of PET images of a Cu-labeled antibody-based PET radiotracer as a noninvasive tool for the assessment of TREM2 expression in the brain and peripheral organs of mice. We used TREM2 knockout mice that lack target expression to investigate data-driven blood normalization of PET images against percentage of injected dose normalization. TREM2 knockout and wild-type mice ( = 11 each) were injected with the radiotracer [Cu]Cu-NODAGA-ATV:4D9 (ATV is antibody transport vehicle). Twenty hours after injection, TREM2 PET was conducted and blood samples were collected. A voxelwise analysis with statistical parametric mapping served to determine voxels that correlate with ex vivo blood radioactivity levels. Furthermore, TREM2 PET signals were compared between mice with and those without TREM2 expression using image-derived blood normalization. Correlation with TREM2 protein expression levels in the lung, liver, spleen, and bone marrow was used to validate organ-specific PET results. Disease models of brain amyloidosis and myocardial infarction were investigated to test for the value of image-derived normalization in mice. Blood radioactivity levels derived from a statistical parametric mapping-derived region of interest demonstrated a robust correlation with radioactivity measurements obtained from ex vivo blood samples. Voxelwise clusters of TREM2 PET signals were more robustly detected after blood normalization of the PET images. Significant voxelwise clusters of TREM2 PET signals in peripheral organs correlated with TREM2 protein expression levels. Furthermore, image-derived normalization enhanced the significance of voxelwise clusters of TREM2 in the brains of ;TfR mice, as well as the TREM2 signal in the myocardial infarct region. Both strongly correlated with ex vivo autoradiography. Normalization of PET images to account for blood levels enhanced the detection of TREM2. This improved methodology for TREM2 PET analysis provides a promising basis for future assessments of TREM2 imaging.
髓系细胞触发受体2（TREM2）在髓系细胞激活中起关键作用，目前正作为几种疾病的潜在治疗靶点进行研究。在本研究中，我们建立了基于铜标记抗体的PET放射性示踪剂PET图像的增强定量分析方法，作为评估小鼠脑和外周器官中TREM2表达的非侵入性工具。我们使用缺乏靶标表达的TREM2基因敲除小鼠，研究PET图像的数据驱动血液归一化与注射剂量百分比归一化。将TREM2基因敲除小鼠和野生型小鼠（各11只）注射放射性示踪剂[⁶⁴Cu]Cu-NODAGA-ATV:4D9（ATV为抗体转运载体）。注射20小时后，进行TREM2 PET检查并采集血样。使用统计参数映射进行体素分析，以确定与体外血液放射性水平相关的体素。此外，使用图像衍生的血液归一化方法比较有和没有TREM2表达的小鼠之间的TREM2 PET信号。通过与肺、肝、脾和骨髓中TREM2蛋白表达水平的相关性来验证器官特异性PET结果。研究了脑淀粉样变性和心肌梗死的疾病模型，以测试图像衍生归一化在小鼠中的价值。从统计参数映射衍生的感兴趣区域获得的血液放射性水平与从体外血样获得的放射性测量值显示出很强的相关性。PET图像进行血液归一化后，TREM2 PET信号的体素簇检测更可靠。外周器官中TREM2 PET信号的显著体素簇与TREM2蛋白表达水平相关。此外，图像衍生的归一化增强了TfR小鼠脑中TREM2体素簇的显著性，以及心肌梗死区域的TREM2信号。两者均与体外放射自显影密切相关。PET图像针对血液水平进行归一化提高了TREM2的检测能力。这种改进的TREM2 PET分析方法为未来TREM2成像评估提供了有前景的基础。
