Division of Experimental Medicine, Imperial College, Hammersmith Hospital, London, United Kingdom.
J Nucl Med. 2011 Jan;52(1):24-32. doi: 10.2967/jnumed.110.079459. Epub 2010 Dec 13.
11C-PBR28 PET can detect the 18-kDa translocator protein (TSPO) expressed within macrophages. However, quantitative evaluation of the signal in brain tissue from donors with multiple sclerosis (MS) shows that PBR28 binds the TSPO with high affinity (binding affinity [Ki], ∼4 nM), low affinity (Ki, ∼200 nM), or mixed affinity (2 sites with Ki, ∼4 nM and ∼300 nM). Our study tested whether similar binding behavior could be detected in brain tissue from donors with no history of neurologic disease, with TSPO-binding PET ligands other than 11C-PBR28, for TSPO present in peripheral blood, and with human brain PET data acquired in vivo with 11C-PBR28.
The affinity of TSPO ligands was measured in the human brain postmortem from donors with a history of MS (n=13), donors without any history of neurologic disease (n=20), and in platelets from healthy volunteers (n=13). Binding potential estimates from thirty-five 11C-PBR28 PET scans from an independent sample of healthy volunteers were analyzed using a gaussian mixture model.
Three binding affinity patterns were found in brains from subjects without neurologic disease in similar proportions to those reported previously from studies of MS brains. TSPO ligands showed substantial differences in affinity between subjects classified as high-affinity binders (HABs) and low-affinity binders (LABs). Differences in affinity between HABs and LABs are approximately 50-fold with PBR28, approximately 17-fold with PBR06, and approximately 4-fold with DAA1106, DPA713, and PBR111. Where differences in affinity between HABs and LABs were low (∼4-fold), distinct affinities were not resolvable in binding curves for mixed-affinity binders (MABs), which appeared to express 1 class of sites with an affinity approximately equal to the mean of those for HABs and LABs. Mixed-affinity binding was detected in platelets from an independent sample (HAB, 69%; MAB, 31%), although LABs were not detected. Analysis of 11C-PBR28 PET data was not inconsistent with the existence of distinct subpopulations of HABs, MABs, and LABs.
With the exception of 11C-PK11195, all TSPO PET ligands in current clinical application recognize HABs, LABs, and MABs in brain tissue in vitro. Knowledge of subjects' binding patterns will be required to accurately quantify TSPO expression in vivo using PET.
检测 11C-PBR28 PET 是否可检测到多发性硬化症（MS）供体脑组织中表达的 18kDa 转位蛋白（TSPO）。然而，对 MS 供体脑组织中信号的定量评估表明，PBR28 与 TSPO 具有高亲和力（结合亲和力[Ki]，约 4 nM）、低亲和力（Ki，约 200 nM）或混合亲和力（2 个 Ki 值分别为 4 nM 和 300 nM）。我们的研究测试了是否可以在无神经系统疾病病史的供体脑组织中检测到类似的结合行为，是否可以使用除 11C-PBR28 以外的其他 TSPO 结合 PET 配体来检测外周血中的 TSPO，以及是否可以使用 11C-PBR28 在人体大脑中进行 PET 数据。
在有 MS 病史的供体（n=13）、无神经系统疾病病史的供体（n=20）和健康志愿者的血小板中测量 TSPO 配体的亲和力。使用高斯混合模型分析来自 35 例独立健康志愿者的 11C-PBR28 PET 扫描的结合潜力估计值。
在无神经系统疾病病史的供体脑组织中发现了三种结合亲和力模式，与先前报道的 MS 脑组织研究相似。TSPO 配体在亲和力方面存在明显差异，高亲和力结合物（HAB）和低亲和力结合物（LAB）之间的差异约为 50 倍，PBR28 为 17 倍，PBR06 为 17 倍，DAA1106、DPA713 和 PBR111 为 4 倍。当 HAB 和 LAB 之间的亲和力差异较低（约 4 倍）时，混合亲和力结合物（MAB）的结合曲线无法分辨出明显的亲和力差异，这些 MAB 似乎表达了一类亲和力与 HAB 和 LAB 的平均值大致相同的结合物。在来自独立样本的血小板中检测到混合亲和力结合物（HAB，69%；MAB，31%），尽管未检测到 LAB。11C-PBR28 PET 数据的分析并不与 HAB、MAB 和 LAB 的不同亚群的存在相矛盾。
除 11C-PK11195 外，目前临床应用的所有 TSPO PET 配体均在体外检测到脑组织中的 HAB、LAB 和 MAB。使用 PET 准确量化体内 TSPO 表达需要了解供体的结合模式。
