A Simple Kit Formulation for Preparation and Exploratory Human Studies of a Novel 99mTc-Labeled Fibroblast Activation Protein Inhibitor Tracer for Imaging of the Fibroblast Activation Protein in Cancers
A Simple Kit Formulation for Preparation and Exploratory Human Studies of a Novel 99mTc-Labeled Fibroblast Activation Protein Inhibitor Tracer for Imaging of the Fibroblast Activation Protein in Cancers
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一种用于新型99m锝标记成纤维细胞激活蛋白抑制剂示踪剂制备及探索性人体研究的简易试剂盒配方，该示踪剂用于癌症中成纤维细胞激活蛋白的成像
DOI：
10.1021/acs.molpharmaceut.2c01094
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发表时间：
2023-04-21
影响因子：
4.9
通讯作者：
Wang，Jing
中科院分区：
文献类型：
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作者：
Ruan，Qing;Zhou，Cheng;Wang，Jing
成纤维细胞活化蛋白（FAP）是肿瘤诊断和治疗的潜在靶点，因为它选择性地表达于大多数实体瘤间质中的癌相关成纤维细胞的细胞膜上。本研究的目的是开发一种99 mTc标记的成纤维细胞活化蛋白抑制剂（FAPI）示踪剂，评价其在裸鼠体内的显像效果，并进一步研究其在健康志愿者体内的生物分布和肿瘤患者体内的摄取情况。设计并合成了一种含脯氨酸的FAP衍生配体（DP-FAPI），通过试剂盒制备了稳定的99 mTc标记的FAP衍生配体（[99 mTc]Tc-DP-FAPI），并在转染FAP的HT-1080细胞（FAP-HT-1080）中进行了体外摄取和饱和结合实验。在荷U87 MG肿瘤的BALB/c裸鼠中进行生物分布表征和微单光子发射计算机断层扫描（SPECT）成像。在4名健康志愿者和3名胃肠道肿瘤患者中进行了首次人体应用，体外测定结果表明，[99 mTc]Tc-DP-FAPI对FAP具有很高的靶向亲和力。生物分布和micro-SPECT成像研究表明，[99 mTc]Tc-DP-FAPI表现出高摄取和高肿瘤与非靶向比率。在4名健康志愿者中，[99 mTc]Tc-DP-FAPI的计算有效剂量约<5 mSv。在3例胃肠道肿瘤患者中，[99 mTc]Tc-DP-FAPI定量SPECT/CT显示高且可靠的摄取。[99 mTc]Tc-DP-FAPI对FAP具有较高的选择性和亲和力。[99 mTc]Tc-DP-FAPI在原发肿瘤显像中的安全性和有效性已得到动物和临床研究的证实，揭示了该示踪剂潜在的临床应用价值。
Fibroblast activation protein (FAP) is a potential target for tumor diagnosis and treatment because it is selectively expressed on the cell membrane of cancer-associated fibroblasts in most solid tumor stroma. The aim of this study was to develop a99mTc-labeled fibroblast activation protein inhibitor (FAPI) tracer, evaluate its imaging efficacy in nude mice, and further explore its biodistribution in healthy volunteers and uptake in tumor patients. An FAPI-derived ligand (DP-FAPI) containingd-proline was designed and synthesized as a linker, and a stable hydrophilic99mTc-labeled complex ([99mTc]Tc-DP-FAPI) was obtained by kit formulation.In vitrocellular uptake and saturation binding assays were performed in FAP-transfected HT-1080 cells (FAP-HT-1080). The biodistribution was characterized, and micro-single-photon emission computed tomography (SPECT) imaging was performed in BALB/c nude mice bearing U87 MG tumors. Furthermore, a first-in-man application was performed in four healthy volunteers and three patients with gastrointestinal tumors.In vitro, the nanomolarKdvalues of [99mTc]Tc-DP-FAPI indicated that it had significantly high target affinity for FAP. Biodistribution and micro-SPECT imaging studies showed that [99mTc]Tc-DP-FAPI exhibited high uptake and high tumor-to-nontargeted ratios. The calculated effective dose for [99mTc]Tc-DP-FAPI was approximately <5 mSv in four healthy volunteers. In three patients with gastrointestinal tumors, [99mTc]Tc-DP-FAPI quantitative SPECT/CT revealed high and reliable uptake. [99mTc]Tc-DP-FAPI exhibited high selectivity and affinity for FAPin vitro. The safety and effectiveness of [99mTc]Tc-DP-FAPI in primary tumor imaging have been confirmed by animal and clinical studies, revealing the potential clinical application value of this tracer.