Synthesis, Preclinical Evaluation, and a Pilot Clinical PET Imaging Study of 68 Ga-Labeled FAPI Dimer

作者：Liang Zhao, Bo Niu, Jianyang Fang, Yizhen Pang, Siyang Li, Chengrong Xie, Long Sun, Xianzhong Zhang, Zhide Guo, Qin Lin, Haojun Chen · 发表于：Journal of Nuclear Medicine · 年份：2021 · DOI：10.2967/jnumed.121.263016 · 被引用次数：163 · 研究领域：Peptidase Inhibition and Analysis、Cardiac Structural Anomalies and Repair、Radiopharmaceutical Chemistry and Applications

Cancer-associated fibroblasts (CAFs) are crucial components of the tumor microenvironment. Fibroblast activation protein (FAP) is overexpressed in CAFs. FAP-targeted molecular imaging agents, including FAP inhibitor (FAPI)-04 and FAPI-46, have shown promising results in tumor diagnosis. However, these molecules have relatively short tumor-retention time for peptide-targeted radionuclide therapy applications. We aimed to design a 68 Ga-labeled FAPI dimer (denoted as 68 Ga-DOTA-2P(FAPI)2) to optimize the pharmacokinetics and evaluate whether this form is more effective than its monomeric analogs. Methods: 68 Ga-DOTA-2P(FAPI)2 was synthesized based on the quinoline-based FAPI variants (FAPI-46), and its binding properties were assayed in CAFs. Preclinical pharmacokinetics was determined in FAP-positive patient-derived xenografts (PDXs) using small-animal PET and biodistribution experiments. The effective dosimetry of 68 Ga-DOTA-2P(FAPI)2 was evaluated in three healthy volunteers, and PET/ CT imaging of 68 Ga-FAPI-46 and 68 Ga-DOTA-2P(FAPI)2 was performed in three cancer patients. Results: 68 Ga-DOTA-2P(FAPI)2 was stable in phosphate-buffered saline and fetal bovine serum for 4 h. The FAPI dimer showed high affinity and specificity for FAP in-vitro and in-vivo. The tumor uptake of 68 Ga-DOTA-2P(FAPI)2 was approximately two-fold stronger than that of 68 Ga-FAPI-46 in PDXs, while the healthy organs showed low tracer uptake and fast body clearance. The effective dose of ...