Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg Germany.
Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany.
J Nucl Med. 2020 Oct;61(10):1507-1513. doi: 10.2967/jnumed.119.239731. Epub 2020 Mar 13.
Most epithelial tumors recruit fibroblasts and other nonmalignant cells and activate them into cancer-associated fibroblasts. This often leads to overexpression of the membrane serine protease fibroblast-activating protein (FAP). It has already been shown that DOTA-bearing FAP inhibitors (FAPIs) generate high-contrast images with PET/CT scans. Since SPECT is a lower-cost and more widely available alternative to PET, Tc-labeled FAPIs represent attractive tracers for imaging applications in a larger number of patients. Furthermore, the chemically homologous nuclide Re is available from generators, which allows FAP-targeted endoradiotherapy. For the preparation of Tc-tricarbonyl complexes, a chelator was selected whose carboxylic acids can easily be converted into various derivatives in the finished product, enabling a platform strategy based on the original tracer. The obtained Tc complexes were investigated in vitro by binding and competition experiments on FAP-transfected HT-1080 (HT-1080-FAP) or on mouse FAP-expressing (HEK-muFAP) and CD26-expressing (HEKCD26) HEK cells and characterized by planar scintigraphy and organ distribution studies in tumor-bearing mice. Furthermore, a first-in-humans application was done on 2 patients with ovarian and pancreatic cancer, respectively. Tc-FAPI-19 showed specific binding to recombinant FAP-expressing cells with high affinity. Unfortunately, liver accumulation, biliary excretion, and no tumor uptake were observed on planar scintigraphy for a HT-1080-FAP-xenotransplanted mouse. To improve the pharmacokinetic properties, hydrophilic amino acids were attached to the chelator moiety of the compound. The resulting Tc-labeled FAPI tracers revealed excellent binding properties (≤45% binding; >95% internalization), high affinity (half-maximal inhibitory concentration, 6.4-12.7 nM), and significant tumor uptake (≤5.4% injected dose per gram of tissue) in biodistribution studies. The lead candidate Tc-FAPI-34 was applied for diagnostic scintigraphy and SPECT of patients with metastasized ovarian and pancreatic cancer for follow-up to therapy with Y-FAPI-46. Tc-FAPI-34 accumulated in the tumor lesions, as also shown on PET/CT imaging using Ga-FAPI-46. Tc-FAPI-34 represents a powerful tracer for diagnostic scintigraphy, especially when PET imaging is not available. Additionally, the chelator used in this compound allows labeling with the therapeutic nuclide Re, which is planned for the near future.
大多数上皮肿瘤招募成纤维细胞和其他非恶性细胞，并将其激活为癌相关成纤维细胞。这通常导致膜丝氨酸蛋白酶成纤维细胞激活蛋白（FAP）的过度表达。已经表明，带有 DOTA 的 FAP 抑制剂（FAPIs）在 PET/CT 扫描中生成高对比度图像。由于 SPECT 是 PET 的成本更低且更广泛可用的替代方法，因此 Tc 标记的 FAPIs 代表了用于对更多患者进行成像应用的有吸引力的示踪剂。此外，可从发生器获得化学同源的 Re 核素，这允许进行 FAP 靶向的内放射治疗。为了制备 Tc 三羰基配合物，选择了一种螯合剂，其羧酸可在成品中很容易地转化为各种衍生物，从而基于原始示踪剂实现平台策略。通过在转染 FAP 的 HT-1080（HT-1080-FAP）或表达小鼠 FAP（HEK-muFAP）和表达 CD26（HEKCD26）的 HEK 细胞上进行结合和竞争实验，体外研究了获得的 Tc 配合物，并通过肿瘤荷瘤小鼠的平面闪烁显像和器官分布研究对其进行了表征。此外，分别在 2 名患有卵巢癌和胰腺癌的患者中进行了首次人体应用。Tc-FAPI-19 与高亲和力的重组 FAP 表达细胞特异性结合。不幸的是，在 HT-1080-FAP 异种移植小鼠的平面闪烁显像中观察到肝蓄积、胆汁排泄和无肿瘤摄取。为了改善药代动力学特性，将亲水性氨基酸附着到化合物的螯合剂部分。在生物分布研究中，所得到的 Tc 标记的 FAPI 示踪剂显示出优异的结合特性（≤45％结合；>95％内化）、高亲和力（半最大抑制浓度，6.4-12.7 nM）和显著的肿瘤摄取（≤5.4％每克组织的注入剂量）。先导候选物 Tc-FAPI-34 用于转移性卵巢癌和胰腺癌患者的诊断闪烁显像和 SPECT 随访，以进行 Y-FAPI-46 的治疗。Tc-FAPI-34 在肿瘤病变中积累，如使用 Ga-FAPI-46 进行的 PET/CT 成像所示。Tc-FAPI-34 是一种用于诊断闪烁显像的强大示踪剂，特别是在无法进行 PET 成像时。此外，该化合物中使用的螯合剂允许用治疗性核素 Re 进行标记，这计划在不久的将来进行。
