Radiopharmaceutical therapies (RPTs) based on fibroblast activation protein (FAP) and FAP inhibitors (FAPIs) are a new option for progressive metastatic cancer in patients pretreated multiple times. To date, published in-human data refer to initial experiences with β-emitting ⁹⁰Y- and ¹⁷⁷Lu-based RPT. However, the short tumor retention time of FAPI ligands is considered a major limitation of FAPI RPT. Therefore, fractionated FAPI RPT with ²¹³Bi, an α-emitter with a half-life of 46 min, appears to be a promising FAPI RPT regimen. Here, we report on our initial experiences with regard to the feasibility, tolerability, and response of fractionated ²¹³Bi-FAPI-46 RPT. Methods: Six patients (4 women and 2 men) with progressive metastatic solid tumors (3 colon cancer, 1 anal cancer, 1 breast cancer, and 1 prostate cancer) aged 16–77 y were treated with a mean of 1,609 MBq of ²¹³Bi-FAPI-46, fractionated into 53 single applications (range, 5–12 RPT applications per patient; mean, 8.8 applications) over a period of up to 107 h per patient. Of the 6 patients, 4 patients received adjuvant treatment with pembrolizumab. ¹⁸F-FDG (4 patients) and ⁶⁸Ga-FAPI-46 (5 patients) PET/CT scans were performed before and after RPT. PET images were assessed visually and by calculating total lesion glycolysis and total lesion FAPI. Results: RPT with ²¹³Bi-FAPI-46 was well tolerated without adverse side effects. In terms of visual response assessment, there was 1 partial response (16.7%), 1 patient with stable disease (16.7%), and 4 patients with progressive disease (66.7%). Concordantly, total lesion glycolysis and total lesion FAPI were decreased in the responding patient (not applicable and −24.3%, respectively), slightly decreased in the patient with stable disease (−10.6% and −5.9%, respectively), and increased in the 4 patients with progression (mean, +104.4% and +321.3%, respectively). Conclusion: Fractionated FAPI RPT with the short-half-life α-emitter ²¹³Bi-FAPI-46 is a promising approach that matches the pharmacokinetics of FAPI-46 better than the ¹⁷⁷Lu- or ⁹⁰Y-labeled compounds. In this pilot project, fractionated RPT with ²¹³Bi-FAPI-46 showed good clinical tolerability and even led to regressive or stable disease in the short term in 2 of 6 patients. Further studies with larger patient cohorts are required to evaluate the actual efficacy and long-term effects of this variant of FAPI RPT.

基于成纤维细胞活化蛋白 （FAP） 和 FAP 抑制剂 （FAPI） 的放射性药物治疗 （RPT） 是多次治疗患者进行性转移性癌症的新选择。迄今为止，已发布的人体数据是指基于 β 发射 ⁹⁰Y 和 ¹⁷⁷Lu 的 RPT 的初始经验。然而，FAPI 配体的短肿瘤保留时间被认为是 FAPI RPT 的主要限制。因此，具有 ²¹³Bi 的分级 FAPI RPT（一种半衰期为 46 分钟的α发射极）似乎是一种很有前途的 FAPI RPT 方案。在这里，我们报告了我们在分级 ²¹³Bi-FAPI-46 RPT 的可行性、耐受性和反应方面的初步经验。方法：6 例年龄在 16-77 岁之间的进行性转移性实体瘤患者 （4 例女性和 2 例男性） （3 例结肠癌、1 例肛门癌、1 例乳腺癌和 1 例前列腺癌） 接受平均 1,609 MBq 的 ²¹³ 治疗Bi-FAPI-46，在每位患者长达 107 小时的时间内分馏成 53 个单次应用（范围，每位患者 5-12 次 RPT 应用;平均 8.8 次应用）。在 6 例患者中，4 例患者接受了 pembrolizumab 的辅助治疗。¹⁸在 RPT 前后进行 F-FDG （4 例患者） 和 ⁶⁸例 Ga-FAPI-46 （5 例） PET/CT 扫描。通过计算总病灶糖酵解和总病灶 FAPI 来目视评估 PET 图像。结果：²¹³Bi-FAPI-46 的 RPT 耐受性良好，无不良副作用。在视觉反应评估方面，有 1 例部分缓解 （16.7%），1 例病情稳定 （16.7%） 和 4 例疾病进展患者 （66.7%）。 一致地，反应患者的总病灶糖酵解和总病灶 FAPI 降低（分别为 -24.3%），疾病稳定的患者略有降低（分别为 -10.6% 和 -5.9%），4 名进展患者增加（平均值分别为 +104.4% 和 +321.3%）。结论：具有短半衰期 α 发射极 ²¹³Bi-FAPI-46 的分级 FAPI RPT 是一种很有前途的方法，它比 ¹⁷⁷Lu 或 ⁹⁰Y 标记的化合物更匹配 FAPI-46 的药代动力学。在这个试点项目中，具有 ²¹³Bi-FAPI-46 的分次 RPT 显示出良好的临床耐受性，甚至导致 6 名患者中有 2 名在短期内出现疾病消退或稳定。需要对更大的患者队列进行进一步研究，以评估这种 FAPI RPT 变体的实际疗效和长期影响。