开发了一款新型基于HER2 affibody的[18F]AlF-RESCA-HER2-BCH分子探针，用于减少肾脏摄取，并与[18F]AlF-NOTA-HER2-BCH进行了评估和比较。在临床前研究中，使用HER2阳性胃癌患者源性异种移植模型(PDX)，在注射后的0.5-1（动态）、2、4和6小时进行了微小PET/CT检查。在阻断实验中，注射探针时向其共同注射0.5毫克的冷affibody。在注射后的2小时内，在HER2阳性PDX模型上进行了生物分布研究。在临床研究中，对5名乳腺癌患者（4例HER2阳性和1例HER2低表达）进行PET/CT图像检查，注射了231.29±17.77 MBq [18F]AlF-NOTA-HER2-BCH或[18F]AlF-RESCA-HER2-BCH，并于注射后2小时和4小时测量了半定量分析所需的肿瘤和来源器官标准摄取值（SUVs）。使用OLINDA/EXM软件（版本1.2）计算放射性剂量。[18F]AlF-NOTA-HER2-BCH和[18F]AlF-RESCA-HER2-BCH都稳定地标记了[18F]F，并具有高的结合特异性和亲和力。两种示踪剂的微小PET/CT都能清晰地显示HER2阳性PDX肿瘤，并在注射后的2小时内具有高摄取量(16.24±1.74% ID/g和14.39±2.45% ID/g)。[18F]AlF-RESCA-HER2-BCH的肾脏积累明显低于[18F]AlF-NOTA-HER2-BCH（在注射后的2小时内分别为5.16±0.22% ID/g和158.73±5.44% ID/g，p<0.0001）。在临床研究中，[18F]AlF-NOTA-HER2-BCH和[18F]AlF-RESCA-HER2-BCH都显示了良好的肿瘤靶向和图像对比度。[18F]AlF-RESCA-HER2-BCH在原发肿瘤和转移部位均显示出较高的SUVmax，并且转移部位的靶向-非靶向比显著高于[18F]AlF-NOTA-HER2-BCH。此外，[18F]AlF-RESCA-HER2-BCH的肾脏累积低于[18F]AlF-NOTA-HER2-BCH(在注射后的2小时为43.56±7.88对79.81±3.81，p<0.0001，在注射后的4小时为33.23±6.89对78.63±4.00，p<0.0001)，并且肾脏吸收剂量明显低于[18F]AlF-NOTA-HER2-BCH(0.4450±0.1117 mGy/MBq对0.8030±0.1604 mGy/MBq，p<0.01)。[18F]AlF-RESCA-HER2-BCH在转移部位的检测中具有更好的图像对比度，且靶向-非靶向比更高。值得注意的是，[18F]AlF-RESCA-HER2-BCH的肾脏累积低于[18F]AlF-NOTA-HER2-BCH。© 2023年。作者（以独家许可证的形式）授权给Springer-Verlag GmbH Germany，Springer Nature的一部分。

A novel HER2 affibody-based molecular probe, [18F]AlF-RESCA-HER2-BCH, was developed for reducing renal uptake, evaluated, and compared with [18F]AlF-NOTA-HER2-BCH.In preclinical studies, micro-PET/CT was performed using HER2-positive gastric cancer patient-derived xenografts (PDX) model at 0.5-1 (dynamic), 2, 4, and 6 h post-injection. For blocking experiment, 0.5 mg cold affibody was co-injected with probes. Biodistribution were performed on HER2-positive PDX models at 2 h post-injection. For clinical study, PET/CT images were acquired at 2 h and 4 h after injection of 231.29 ± 17.77 MBq [18F]AlF-NOTA-HER2-BCH or [18F]AlF-RESCA-HER2-BCH in five breast cancer patients (4 HER2-positive and 1 HER2-low). Standardized uptake values (SUVs) were measured in tumors and source-organs for semi-quantitative analysis. The OLINDA/EXM software (version 1.2) was used to calculate the radiation doses.[18F]AlF-NOTA-HER2-BCH and [18F]AlF-RESCA-HER2-BCH were stably labeled with [18F]F, with high binding specificity and affinity to HER2. Micro-PET/CT of both tracers could clearly visualize HER2-positive PDX tumors with high uptake of 16.24 ± 1.74% ID/g and 14.39 ± 2.45% ID/g at 2 h post-injection. The renal accumulation of [18F]AlF-RESCA-HER2-BCH was significantly lower than that of [18F]AlF-NOTA-HER2-BCH (5.16 ± 0.22% ID/g vs. 158.73 ± 5.44% ID/g at 2 h, p < 0.0001). In the clinical study, both [18F]AlF-NOTA-HER2-BCH and [18F]AlF-RESCA-HER2-BCH demonstrated favorable tumor targeting and image contrast. [18F]AlF-RESCA-HER2-BCH showed a higher SUVmax in both primary tumor and metastases, and a significantly higher target-to-nontarget ratio in metastases than [18F]AlF-NOTA-HER2-BCH. Moreover, [18F]AlF-RESCA-HER2-BCH had lower renal accumulation (43.56 ± 7.88 vs. 79.81 ± 3.81 at 2 h, p < 0.0001; 33.23 ± 6.89 vs. 78.63 ± 4.00 at 4 h, p < 0.0001) as well as a significantly lower renal absorbed dose than [18F]AlF-NOTA-HER2-BCH (0.4450 ± 0.1117 mGy/MBq vs. 0.8030 ± 0.1604 mGy/MBq, p < 0.01).[18F]AlF-RESCA-HER2-BCH tended to provide better image contrast than [18F]AlF-NOTA-HER2-BCH with a higher target-to-nontarget ratio in detection of metastases. Notably, [18F]AlF-RESCA-HER2-BCH had lower renal accumulation than [18F]AlF-NOTA-HER2-BCH.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.