PET using ⁶⁸Ga-labeled fibroblast activation protein (FAP) inhibitors (FAPIs) holds high potential for diagnostic imaging of various malignancies, including lung cancer (LC). However, ¹⁸F-FDG PET is still the clinical gold standard for LC imaging. Several subtypes of LC, especially lepidic LC, are frequently ¹⁸F-FDG PET–negative, which markedly hampers the assessment of single pulmonary lesions suggestive of LC. Here, we evaluated the diagnostic potential of static and dynamic ⁶⁸Ga-FAPI-46 PET in the ¹⁸F-FDG–negative pulmonary lesions of 19 patients who underwent surgery or biopsy for histologic diagnosis after PET imaging. For target validation, FAP expression in lepidic LC was confirmed by FAP immunohistochemistry. Methods: Hematoxylin and eosin staining and FAP immunohistochemistry of 24 tissue sections of lepidic LC from the local tissue bank were performed and analyzed visually. Clinically, 19 patients underwent static and dynamic ⁶⁸Ga-FAPI-46 PET in addition to ¹⁸F-FDG PET based on individual clinical indications. Static PET data of both examinations were analyzed by determining SUV_max, SUV_mean, and tumor-to-background ratio (TBR) against the blood pool, as well as relative parameters (⁶⁸Ga-FAPI-46 in relation to¹⁸F-FDG), of histologically confirmed LC and benign lesions. Time–activity curves and dynamic parameters (time to peak, slope, k₁, k₂, k₃, and k₄) were extracted from dynamic ⁶⁸Ga-FAPI-46 PET data. The sensitivity and specificity of all parameters were analyzed by calculating receiver-operating-characteristic curves. Results: FAP immunohistochemistry confirmed the presence of strongly FAP-positive cancer-associated fibroblasts in lepidic LC. LC showed markedly elevated ⁶⁸Ga-FAPI-46 uptake, higher TBRs, and higher ⁶⁸Ga-FAPI-46–to–¹⁸F-FDG ratios for all parameters than did benign pulmonary lesions. Dynamic imaging analysis revealed differential time–activity curves for LC and benign pulmonary lesions: initially increasing time–activity curves with a decent slope were typical of LC, and steadily decreasing time–activity curve indicated benign pulmonary lesions, as was reflected by a significantly increased time to peak and significantly smaller absolute values of the slope for LC. Relative ⁶⁸Ga-FAPI-46–to–¹⁸F-FDG ratios regarding SUV_max and TBR showed the highest sensitivity and specificity for the discrimination of LC from benign pulmonary lesions. Conclusion: ⁶⁸Ga-FAPI-46 PET is a powerful new tool for the assessment of single ¹⁸F-FDG–negative pulmonary lesions and may optimize patient stratification in this clinical setting.

使用 ⁶⁸ Ga 标记的成纤维细胞激活蛋白 (FAP) 抑制剂 (FAPI) 的 PET 在各种恶性肿瘤（包括肺癌 (LC)）的诊断成像方面具有很高的潜力。然而， ¹⁸ F-FDG PET 仍然是 LC 成像的临床金标准。 LC 的几种亚型，尤其是鳞屑性 LC，通常 ¹⁸ F-FDG PET 阴性，这明显妨碍了对提示 LC 的单一肺部病变的评估。在这里，我们评估了静态和动态 ⁶⁸ Ga-FAPI-46 PET 对 19 名接受手术或活检进行组织学检查的患者 ¹⁸ F-FDG 阴性肺部病变的诊断潜力。 PET 成像后诊断。为了进行靶标验证，通过 FAP 免疫组织化学证实了贴壁 LC 中的 FAP 表达。方法：对当地组织库中的 24 个贴壁 LC 组织切片进行苏木精和伊红染色以及 FAP 免疫组织化学分析并进行目视分析。临床上，19名患者根据个体临床指征，除 ¹⁸ F-FDG PET外，还接受了静态和动态 ⁶⁸ Ga-FAPI-46 PET检查。通过确定 SUV _max 、 SUV _mean 和肿瘤背景比 (TBR) 与血池以及相关参数 (< b9> Ga-FAPI-46 与 ¹⁸ F-FDG 相关），经组织学证实的 LC 和良性病变。时间-活性曲线和动态参数（达峰时间、斜率、k ₁ 、k ₂ 、k ₃ 和 k ₄ ）是从动态 ⁶⁸ Ga-FAPI-46 PET 数据中提取的。通过计算接受者操作特征曲线来分析所有参数的敏感性和特异性。 结果：FAP 免疫组织化学证实鳞状 LC 中存在强 FAP 阳性的癌症相关成纤维细胞。 LC 显示显着升高的 ⁶⁸ Ga-FAPI-46 摄取、较高的 TBR 和较高的 ⁶⁸ Ga-FAPI-46–to– ¹⁸ F-FDG 比率所有参数均优于良性肺部病变。动态成像分析揭示了 LC 和良性肺部病变的不同时间 - 活动曲线：最初以适当斜率增加的时间 - 活动曲线是 LC 的典型特征，而稳定下降的时间 - 活动曲线表明良性肺部病变，正如LC 达到峰值的时间和明显更小的斜率绝对值。 SUV _max 和 TBR 的相对 ⁶⁸ Ga-FAPI-46–to– ¹⁸ F-FDG 比率显示出区分 LC 和 TBR 的最高灵敏度和特异性良性肺部病变。结论： ⁶⁸ Ga-FAPI-46 PET 是评估单个 ¹⁸ F-FDG 阴性肺部病变的强大新工具，并且可以优化该临床环境中的患者分层。