胰腺导管腺癌（PDAC）是一种侵袭性且快速进展的恶性肿瘤。患者管理的一个主要挑战是缺乏可靠的成像工具来监测肿瘤对治疗的反应。以高 I 型胶原为特征的肿瘤相关纤维化是 PDAC 的标志，新辅助放化疗 (CRT) 后纤维化进一步加剧。我们假设使用 I 型胶原特异性成像探针 68Ga-CBP8 的分子正电子发射断层扫描 (PET) 可以检测和测量小鼠模型和 PDAC 患者对标准治疗的肿瘤纤维化变化。方法：我们评估了 68Ga-CBP8 PET 对肿瘤胶原的特异性及其根据人类 PDAC 裸鼠模型纤维化动态变化（包括 FOLFIRNOX 敏感（PANC-1 和 PDAC6）和耐 FOLFIRINOX (SU.86.86)。接下来，我们证明了 68Ga-CBP8 对切除的人 PDAC 和胰腺组织中沉积的胶原蛋白的特异性和敏感性。八名新诊断 PDAC 的男性参与者（49-65 岁）接受了动态 68Ga-CBP8 PET/MRI，五名在完成标准 CRT 后接受了随访 68Ga-CBP8 PET/MRI。 PET 参数与肿瘤胶原含量和组织学反应标志物相关。结果：与非结合 68Ga-CNBP 探针相比，68Ga-CBP8 在使用 PET 成像的两种 PDAC 小鼠模型中显示出与 PDAC 的特异性结合，并使用放射自显影技术与切除的人 PDAC 结合（所有比较 P < 0.05）。在 PANC-1 和 PDAC6 模型中 FOLFIRINOX 治疗后，68Ga-CBP8 PET 在小鼠模型中显示肿瘤信号增加 2 倍（P < 0.01），但在 FOLFIRINOX 耐药 SU.86.86 模型中治疗后没有显着增加。与未处理的组织相比，经处理的组织中 68Ga-CBP8 与切除的人 PDAC 的结合显着更高 (P < 0.0001)。 CRT 前 PDAC 患者的 PET/MRI 显示肿瘤中的 68Ga-CBP8 摄取显着高于胰腺（SUVmean：2.35 ± 0.36 vs. 1.99 ± 0.25，P = 0.036，n = 8）。与未治疗的肿瘤相比，CRT 后的 PET 肿瘤值显着增加（SUV 平均值：2.83 ± 0.30 与 2.25 ± 0.41，P = 0.01，n = 5）。 CRT 后胶原蛋白沉积显着增加（治疗肿瘤与未治疗肿瘤中胶原沉积分别为 59 ± 9% 与 30 ± 9%，P=0.0005）。肿瘤和胰腺胶原含量与 SUVmean 呈正相关（R2 = 0.54，P = 0.0007）。结论：本研究证明了 68Ga-CBP8 PET 对肿瘤 I 型胶原的特异性，及其根据 PDAC 纤维化的动态变化区分应答者和无应答者的能力。结果强调了胶原蛋白 PET 作为监测 PDAC 患者治疗反应的非侵入性工具的潜在用途。© 作者。

Pancreatic ductal adenocarcinoma (PDAC) is an invasive and rapidly progressive malignancy. A major challenge in patient management is the lack of a reliable imaging tool to monitor tumor response to treatment. Tumor-associated fibrosis characterized by high type I collagen is a hallmark of PDAC, and fibrosis further increases in response to neoadjuvant chemoradiotherapy (CRT). We hypothesized that molecular positron emission tomography (PET) using a type I collagen-specific imaging probe, 68Ga-CBP8 can detect and measure changes in tumor fibrosis in response to standard treatment in mouse models and patients with PDAC. Methods: We evaluated the specificity of 68Ga-CBP8 PET to tumor collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in nude mouse models of human PDAC including FOLFIRNOX-sensitive (PANC-1 and PDAC6) and FOLFIRINOX-resistant (SU.86.86). Next, we demonstrated the specificity and sensitivity of 68Ga-CBP8 to the deposited collagen in resected human PDAC and pancreas tissues. Eight male participant (49-65 y) with newly diagnosed PDAC underwent dynamic 68Ga-CBP8 PET/MRI, and five underwent follow up 68Ga-CBP8 PET/MRI after completing standard CRT. PET parameters were correlated with tumor collagen content and markers of response on histology. Results: 68Ga-CBP8 showed specific binding to PDAC compared to non-binding 68Ga-CNBP probe in two mouse models of PDAC using PET imaging and to resected human PDAC using autoradiography (P < 0.05 for all comparisons). 68Ga-CBP8 PET showed 2-fold higher tumor signal in mouse models following FOLFIRINOX treatment in PANC-1 and PDAC6 models (P < 0.01), but no significant increase after treatment in FOLFIRINOX resistant SU.86.86 model. 68Ga-CBP8 binding to resected human PDAC was significantly higher (P < 0.0001) in treated versus untreated tissue. PET/MRI of PDAC patients prior to CRT showed significantly higher 68Ga-CBP8 uptake in tumor compared to pancreas (SUVmean: 2.35 ± 0.36 vs. 1.99 ± 0.25, P = 0.036, n = 8). PET tumor values significantly increased following CRT compared to untreated tumors (SUVmean: 2.83 ± 0.30 vs. 2.25 ± 0.41, P = 0.01, n = 5). Collagen deposition significantly increased in response to CRT (59 ± 9% vs. 30 ± 9%, P=0.0005 in treated vs. untreated tumors). Tumor and pancreas collagen content showed a positive direct correlation with SUVmean (R2 = 0.54, P = 0.0007). Conclusions: This study demonstrates the specificity of 68Ga-CBP8 PET to tumor type I collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in PDAC. The results highlight the potential use of collagen PET as a non-invasive tool for monitoring response to treatment in patients with PDAC.© The author(s).