The NETTER-1, VISION, and TheraP trials proved the efficacy of repeat intravenous application of small radioligands. Application by subcutaneous, intraperitoneal, or oral routes is an important alternative and may yield comparable or favorable organ and tumor radioligand uptake. Here, we assessed organ and tumor biodistribution for various radioligand application routes in healthy mice and models of cancer expressing somatostatin receptor (SSTR), prostate-specific membrane antigen (PSMA), and fibroblast activation protein (FAP). Methods: Healthy and tumor-bearing male C57BL/6 or NOD SCID -mice, respectively, were administered a mean of 6.0 ± 0.5 MBq of ⁶⁸Ga-DOTATOC (RM1-SSTR allograft), 5.3 ± 0.3 MBq of ⁶⁸Ga-PSMA11 (RM1-PSMA allograft), or 4.8 ± 0.2 MBq of ⁶⁸Ga-FAPI46 (HT1080-FAP xenograft) by intravenous, intraperitoneal, subcutaneous, or oral routes. In vivo PET images and ex vivo biodistribution in tumor, organs, and the injection site were assessed up to 5 h after injection. Healthy mice were monitored for up to 7 d after the last scan for signs of stress or adverse reactions. Results: After intravenous, intraperitoneal, and subcutaneous radioligand administration, average residual activity at the injection site was less than 17 percentage injected activity per gram (%IA/g) at 1 h after injection, less than 10 %IA/g at 2 h after injection, and no more than 4 %IA/g at 4 h after injection for all radioligands. After oral administration, at least 50 %IA/g remained within the intestines until 4 h after injection. Biodistribution in organs of healthy mice was nearly equivalent after intravenous, intraperitoneal, and subcutaneous application at 1 h after injection and all subsequent time points (≤1 %IA/g for liver, blood, and bone marrow; 11.2 ± 1.4 %IA/g for kidneys). In models for SSTR-, PSMA- and FAP-expressing cancer, tumor uptake was increased or equivalent for intraperitoneal/subcutaneous versus intravenous injection at 5 h after injection (ex vivo): SSTR, 7.2 ± 1.0 %IA/g (P = 0.0197)/6.5 ± 1.3 %IA/g (P = 0.0827) versus 2.9 ± 0.3 %IA/g, respectively; PSMA, 3.4 ± 0.8 %IA/g (P = 0.9954)/3.9 ± 0.8 %IA/g (P = 0.8343) versus 3.3 ± 0.7% IA/g, respectively; FAP, 1.1 ± 0.1 %IA/g (P = 0.9805)/1.1 ± 0.1 %IA/g (P = 0.7446) versus 1.0 ± 0.2 %IA/g, respectively. Conclusion: In healthy mice, biodistribution of small theranostic ligands after intraperitoneal/subcutaneous application is nearly equivalent to that after intravenous injection. Subcutaneous administration resulted in the highest absolute SSTR tumor and tumor-to-organ uptake as compared with the intravenous route, warranting further clinical assessment.

NETTER-1、VISION 和 TheraP 试验证明了重复静脉内应用小放射配体的功效。通过皮下、腹膜内或口服途径应用是一种重要的替代方法，可能会产生相当或有利的器官和肿瘤放射性配体摄取。在这里，我们评估了健康小鼠和表达生长抑素受体 (SSTR)、前列腺特异性膜抗原 (PSMA) 和成纤维细胞活化蛋白 (FAP) 的癌症模型中各种放射配体应用途径的器官和肿瘤生物分布。方法：分别对健康和荷瘤雄性 C57BL/6 或 NOD SCID 小鼠施用平均 6.0 ± 0.5 MBq 的⁶⁸ Ga-DOTATOC（RM1-SSTR 同种异体移植物）、5.3 ± 0.3 MBq 的⁶⁸ Ga-PSMA11（ RM1-PSMA 同种异体移植物）或 4.8 ± 0.2 MBq⁶⁸ Ga-FAPI46（HT1080-FAP 异种移植物）通过静脉内、腹膜内、皮下或口服途径。体内 PET 图像和肿瘤、器官和注射部位的离体生物分布在注射后 5 小时内进行评估。在最后一次扫描压力或不良反应迹象后，对健康小鼠进行长达 7 天的监测。结果：在静脉内、腹膜内和皮下放射配体给药后，注射部位的平均残余活性在注射后 1 小时小于每克注射活性的 17% (%IA/g)，在注射后 2 小时小于 10%IA/g , 并且所有放射性配体在注射后 4 小时不超过 4%IA/g。口服给药后，至少有 50%IA/g 残留在肠内，直至注射后 4 小时。在注射后 1 小时和所有后续时间点静脉内、腹膜内和皮下应用后，健康小鼠器官中的生物分布几乎相同（肝脏、血液和骨髓≤1 %IA/g；11.2 ± 1.4 %IA/g用于肾脏）。在表达 SSTR、PSMA 和 FAP 的癌症模型中，P = 0.0197)/6.5 ± 1.3 %IA/g ( P = 0.0827) 对比 2.9 ± 0.3 %IA/g；PSMA，分别为 3.4 ± 0.8 %IA/g ( P = 0.9954)/3.9 ± 0.8 % IA/g ( P = 0.8343) 与 3.3 ± 0.7% IA/g；FAP，分别为 1.1 ± 0.1 %IA/g ( P = 0.9805)/1.1 ± 0.1 %IA/g ( P = 0.7446) 与 1.0 ± 0.2 %IA/g。结论：在健康小鼠中，腹膜内/皮下应用后小治疗诊断配体的生物分布与静脉注射后几乎相同。与静脉内途径相比，皮下给药导致最高的绝对 SSTR 肿瘤和肿瘤到器官的摄取，需要进一步的临床评估。