Recent studies have shown enhanced tumor targeting by novel somatostatin receptor (SSTR) antagonists compared with clinically widely used agonists. However, these results have been obtained mostly in neuroendocrine tumors, and only limited data are available for cancer types with lower SSTR expression, including breast cancer (BC). To date, two studies have reported higher binding of the antagonist than the agonist in BC, but in both studies only a limited number of cases were evaluated. In this preclinical study, we further investigated whether the application of an SSTR antagonist can improve SSTR-mediated BC imaging in a large panel of BC specimens. We also generated an in vivo BC mouse model and performed SPECT/MRI and biodistribution studies. Methods: Binding of ¹¹¹In-DOTA-Tyr³-octreotate (SSTR agonist) and ¹¹¹In-DOTA-JR11 (SSTR antagonist) to 40 human BC specimens was compared using in vitro autoradiography. SSTR2 immunostaining was performed to confirm SSTR2 expression of the tumor cells. Furthermore, binding of the radiolabeled SSTR agonist and antagonist was analyzed in tissue material from 6 patient-derived xenografts. One patient-derived xenograft, the estrogen receptor–positive model T126, was chosen to generate in vivo mouse models containing orthotopic breast tumors for in vivo SPECT/MRI and biodistribution studies after injection with ¹⁷⁷Lu-DOTA-Tyr³-octreotate or ¹⁷⁷Lu-DOTA-JR11. Results: ¹¹¹In-DOTA-JR11 binding to human BC tissue was significantly higher than ¹¹¹In-DOTA-Tyr³-octreotate binding (P < 0.001). The median ratio of antagonist binding versus agonist binding was 3.39 (interquartile range, 2–5). SSTR2 immunostaining confirmed SSTR2 expression on the tumor cells. SPECT/MRI of the mouse model found better tumor visualization with the antagonist. This result was in line with the significantly higher tumor uptake of the radiolabeled antagonist than of the agonist as measured in biodistribution studies 285 min after radiotracer injection (percentage injected dose per gram of tissue: 1.92 ± 0.43 vs. 0.90 ± 0.17; P = 0.002). Conclusion: SSTR antagonists are promising candidates for BC imaging.

最近的研究表明，与临床上广泛使用的激动剂相比，新型生长抑素受体（SSTR）拮抗剂增强了肿瘤靶向性。然而，这些结果大部分是在神经内分泌肿瘤中获得的，并且只有有限的数据可用于具有较低SSTR表达的癌症类型，包括乳腺癌（BC）。迄今为止，两项研究报道了在BC中拮抗剂的结合程度高于激动剂，但在两项研究中仅评估了有限的病例数。在这项临床前研究中，我们进一步研究了SSTR拮抗剂的应用是否可以改善大量BC标本中SSTR介导的BC成像。我们还生成了体内BC小鼠模型，并进行了SPECT / MRI和生物分布研究。方法：结合¹¹¹ In-DOTA-Tyr使用体外放射自显影比较了40例人BC标本的^3-奥曲肽（SSTR激动剂）和^111种In-DOTA-JR11（SSTR拮抗剂）。进行SSTR2免疫染色以确认肿瘤细胞的SSTR2表达。此外，在来自6个患者来源的异种移植物的组织材料中分析了放射性标记的SSTR激动剂和拮抗剂的结合。在注射¹⁷⁷ Lu-DOTA-Tyr ³ - octreotate或¹⁷⁷ Lu后，选择了一种源自患者的异种移植物，即雌激素受体阳性模型T126，以生成包含原位乳腺肿瘤的体内小鼠模型，用于体内SPECT / MRI和生物分布研究。-DOTA-JR11。结果： ¹¹¹In-DOTA-JR11与人BC组织的结合显着高于¹¹¹ In-DOTA-Tyr ^3-奥曲肽的结合（P <0.001）。拮抗剂结合与激动剂结合的中位比为3.39（四分位间距2-5）。SSTR2免疫染色证实了SSTR2在肿瘤细胞上的表达。小鼠模型的SPECT / MRI发现该拮抗剂具有更好的肿瘤可视化效果。该结果与放射性示踪剂注射后285分钟的生物分布研究中测得的放射性标记拮抗剂的肿瘤摄取显着高于激动剂的摄取一致（每克组织注射剂量百分比：1.92±0.43对0.90±0.17；P = 0.002 ）。结论： SSTR拮抗剂有望成为BC成像的候选药物。