Center for Radiopharmaceutical Sciences ETH-PSI, Paul Scherrer Institute, Villigen-PSI, 5232, Switzerland.
AnaPath Services GmbH, Liestal, 4410, Switzerland.
Eur J Nucl Med Mol Imaging. 2024 Nov;51(13):4049-4061. doi: 10.1007/s00259-024-06827-2. Epub 2024 Jul 24.
[Lu]Lu-DOTATATE is an established somatostatin receptor (SSTR) agonist for the treatment of metastasized neuroendocrine neoplasms, while the SSTR antagonist [Lu]Lu-DOTA-LM3 has only scarcely been employed in clinics. Impressive preclinical data obtained with [Tb]Tb-DOTA-LM3 in tumor-bearing mice indicated the potential of terbium-161 as an alternative to lutetium-177. The aim of the present study was to compare the tolerability of Tb- and Lu-based DOTA-LM3 and DOTATATE in immunocompetent mice.
Dosimetry calculations were performed based on biodistribution data of the radiopeptides in immunocompetent mice. Treatment-related effects on blood cell counts were assessed on Days 10, 28 and 56 after application of [Tb]Tb-DOTA-LM3 or [Tb]Tb-DOTATATE at 20 MBq per mouse. These radiopeptides were also applied at 100 MBq per mouse and the effects compared to those observed after application of the Lu-labeled counterparts. Bone marrow smears, blood plasma parameters and organ histology were assessed at the end of the study.
The absorbed organ dose was commonly higher for the SSTR antagonist than for the SSTR agonist and for terbium-161 over lutetium-177. Application of a therapeutic activity level of 20 MBq [Tb]Tb-DOTA-LM3 or [Tb]Tb-DOTATATE was well tolerated without major hematological changes. The injection of 100 MBq of the Tb- and Lu-based somatostatin analogues affected the blood cell counts, however. The lymphocytes were 40-50% lower in treated mice compared to the untreated controls on Day 10 irrespective of the radionuclide employed. At the same timepoint, thrombocyte and erythrocyte counts were 30-50% and 6-12% lower, respectively, after administration of the SSTR antagonist (p < 0.05) while changes were less pronounced in mice injected with the SSTR agonist. All blood cell counts were in the normal range on Day 56. Histological analyses revealed minimal abnormalities in the kidneys, liver and spleen of treated mice. No correlation was observed between the organ dose and frequency of the occurrence of abnormalities.
Hematologic changes were more pronounced in mice treated with the SSTR antagonist than in those treated with the SSTR agonist. Despite the increased absorbed dose delivered by terbium-161 over lutetium-177, [Tb]Tb-DOTA-LM3 and [Tb]Tb-DOTATATE should be safe at activity levels that are recommended for their respective Lu-based analogues.
[Lu]Lu-DOTATATE 是一种已确立的生长抑素受体（SSTR）激动剂，用于治疗转移性神经内分泌肿瘤，而 SSTR 拮抗剂[Lu]Lu-DOTA-LM3 在临床上应用甚少。在荷瘤小鼠中获得的令人印象深刻的[Tb]Tb-DOTA-LM3 的临床前数据表明，铥-161 作为镥-177 的替代物具有潜力。本研究旨在比较免疫功能正常的小鼠中 Tb 和 Lu 基 DOTA-LM3 和 DOTATATE 的耐受性。
根据免疫功能正常小鼠中放射性肽的生物分布数据进行剂量计算。在应用[Tb]Tb-DOTA-LM3 或[Tb]Tb-DOTATATE（每只小鼠 20MBq）后第 10、28 和 56 天，评估治疗相关的血细胞计数变化。还应用了 100MBq 的这些放射性肽，并将其与观察到的 Lu 标记对应物的作用进行了比较。在研究结束时评估骨髓涂片、血浆参数和器官组织学。
对于 SSTR 拮抗剂，与 SSTR 激动剂相比，与镥-177 相比，通常吸收器官剂量更高。应用 20MBq[Tb]Tb-DOTA-LM3 或[Tb]Tb-DOTATATE 的治疗活性水平是可以耐受的，没有出现主要的血液学变化。然而，注射 100MBq 的 Tb 和 Lu 基生长抑素类似物会影响血细胞计数。与未处理的对照组相比，无论使用哪种放射性核素，处理小鼠的淋巴细胞在第 10 天都降低了 40-50%。同时，在施用 SSTR 拮抗剂后，血小板和红细胞计数分别降低了 30-50%和 6-12%（p<0.05），而在注射 SSTR 激动剂的小鼠中，变化不太明显。所有的血细胞计数都在正常范围内。在第 56 天，处理小鼠的肾脏、肝脏和脾脏的组织学分析显示出最小的异常。在器官剂量和异常发生频率之间未观察到相关性。
与 SSTR 激动剂相比，用 SSTR 拮抗剂治疗的小鼠血液学变化更为明显。尽管铥-161 比镥-177 传递的吸收剂量增加，但[Tb]Tb-DOTA-LM3 和[Tb]Tb-DOTATATE 在其各自的 Lu 基类似物推荐的活性水平下应该是安全的。
