Radiolabeled somatostatin receptor (SSTR) antagonists have shown in vivo higher uptake in SSTR-expressing tumors than agonists. In this preclinical study, the SSTR2 antagonist OPS201 (DOTA-JR11; DOTA-[Cpa-c(DCys-Aph(Hor)-DAph(Cbm)-Lys-Thr-Cys)-DTyr-NH₂]) labeled with ¹⁷⁷Lu, ⁹⁰Y, and ¹¹¹In was compared with the SSTR2 agonist ¹⁷⁷Lu-DOTATATE. Methods: Biodistribution, pharmacokinetics, SPECT/CT, and dosimetry studies were performed to assess the bioequivalence of all radiotracers. Use of escalated peptide mass and nephroprotective agents were systematically investigated. Results: The tumor residence time was 15.6 h (13.4–17.7) for ¹⁷⁷Lu-OPS201 (10 pmol) and 6.4 h (5.4–7.3) for ¹⁷⁷Lu-DOTATATE, resulting in a 2.5-times-higher tumor dose for the antagonist than for the agonist (0.854 vs. 0.333 mGy/MBq for a 4-cm tumor). The overall tumor–to–kidney dose ratio was approximately 24% and 32% higher for ¹⁷⁷Lu-OPS201 than for ⁹⁰Y-OPS201 and ¹⁷⁷Lu-DOTATATE, respectively. ¹¹¹In-OPS201 had a biodistribution significantly different from ⁹⁰Y-OPS201 and is therefore not a surrogate for ⁹⁰Y-OPS201 dosimetry studies. Importantly, and in contrast to ¹⁷⁷Lu-DOTATATE, injection of 10, 200, and 2,000 pmol of ¹⁷⁷Lu-OPS201 did not cause any relevant tumor saturation, with tumor uptake 4 h after injection: 23.9, 24.9, and 18.8 percentage of injected activity per gram of tissue (%IA/g), respectively, for the antagonist (P > 0.05), as compared with 17.8, 12.0, and 9.9 %IA/g for the agonist (P < 0.05). Increasing the peptide mass of ¹⁷⁷Lu-OPS201 from 10 to 200 pmol drastically decreased the effective dose from 0.0908 to 0.0184 mSv/MBq and decreased the uptake in the liver, bone marrow, and all SSTR2-expressing organs; thus, the therapeutic index improved considerably. Lysine and succinylated gelatine, alone or in combination, significantly reduced the renal dose of ¹⁷⁷Lu-OPS201 compared with the control group, by 45%, 25%, and 40%, respectively (P < 0.05). The reduction was similar for 10 and 200 pmol, whereas lysine performed better than succinylated gelatine. Conclusion: ¹⁷⁷Lu-OPS201 exhibits higher tumor uptake, longer tumor residence time, and improved tumor–to–kidney dose ratio compared with ¹⁷⁷Lu-DOTATATE and ⁹⁰Y-OPS201. Importantly, the mass-escalation study indicates that an optimized antagonist mass might further improve the safety window of peptide receptor radionuclide therapy by reducing the liver and bone marrow doses as well as the effective dose. Clinical studies are warranted to confirm the efficacy and advantageous toxicity profile of ¹⁷⁷Lu-OPS201.

放射性标记的生长抑素受体（SSTR）拮抗剂已显示出在体内表达SSTR的肿瘤中的摄取比激动剂高。在这项临床前研究中，SSTR2拮抗剂OPS201（DOTA-JR11; DOTA- [Cpa-c（DCys-Aph（Hor）-DAph（Cbm）-Lys-Thr-Cys）-DTyr-NH ₂ ]）标记为¹⁷⁷ Lu ，将⁹⁰ Y和¹¹¹ In与SSTR2激动剂¹⁷⁷ Lu-DOTATATE进行了比较。方法：进行了生物分布，药代动力学，SPECT / CT和剂量学研究，以评估所有放射性示踪剂的生物等效性。系统地研究了升级的肽质量和肾保护剂的使用。结果：^177个肿瘤的停留时间为15.6 h（13.4-17.7）Lu-OPS201（10 pmol）和¹⁷⁷ Lu- DOTATATE的6.4 h（5.4–7.3），导致拮抗剂的肿瘤剂量比激动剂高2.5倍（4-54的激动剂为0.854 vs. 0.333 mGy / MBq）厘米肿瘤）。¹⁷⁷ Lu-OPS201的总体肿瘤与肾脏剂量比分别比⁹⁰ Y-OPS201和¹⁷⁷ Lu- DOTATATE高约24％和32％。¹¹¹ In-OPS201的生物分布与⁹⁰ Y-OPS201显着不同，因此不能替代⁹⁰ Y-OPS201剂量学研究。重要的是，与¹⁷⁷ Lu-DOTATATE相反，注射10、200和2,000 pmol的¹⁷⁷Lu-OPS201并未引起任何相关的肿瘤饱和，注射后4 h的肿瘤摄取：拮抗剂的每克组织注射活性分别为23.9、24.9和18.8％（％IA / g）（P > 0.05） ，与之相比，激动剂的IIA / g为17.8％，12.0％和9.9％IA / g（P <0.05）。将¹⁷⁷ Lu-OPS201的肽质量从10 pmol增加到200 pmol，将有效剂量从0.0908大大降低到0.0184 mSv / MBq，并减少了肝脏，骨髓和所有SSTR2表达器官的摄取。因此，治疗指数大大提高。与对照组相比，单独或联合使用赖氨酸和琥珀酰明胶可显着降低¹⁷⁷ Lu-OPS201的肾脏剂量，分别降低了45％，25％和40％（P <0.05）。10和200 pmol的降低相似，而赖氨酸的性能优于琥珀酰化明胶。结论： ¹⁷⁷ Lu-OPS201与¹⁷⁷ Lu -DOTATATE和⁹⁰ Y-OPS201相比，具有更高的肿瘤吸收率，更长的肿瘤停留时间和更高的肿瘤与肾脏剂量比。重要的是，大规模研究表明，优化的拮抗剂质量可能会通过减少肝脏和骨髓的剂量以及有效剂量来进一步提高肽受体放射性核素治疗的安全性。必须进行临床研究，以确认¹⁷⁷ Lu-OPS201的功效和有利的毒性特征。