Biodistribution, Pharmacokinetics, and Dosimetry of ¹⁷⁷Lu-, ⁹⁰Y-, and ¹¹¹In-Labeled Somatostatin Receptor Antagonist OPS201 in Comparison to the Agonist ¹⁷⁷Lu-DOTATATE: The Mass Effect

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.