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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-NH 2 ]) labeled with 177 Lu, 90 Y, and 111 In was compared with the SSTR2 agonist 177 Lu-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 177 Lu-OPS201 (10 pmol) and 6.4 h (5.4-7.3) for 177 Lu-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 177 Lu-OPS201 than for 90 Y-OPS201 and 177 Lu-DOTATATE, respectively. 111 In-OPS201 had a biodistribution significantly different from 90 Y-OPS201 and is therefore not a surrogate for 90 Y-OPS201 dosimetry studies. Importantly, and in contrast to 177 Lu-DOTATATE, injection of 10, 200, and 2,000 pmol of 177 Lu-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 &gt; 0.05), as compared with 17.8, 12.0, and 9.9 %IA/g for the agonist ( P &lt; 0.05). Increasing the peptide mass of 177 Lu-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 177 Lu-OPS201 compared with the control group, by 45%, 25%, and 40%, respectively ( P &lt; 0.05). The reduction was similar for 10 and 200 pmol, whereas lysine performed better than succinylated gelatine. Conclusion:  177 Lu-OPS201 exhibits higher tumor uptake, longer tumor residence time, and improved tumor-to-kidney dose ratio compared with 177 Lu-DOTATATE and 90 Y-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 177 Lu-OPS201.

the journal of nuclear medicine

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