Highly Increased¹²⁵I-JR11 Antagonist Binding In Vitro Reveals Novel Indications for sst₂Targeting in Human Cancers

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There is recent in vitro and in vivo evidence that somatostatin receptor subtype 2 (sst₂) antagonists are better tools to target neuroendocrine tumors (NETs) than sst₂ agonists. Indeed, antagonists bind to a greater number of sst₂ sites than agonists. Whether sst₂ antagonists could be used successfully to target non-NETs, expressing low sst₂ density, is unknown. Here, we compare quantitatively ¹²⁵I-JR11 sst₂ antagonist binding in vitro with that of the sst₂ agonist ¹²⁵I-Tyr³-octreotide in large varieties of non-NET and NET. Methods: In vitro receptor autoradiography was performed with ¹²⁵I-JR11 and ¹²⁵I-Tyr³-octreotide in cancers from prostate, breast, colon, kidney, thyroid, and lymphoid tissues as well as NETs as reference. Results: In general, ¹²⁵I-JR11 binds to many more sst₂ sites than ¹²⁵I-Tyr³-octreotide. In 13 breast cancers, 8 had a low binding (mean density, 844 ± 168 dpm/mg of tissue) with the agonist whereas 12 had a high binding (mean density, 4,447 ± 1,128 dpm/mg of tissue) with the antagonist. All 12 renal cell cancers showed a low binding of sst₂ with the agonist (mean density, 348 ± 49 dpm/mg of tissue) whereas all cases had a high sst₂ binding with the antagonist (mean density, 3,777 ± 582 dpm/mg of tissue). One of 5 medullary thyroid cancers was positive with the agonist, whereas 5 of 5 were positive with the antagonist. In 15 non-Hodgkin lymphomas, many more sst₂ sites were labeled with the antagonist than with the agonist. In 14 prostate cancers, none had sst₂ binding with the agonist and only 4 had a weak binding with the antagonist. None of 17 colon cancers showed sst₂ sites with the agonist, and only 3 cases were weakly positive with the antagonist. In the various tumor types, adjacent sst₂-expressing tissues such as vessels, lymphocytes, nerves, mucosa, or stroma were more strongly labeled with the antagonist than with the agonist. The reference NET cases, incubated with a smaller amount of tracer, were also found to have many more sst₂ sites measured with the antagonist. Conclusion: All renal cell cancers and most breast cancers, non-Hodgkin lymphomas, and medullary thyroid cancers represent novel indications for the in vivo radiopeptide targeting of sst₂ by sst₂ antagonists, comparable to NET radiotargeting with sst₂ agonists.