Evaluation of 177Lu-DOTA-sst2 Antagonist Versus 177Lu-DOTA-sst2 Agonist Binding in Human Cancers In Vitro

Somatostatin receptor targeting of neuroendocrine tumors using radiolabeled somatostatin agonists is today an established method to image and treat cancer patients. However, in a study using an animal tumor model, somatostatin receptor antagonists were shown to label sst(2)- and sst(3)-expressing tumors in vivo better than agonists, with comparable affinity even though they are not internalized into the tumor cell. In the present study, we evaluated the in vitro binding of the antagonist Lu-177-DOTA-pNO(2)-Phe-c (DCys-Tyr-DTrp-Lys-Thr-Cys) DTyrNH(2) (Lu-177-DOTA-BASS) or the Lu-177-DOTATATE agonist to sst(2)-expressing human tumor samples. Methods: Forty-eight sst(2)-positive human tumor tissue samples (9 ileal carcinoids, 10 pheochromocytomas, 7 breast carcinomas, 10 renal cell carcinomas, and 12 non-Hodgkin lymphomas) were analyzed by in vitro receptor autoradiography for the expression of sst(2), comparing the binding capacity of Lu-177-DOTA-BASS and Lu-177-DOTATATE in successive tissue sections. The autoradiograms were quantitated using an electronic autoradiography detection system. Results: In all cases, the radiolabeled antagonist bound to more receptor sites than did the agonist. The mean ratios of the antagonist Lu-177-DOTA-BASS to the agonist Lu-177-DOTATATE were 4.2 +/- 0.5 in the 9 ileal carcinoids, 12 6 3 in the 10 pheochromocytomas, 11 6 4 in the 7 breast carcinomas, 5.1 +/- 0.6 in the 10 renal cell carcinomas, and 4.8 +/- 0.7 in the 12 non-Hodgkin lymphomas. Conclusion: The present in vitro human data, together with previous in vivo animal tumor data, are strong arguments indicating that sst(2) antagonists may be worth testing in vivo in patients in a wide range of tumors including nonneuroendocrine tumors.