Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors

Targeting neuroendocrine tumors expressing somatostatin receptor subtypes (sst) with radiolabeled somatostatin agonists is an established diagnostic and therapeutic approach in oncology. While agonists readily internalize into tumor cells, permitting accumulation of radioactivity, radiolabeled antagonists do not, and they have not been considered for tumor targeting. The macrocyclic chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was coupled to two potent somatostatin receptor-selective peptide antagonists [NH₂-CO-c(DCys-Phe-Tyr-DAgl⁸(Me,2-naphthoyl)-Lys-Thr-Phe- Cys)-OH (sst₃-ODN-8) and a sst₂-selective antagonist (sst₂-ANT)], for labeling with ^111/natln. ^111/natln-DOTA-sst₃-ODN-8 and 111/natln-DOTA-[4-NO ₂-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH₂] ^111/natln-DOTA-SSt₂-ANT) showed high sst₃- and sst₂-binding affinity, respectively. They did not trigger sst ₃ or sst₂ internalization but prevented agonist-stimulated internalization. ¹¹¹ln-DOTA-sst₃-ODN-8 and ¹¹¹ln-DOTA-sst₂-ANT were injected intravenously into mice bearing sst₃- and sst₂-expressing tumors, and their biodistribution was monitored. In the sst₃-expressing tumors, strong accumulation of ¹¹¹ln-DOTA-sst₃-ODN-8 was observed, peaking at 1 h with 60% injected radioactivity per gram of tissue and remaining at a high level for >72 h. Excess of sst₃-ODN-8 blocked uptake. As a control, the potent agonist ¹¹¹ln-DOTA-[1-Nal³]- octreotide, with strong sst₃-binding and internalization properties showed a much lower and shorter-lasting uptake in sst₃-expressing tumors. Similarly, ¹¹¹ln-DOTA-sst₂-ANT was injected into mice bearing sst₂-expressing tumors. Tumor uptake was considerably higher than with the highly potent sst₂-selective agonist ¹¹¹ln-diethylenetriaminepentaacetic acid-[Tyr³,Thr ⁸]-octreotide (¹¹¹ln-DTPA-TATE). Scatchard plots showed that antagonists labeled many more sites than agonists. Somatostatin antagonist radiotracers therefore are preferable over agonists for the in vivo targeting of sst₃- or sst₂-expressing tumors. Antagonist radioligands for other peptide receptors need to be evaluated in nuclear oncology as a result of this paradigm shift.