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

Abstract

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 [NH 2-CO-c(DCys-Phe-Tyr-DAgl 8(Me,2-naphthoyl)-Lys-Thr-Phe-Cys)-OH (sst 3-ODN-8) and a sst 2-selective antagonist (sst 2-ANT)], for labeling with 111/nat In.111/nat In-DOTA-sst 3-ODN-8 and 111/nat In-DOTA–[4-NO 2-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH 2] (111/nat In-DOTA-sst 2-ANT) showed high sst 3- and sst 2-binding affinity, respectively. They did not trigger sst 3 or sst 2 internalization but prevented agonist-stimulated internalization.111 In-DOTA-sst 3-ODN-8 and 111 In-DOTA-sst 2-ANT were injected intravenously into mice bearing sst 3- and sst 2-expressing tumors, and their biodistribution was monitored. In the sst 3-expressing tumors, strong accumulation of 111 In-DOTA-sst 3-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 sst 3-ODN-8 blocked uptake. As a control, the potent agonist 111 In-DOTA–[1-Nal 3]-octreotide, with strong sst 3-binding and internalization properties showed a much lower and shorter-lasting uptake in sst 3-expressing tumors. Similarly,111 In-DOTA-sst 2-ANT was injected into mice bearing sst 2-expressing tumors. Tumor uptake was considerably higher than with the highly potent sst 2-selective agonist 111 In-diethylenetriaminepentaacetic acid–[Tyr 3,Thr 8]-octreotide (111 In-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 sst 3- or sst 2-expressing tumors. Antagonist radioligands for other peptide receptors need to be evaluated in nuclear oncology as a result of this paradigm shift.