Radiolabeled somatostatin receptor antagonists are preferable to agonists forin vivopeptide receptor targeting of tumors

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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 [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 with111/natIn.111/natIn-DOTA-sst3-ODN-8 and111/natIn-DOTA–[4-NO2-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH2] (111/natIn-DOTA-sst2-ANT) showed high sst3- and sst2-binding affinity, respectively. They did not trigger sst3or sst2internalization but prevented agonist-stimulated internalization.111In-DOTA-sst3-ODN-8 and111In-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 of111In-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 agonist111In-DOTA–[1-Nal3]-octreotide, with strong sst3-binding and internalization properties showed a much lower and shorter-lasting uptake in sst3-expressing tumors. Similarly,111In-DOTA-sst2-ANT was injected into mice bearing sst2-expressing tumors. Tumor uptake was considerably higher than with the highly potent sst2-selective agonist111In-diethylenetriaminepentaacetic acid–[Tyr3,Thr8]-octreotide (111In-DTPA-TATE). Scatchard plots showed that antagonists labeled many more sites than agonists. Somatostatin antagonist radiotracers therefore are preferable over agonists for thein vivotargeting 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.

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