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

Mihaela Ginj, Hanwen Zhang, Beatrice Waser, Renzo Cescato, Damian Wild, Xuejuan Wang, Judit Erchegyi, Jean Rivier, Helmut R. Mäcke, Jean Claude Reubi

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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.

Original languageEnglish
Pages (from-to)16436-16441
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number44
StatePublished - Oct 31 2006


  • Antagonist radioligands
  • Neuropeptides
  • Peptide hormones
  • Receptor internalization
  • Tumor targeting


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