Journal Article

Radiolabeled Somatostatin Receptor Antagonists Are Preferable to Agonists for in Vivo Peptide Receptor Targeting of Tumors

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

2006

Overview

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-DAgI⁸(Me,2-naphthoyl)-Lys-ThrPhe-Cys)-OH (sst₃-ODN-8) and a sst₂-selective antagonist (sst₂-ANT)], for labeling with$^{1ll/nat}ln$.$^{111/nat}ln-DOTA-sst_{3}-ODN-8$and$^{111/nat}lnDOTA-[4-NO_{2}-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH_{2}] (^{1ll/nat}lnDOTA-sst_{2}-ANT)$showed high sst₃- and sst₂-binding affinity, respectively. They did not trigger sst₃ or sst₂ internalization but prevented agonist-stimulated internalization.$^{111}ln-DOTA-sst_{3}ODN-8$and$^{111}1n-DOTA-sst_{2}-ANT$were injected intravenously into mice bearing sst₃- and sst₂-expressing tumors, and their biodistribution was monitored. In the sst₃-expressing tumors, strong accumulation of$^{111}ln-DOTA-sst_{3}-ODN-8$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 sst₃-ODN-8 blocked uptake. As a control, the potent agonist$^{111}1n-DOTA-[1-Nal^{3}]-octreotide$, with strong sst₃-binding and internalization properties showed a much lower and shorter-lasting uptake in sst3-expressing tumors. Similarly,$^{111}1n-DOTA-sst_{2}-ANT$was injected into mice bearing sst₂expressing tumors. Tumor uptake was considerably higher than with the highly potent sst₂-selective agonist$^{111}1n-diethylenetriaminepentaacetic$acid-[Tyr⁳,Thr⁸]-octreotide ($^{111}1n-DTPA-TATE$). 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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Agonists / Animals / Antagonist drugs / Antagonists / Biological Sciences / Cells / Fluorescent antibody techniques / HEK293 cells / Humans / Internalization / Mice / Mice, Nude / Molecular Structure / Molecules / Neoplasms - metabolism / Neoplasms - pathology / Oncology / Peptide receptors / Peptides / Radioactive decay / Radioactive tracers / Radioactivity / Radioligand Assay / Receptors / Receptors, Peptide - metabolism / Receptors, Somatostatin - agonists / Receptors, Somatostatin - antagonists & inhibitors / Receptors, Somatostatin - chemistry / Receptors, Somatostatin - metabolism / Somatostatin - analogs & derivatives / Somatostatin - metabolism / Somatostatin receptors / Tumors