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Internalization of Sst2, Sst3, and Sst5 Receptors: Effects of Somatostatin Agonists and Antagonists

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Internalization of Sst2, Sst3, and Sst5 Receptors: Effects of Somatostatin Agonists and Antagonists Internalization of sst2, sst3, and sst5 Receptors: Effects of Somatostatin Agonists and Antagonists Renzo Cescato, PhD1; Stefan Schulz, PhD2; Beatrice Waser1;Ve´ronique Eltschinger1; Jean E. Rivier, PhD3; Hans-Ju¨rgen Wester, PhD4; Michael Culler, PhD5; Mihaela Ginj, PhD6; Qisheng Liu, MD, PhD7; Agnes Schonbrunn, PhD7; and Jean Claude Reubi, MD1 1Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Berne, Switzerland; 2Institute of Pharmacology and Toxicology, Otto-von-Guericke University, Magdeburg, Germany; 3Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, California; 4Nuklearmedizinische Klinik und Poliklinik, Technical University of Munich, Munich, Germany; 5Endocrine Research, Beaufour-Ipsen Group, Milford, Massachusetts; 6Division of Radiological Chemistry, University Hospital, Basel, Switzerland; and 7Department of Integrative Biology and Pharmacology, University of Texas Health Science Center–Houston, Houston, Texas sensitive and reproducible immunocytochemical methods, the The uptake of radiolabeled somatostatin analogs by tumor cells ability of various somatostatin analogs to induce sst2, sst3, and through receptor-mediated internalization is a critical process sst5 internalization has been qualitatively and quantitatively de- for the in vivo targeting of tumoral somatostatin receptors. In termined. Whereas all agonists triggered sst2 and sst3 internali- the present study, the somatostatin receptor internalization in- zation, sst5 internalization was induced by natural somatostatin duced by a variety of somatostatin analogs was measured with peptides but not by synthetic high-affinity sst5 agonists. Such new immunocytochemical methods that allow characterization assays will be of considerable help for the future characterization of trafficking of the somatostatin receptor subtype 2 (sst2), so- of ligands foreseen for nuclear medicine applications. matostatin receptor subtype 3 (sst3), and somatostatin receptor Key Words: somatostatin receptors; receptor internalization; subtype 5 (sst5) in vitro at the protein level. Methods: Human antagonist; tumor targeting; receptor immunocytochemistry embryonic kidney 293 (HEK293) cells expressing the sst2, sst3, J Nucl Med 2006; 47:502–511 or the sst5 were used in a morphologic immunocytochemical in- ternalization assay using specific sst2, sst3 and sst5 antibodies to qualitatively and quantitatively determine the capability of so- matostatin agonists or antagonists to induce somatostatin receptor internalization. In addition, the internalization properties of a se- lection of these agonists have been compared and quantified in Interest in somatostatin and somatostatin analogs is in- creasing, largely because of the success of in vivo targeting sst2-expressing CHO-K1 cells using an ELISA. Results: Agonists with a high sst2-binding affinity were able to induce sst2 internal- of somatostatin receptors in tumors (1). In this clinical ization in the HEK293 and CHO-K1 cell lines. New sst2 agonists, application, not only is binding of the radiolabeled somato- such as Y-DOTA-TATE, Y-DOTA-NOC, Lu-DOTA-BOC-ATE (where statin analogs to the receptor important but also internal- DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic ization of the receptor–ligand complex for successful in 3 8 3 acid; TATE is [Tyr , Thr ]-octreotide; NOC is [1-NaI ]-octreotide; vivo targeting of tumoral peptide receptors using radio- and BOC-ATE is [BzThi3, Thr8]-octreotide), iodinated sugar- containing octreotide analogs, or BIM-23244 were considerably peptides (1,2). Therefore, during the course of optimal development of new radiopeptide analogs for in vivo more potent in internalizing sst2 than was DTPA-octreotide (where DTPA is diethylenetriaminepentaacetic acid). Similarly, receptor targeting, peptides need to be tested not only for compounds with high sst3 affinity such as KE108 were able to in- receptor binding and biodistribution but also for their duce sst3 internalization. In sst2- or sst3-expressing cell lines, receptor internalization properties. agonist-induced receptor internalization was efficiently abolished Most of the internalization studies performed with radio- by sst2- or sst3-selective antagonists, respectively. Antagonists peptides, including radiolabeled somatostatin analogs, have alone had no effect on sst or sst internalization. We also showed 2 3 been done with methods that measure internalization of the that somatostatin-28 and somatostatin-14 can induce sst5 inter- radioligand but not of the receptor itself (3–8). Although nalization. Unexpectedly, however, potent sst5 agonists such as KE108, BIM-23244, and L-817,818 were not able to induce sst5 such methods give a good indication of the internalization internalization under the same conditions. Conclusion: Using capability of a given radioligand, they are not always easy to interpret because of the extremely complex mechanisms of intracellular receptor trafficking and intracellular pro- Received Jul. 6, 2005; revision accepted Sep. 23, 2005. For correspondence or reprints contact: Jean Claude Reubi, MD, Division cessing of the internalized radioligand (9); furthermore, in of Cell Biology and Experimental Cancer Research, Institute of Pathology, these radioligand internalization studies, receptor inter- University of Berne, P.O. Box 62, Murtenstrasse 31, CH-3010 Berne, Switzerland. nalization can be quantitated only at subsaturating ligand E-mail: [email protected] concentrations, rather than at a large range of agonist 502 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 47 • No. 3 • March 2006 concentrations and receptor occupancies. Finally, the role pansomatostatins such as KE108 (18); or of analogs selec- of agonists versus antagonists in the internalization process tive for sst2 (L-779,976) (24), for sst5 (L-817,818) (24), or could not be thoroughly investigated in the previous stud- for both NOC-ATE ([1-NaI3, Thr8]-octreotide) (25) and ies: Although there is a consensus that antagonists gener- BIM-23244 (17). A number of chelated analogs of the first ally do not trigger the internalization of G-protein–coupled generation (DTPA-octreotide [where DTPA is diethylene- receptors (10), examples exist of peptide receptor antago- triaminepentaacetic acid] or DOTA-lanreotide) (26)or nists that do stimulate internalization, such as cholecysto- second generation (Y-DOTA-NOC, Y-DOTA-TATE, Lu- kinin-, 5-HT2A-, endothelin-, and neuropeptide Y–analogs DOTA-BOC-ATE, or Lu-DOTA-NOC-ATE) (where TATE (10–13). In the somatostatin receptor field, a recent report is [Tyr3, Thr8]-octreotide and BOC-ATE is [BzThi3, Thr8]- indicated that somatostatin receptor agonists, but not so- octreotide) (4,26) have also been tested, as well as several matostatin receptor antagonists, are able to internalize the iodinated, sugar-containing octreotide analogs (27). For somatostatin receptor subtype 2 (sst2)(14). Many studies comparison, established sst2 or sst3 antagonists have been describing new radiopeptides for in vivo targeting do not used (28,29). This study focused on sst2 internalization, give experimental evidence of whether these radioligands because sst2 is the most important somatostatin receptor are agonists or antagonists. from a clinical point of view (1) and because most of the Somatostatin action is mediated by 5 somatostatin re- clinically available somatostatin analogs have a strong sst2 ceptors (15). However, not all will equally internalize on affinity (15,26). However, sst3 and sst5 internalization has agonist binding (15,16). sst2, somatostatin receptor subtype also been investigated because many of the newly devel- 3 (sst3), and somatostatin receptor subtype 5 (sst5) are oped compounds have affinities for somatostatin receptors internalized to a much higher extent than is somatostatin other than the sst2 subtype. receptor subtype 1 (sst1) or somatostatin receptor subtype 4 (sst4)(15,16). Up to now, clinically relevant radioligands MATERIALS AND METHODS were predominantly tested for internalization on sst2 model systems (3–7,14) because of their predominant sst2-binding Reagents affinity. Recently, however, increasing numbers of reports All reagents were of the best grade available and were have been published on the development of somatostatin purchased from common suppliers. The R2-88 antibody to the analogs with distinct affinity profiles for sst2, sst3, and sst5 sst2A was generated as previously described and has been exten- such as DOTA-NOC (where DOTA is 1,4,7,10-tetraazacy- sively characterized (30,31). The sst3-specific antibody (SS-850) clododecane-1,4,7,10-tetraacetic acid and NOC is [1-NaI3]- and the corresponding C-terminal antigen peptide (S-851) were octreotide) (4), BIM-23244 (17), or even analogs with a purchased from Gramsch Laboratories. The sst5-specific antibody (6005) and the corresponding antigen peptide (amino acids 12220 pansomatostatin profile such as KE108 (18). Thus, a thor- of the human sst5) were provided by Dr. Stefan Schulz. The ough investigation of the internalization properties of these secondary antibody Alexa Fluor 488 goat antirabbit IgG (H1L) analogs is required at each of the somatostatin receptor was from Molecular Probes, Inc. The rabbit polyclonal hemag- subtypes. glutinin epitope antibodies were purchased from Covance or from One aim of the present study was to evaluate a variety of Sigma-Aldrich. The horseradish peroxidase substrate kit and the somatostatin analogs, either in clinical use or in develop- goat antirabbit IgG (H1L)-horseradish
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