[DOTA]Somatostatin-14 analogs and their (111)In-radioligands: effects of decreasing ring-size on sst1-5 profile, stability and tumor targeting.

Abstract

Multiple somatostatin receptor (sst)-subtype expression has been manifested in several human tumors. Hence, the availability of radiopeptides retaining the full pansomatostatin profile of the native hormone (SS14) is expected to increase the sensitivity and broaden the clinical indications of currently applied sst2-preferring cyclic octapeptide radioligands, like OctreoScan(®) ([(111)In-DTPA]octreotide). On the other hand, SS14 has been excluded from clinical use due to its rapid in vivo degradation. We herein present a small library of seven novel cyclic SS14-mimics carrying at their N-terminus the universal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) for stable binding of medically useful radiometals, like (111)In. By decreasing the number of amino acids composing the ring in their structure from 12 up to 6 AA, we induced important changes in key-biological parameters in vitro and in vivo. In particular, we observed unexpected changes and even total loss of sst1-5-affinity (6AA-ring), as well as weaker sst2-internalization efficacy as the ring size decreased. In contrast, in vivo stability increased with decreasing ring size, reaching its maximum in the 6AA-ring analogs. Interestingly, only the 12AA- and 9AA-ring members of this series showed sst2-specific uptake in AR4-2J tumors in mice revealing the prominent role of ring size on the biological response of tested SS14-derived radioligands.

• Authors: Aikaterini Tatsi, Theodosia Maina, Renzo Cescato, Beatrice Waser, Eric P Krenning, Marion de Jong, Paul Cordopatis, Jean-Claude Reubi, Berthold A Nock
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 73 Pg. 30-7 (Feb 12 2014) ISSN: 1768-3254 [Electronic] France
• PMID: 24378707 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Chemical References

• Heterocyclic Compounds, 1-Ring
• Indium Radioisotopes
• Ligands
• Radiopharmaceuticals
• Receptors, Somatostatin
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
• Somatostatin

Topics

• Animals
• Autoradiography
• Cell Line, Tumor
• Drug Stability
• HEK293 Cells
• Heterocyclic Compounds, 1-Ring (chemistry)
• Humans
• Indium Radioisotopes
• Ligands
• Mice
• Mice, SCID
• Microscopy, Fluorescence
• Molecular Structure
• Neoplasms (diagnosis, metabolism)
• Protein Binding
• Radiopharmaceuticals (blood, chemical synthesis, chemistry)
• Rats
• Receptors, Somatostatin (genetics, metabolism)
• Somatostatin (analogs & derivatives, blood, chemistry)
• Structure-Activity Relationship
• Tissue Distribution