title: [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.affiliation: Molecular Radiopharmacy, INRASTES, NCSR "Demokritos", Ag. Paraskevi Attikis, GR-153 10 Athens, Greece; Department of Radiology, Erasmus MC, 3015 GD, Rotterdam, The Netherlands.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Tatsi
authors.affiliation: Molecular Radiopharmacy, INRASTES, NCSR "Demokritos", Ag. Paraskevi Attikis, GR-153 10 Athens, Greece.
authors.forename: Theodosia
authors.initials: T
authors.lastname: Maina
authors.affiliation: Institute of Pathology, University of Berne, CH-3010 Berne, Switzerland.
authors.forename: Renzo
authors.initials: R
authors.lastname: Cescato
authors.affiliation: Institute of Pathology, University of Berne, CH-3010 Berne, Switzerland.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Waser
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, 3015 GD, Rotterdam, The Netherlands.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Krenning
authors.affiliation: Department of Nuclear Medicine, Erasmus MC, 3015 GD, Rotterdam, The Netherlands; Department of Radiology, Erasmus MC, 3015 GD, Rotterdam, The Netherlands.
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
authors.affiliation: Department of Pharmacy, University of Patras, GR-26500 Patras, Greece.
authors.forename: Paul
authors.initials: P
authors.lastname: Cordopatis
authors.affiliation: Institute of Pathology, University of Berne, CH-3010 Berne, Switzerland.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Reubi
authors.affiliation: Molecular Radiopharmacy, INRASTES, NCSR "Demokritos", Ag. Paraskevi Attikis, GR-153 10 Athens, Greece. Electronic address: nock_berthold.a@hotmail.com.
authors.forename: Berthold A
authors.initials: BA
authors.lastname: Nock
mesh_terms: D000818:Animals; D001345:Autoradiography; D045744:Cell Line, Tumor; D004355:Drug Stability; D057809:HEK293 Cells; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006801:Humans; D007205:Indium Radioisotopes; D008024:Ligands; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D009369:Neoplasms / Q000175:diagnosis / Q000378:metabolism; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D008024:Ligands; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D013004:Somatostatin
keywords: (111)In-radiopeptide; DOTA-conjugated somatostatin; Pansomatostatin radioligand; Radiotracer stability; Tumor targeting