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

Tatsi, Aikaterini; Maina, Theodosia; Cescato, Renzo; Waser, Beatrice; Krenning, Eric P; de Jong, Marion; Cordopatis, Paul; Reubi, Jean-Claude; Nock, Berthold A (2014). [DOTA]Somatostatin-14 analogs and their (111)In-radioligands: effects of decreasing ring-size on sst1-5 profile, stability and tumor targeting. European journal of medicinal chemistry, 73, pp. 30-37. Elsevier Masson SAS 10.1016/j.ejmech.2013.12.003

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Pavillon 52 > Forschungsgruppe Klinische Radiopharmazie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Pavillon 52 > Forschungsgruppe Klinische Radiopharmazie

UniBE Contributor:

Cescato, Renzo; Waser, Beatrice and Reubi, Jean-Claude

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0223-5234

Publisher:

Elsevier Masson SAS

Language:

English

Submitter:

Doris Haefelin

Date Deposited:

13 Apr 2015 11:21

Last Modified:

05 Nov 2015 13:55

Publisher DOI:

10.1016/j.ejmech.2013.12.003

PubMed ID:

24378707

Uncontrolled Keywords:

(111)In-radiopeptide; DOTA-conjugated somatostatin; Pansomatostatin radioligand; Radiotracer stability; Tumor targeting

BORIS DOI:

10.7892/boris.66522

URI:

https://boris.unibe.ch/id/eprint/66522

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