[DOTA]Somatostatin-14 analogs and their ¹¹¹In-radioligands: Effects of decreasing ring-size on sst_1-5 profile, stability and tumor targeting

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• 作者：Aikaterini Tatsi ; Theodosia Maina ; Renzo Cescato ; Beatrice Waser ; Eric P. Krenning ; Marion de Jong ; Paul Cordopatis ; Jean-Claude Reubi ; Berthold A. Nock
• 关键词：DOTA-conjugated somatostatin ; 111In-radiopeptide ; Pansomatostatin radioligand ; Radiotracer stability ; Tumor targeting
• 刊名：European Journal of Medicinal Chemistry
• 出版年：12 February, 2014
• 年：2014
• 卷：73
• 期：Complete
• 页码：30-37
• 全文大小：884 K

文摘

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^庐 ([¹¹¹In-DTPA]octreotide). On the other hand, SS14 has been excluded from clinical use due to its rapid in聽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 ¹¹¹In. 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聽vitro and in聽vivo. In particular, we observed unexpected changes and even total loss of sst_1-5-affinity (6AA-ring), as well as weaker sst₂-internalization efficacy as the ring size decreased. In contrast, in聽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.