Tumor Diagnosis with New 111In-Radioligands Based on Truncated Human Gastrin Releasing Peptide Sequences: Synthesis and Preclinical Comparison

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• 作者：Panteleimon J. Marsouvanidis ; Theodosia Maina ; Werner Sallegger ; Eric P. Krenning ; Marion de Jong ; Berthold A. Nock
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8579-8587
• 全文大小：367K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

Radiolabeled analogs of the frog tetradecapeptide bombesin (BBN) have been proposed for diagnosis and therapy of gastrin releasing peptide receptor (GRPR)-expressing tumors. Following a different and yet unexplored approach, we have developed four novel ¹¹¹In-labeled truncated analogs of the human 27-mer GRP after conjugation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) at the N-terminus of GRP(13/14/17/18鈥?7) fragments. Analog affinities for the human GRPR determined against [¹²⁵I-Tyr⁴]BBN were at the nanomolar level and dependent on truncation site. The respective ¹¹¹In radioligands specifically internalized in GRPR-expressing PC-3 cells. The shorter chain [¹¹¹In-DOTA]GRP(17/18鈥?7) analogs showed higher metabolic stability in mice. Radioligands specifically localized in human PC-3 xenografts in SCID mice, with [¹¹¹In-DOTA]GRP(17鈥?7) exhibiting the most favorable pharmacokinetic profile. This study has demonstrated the efficacy of human GRP-based radiopeptides to target GRPR-positive lesions in vivo and has revealed the impact of GRP chain length on key biological parameters of resulting radiotracers.