Gastrin Releasing Peptide Receptor-Directed Radioligands Based on a Bombesin Antagonist: Synthesis, 111In-Labeling, and Preclinical Profile

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• 作者：Panteleimon J. Marsouvanidis ; Berthold A. Nock ; Bouchra Hajjaj ; Jean-Alain Fehrentz ; Luc Brunel ; C茅line M鈥橩admi ; Linda van der Graaf ; Eric P. Krenning ; Theodosia Maina ; Jean Martinez ; Marion de Jong
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 28, 2013
• 年：2013
• 卷：56
• 期：6
• 页码：2374-2384
• 全文大小：426K
• 年卷期：v.56,no.6(March 28, 2013)
• ISSN：1520-4804

文摘

Novel bombesin (BBN) antagonists were synthesized by coupling the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to H-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH₂ (JMV594) through linkers of increasing number of (尾Ala)_x residues (x = 1鈥?). Labeling with ¹¹¹In afforded the respective radiotracers in high purity and high specific activity. Bioconjugate affinity for the gastrin releasing peptide receptor (GRPR) as determined against [¹²⁵I-Tyr⁴]BBN was high (IC₅₀ values in the lower nanomolar range). Radioligands poorly internalized in PC-3 cells at 37 掳C. Radiopeptides remained >60% intact 5 min after entering the bloodstream of healthy mice. After injection in SCID mice bearing human PC-3 xenografts all analogues showed high tumor uptake and rapid background clearance via the kidneys into urine. Interestingly, pancreatic uptake, albeit GRPR-specific, declined rapidly with time. ¹¹¹In-DOTA-(尾Ala)₂-JMV594 achieved the highest tumor values among the group (17.0 卤 2.8%ID/g vs. 8鈥?0%ID/g, respectively, at 4 h pi) indicating that the (尾Ala)₂-linker favors in vivo interaction of radiopeptides with the GRPR.