[99mTc]Demomedin C, a Radioligand Based on Human Gastrin Releasing Peptide(18-27): Synthesis and Preclinical Evaluation in Gastrin Releasing Peptide Receptor-Expressing Models

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• 作者：Berthold A. Nock ; Renzo Cescato ; Eleni Ketani ; Beatrice Waser ; Jean Claude Reubi ; Theodosia Maina
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 11, 2012
• 年：2012
• 卷：55
• 期：19
• 页码：8364-8374
• 全文大小：435K
• 年卷期：v.55,no.19(October 11, 2012)
• ISSN：1520-4804

文摘

The synthesis and preclinical evaluation of [^99mTc]Demomedin C in GRPR-expressing models are reported. Demomedin C resulted by coupling a Boc-protected N₄-chelator to neuromedin C (human GRP(18-27)), which, after ^99mTc-labeling, afforded [^99mTc]Demomedin C. Demomedin C showed high affinity and selectivity for the GRPR during receptor autoradiography on human cancer samples (IC₅₀ in nM: GRPR, 1.4 卤 0.2; NMBR, 106 卤 18; and BB₃R, >1000). It triggered GRPR internalization in HEK-GRPR cells and Ca²⁺ release in PC-3 cells (EC₅₀ = 1.3 nM). [^99mTc]Demomedin C rapidly and specifically internalized at 37 掳C in PC-3 cells and was stable in mouse plasma. [^99mTc]Demomedin C efficiently and specifically localized in human PC-3 implants in mice (9.84 卤 0.81%ID/g at 1 h pi; 6.36 卤 0.85%ID/g at 4 h pi, and 0.41 卤 0.07%ID/g at 4 h pi block). Thus, human GRP-based radioligands, such as [^99mTc]Demomedin C, can successfully target GRPR-expressing human tumors in vivo while displaying attractive biological features鈥攅.g. higher GRPR-selectivity鈥攙s their frog-homologues.