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

作者：Nock Berthold A; Cescato Renzo; Ketani Eleni; Waser Beatrice; Reubi Jean Claude; Maina Theodosia^*

来源：Journal of Medicinal Chemistry, 2012, 55(19): 8364-8374.

DOI：10.1021/jm300741f

The synthesis and preclinical evaluation of [Tc-99m]Demomedin C in GRPR-expressing models are reported. Demomedin C resulted by coupling a Boc-protected N-4-chelator to neuromedin C (human GRP(18-27)), which, after Tc-99m-labeling, afforded [Tc-99m]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 +/- 0.2; NMBR, 106 +/- 18; and BB3R, %26gt;1000). It triggered GRPR internalization in HEK-GRPR cells and Ca2+ release in PC-3 cells (EC50 = 1.3 nM). [Tc-99m]Demomedin C rapidly and specifically internalized at 37 degrees C in PC-3 cells and was stable in mouse plasma. [Tc-99m]Demomedin C efficiently and specifically localized in human PC-3 implants in mice (9.84 +/- 0.81%ID/g at 1 h pi; 6.36 +/- 0.8596ID/g at 4 h pi, and 0.41 +/- 0.07%ID/g at 4 h pi block). Thus, human GRP-based radioligands, such as [Tc-99m]Demomedin C, can successfully target GRPR-expressing human tumors in vivo while displaying attractive biological features-e.g. higher GRPR-selectivity-vs their frog-homologues.

• 出版日期2012-10-11