[99mTc]Demomedin C, a Radioligand Based on Human Gastrin Releasing Peptide(18-27): Synthesis and Preclinical Evaluation in Gastrin Releasing Peptide Receptor-Expressing Models
Berthold Artur Nock , Renzo Cescato , Eleni Ketani , B. Waser , J. C. Reubi , T. Maina, J. Med. Chem., Just Accepted Manuscript
DOI: 10.1021/jm300741f
Publication Date (Web): September 11, 2012
Copyright © 2012 American Chemical Society

The synthesis and preclinical evaluation of [99mTc]Demomedin C in gastrin releasing peptide receptor(GRPR)-expressing models are reported. Demomedin C resulted by coupling a Boc-protected N4-chelator to neuromedin C (human GRP(18-27)) and 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±0.2; NMBR, 106±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 37oC 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±0.81%ID/g at 1 h pi; 6.36±0.85%ID/g at 4 h pi and 0.41±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 – e.g. higher GRPR-selectivity – vs. their frog-homologs.