Abstract
The synthesis and preclinical evaluation of [(99m)Tc]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 (99m)Tc-labeling, afforded [(99m)Tc]Demomedin C. Demomedin C showed high affinity and selectivity for the GRPR during receptor autoradiography on human cancer samples (IC(50) in nM: GRPR, 1.4 ± 0.2; NMBR, 106 ± 18; and BB(3)R, >1000). It triggered GRPR internalization in HEK-GRPR cells and Ca(2+) release in PC-3 cells (EC(50) = 1.3 nM). [(99m)Tc]Demomedin C rapidly and specifically internalized at 37 °C in PC-3 cells and was stable in mouse plasma. [(99m)Tc]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 [(99m)Tc]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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Sequence
-
Animals
-
Anura
-
Autoradiography
-
Binding, Competitive
-
Bombesin / chemical synthesis*
-
Bombesin / chemistry
-
Bombesin / pharmacokinetics
-
Bronchial Neoplasms / diagnostic imaging
-
Bronchial Neoplasms / metabolism
-
Calcium / metabolism
-
Cell Line, Tumor
-
Cell Membrane / metabolism
-
Drug Screening Assays, Antitumor
-
Humans
-
Ileal Neoplasms / diagnostic imaging
-
Ileal Neoplasms / metabolism
-
Ligands
-
Male
-
Mice
-
Mice, SCID
-
Microscopy, Fluorescence
-
Neoplasm Transplantation
-
Oligopeptides / chemical synthesis*
-
Oligopeptides / chemistry
-
Oligopeptides / pharmacokinetics
-
Organotechnetium Compounds / chemical synthesis*
-
Organotechnetium Compounds / chemistry
-
Organotechnetium Compounds / pharmacokinetics
-
Peptide Fragments / chemical synthesis*
-
Peptide Fragments / chemistry
-
Peptide Fragments / pharmacokinetics
-
Prostatic Neoplasms / diagnostic imaging
-
Prostatic Neoplasms / metabolism
-
Radionuclide Imaging
-
Radiopharmaceuticals / chemical synthesis*
-
Radiopharmaceuticals / chemistry
-
Radiopharmaceuticals / pharmacokinetics
-
Receptors, Bombesin / agonists
-
Receptors, Bombesin / metabolism*
-
Species Specificity
-
Structure-Activity Relationship
-
Technetium*
-
Tissue Distribution
-
Transplantation, Heterologous
Substances
-
Ligands
-
Oligopeptides
-
Organotechnetium Compounds
-
Peptide Fragments
-
Radiopharmaceuticals
-
Receptors, Bombesin
-
technetium 99m demomedin C
-
Technetium
-
neuromedin C
-
Bombesin
-
Calcium