[(99m)Tc]Demomedin C, a radioligand based on human gastrin releasing peptide(18-27): synthesis and preclinical evaluation in gastrin releasing peptide receptor-expressing models

J Med Chem. 2012 Oct 11;55(19):8364-74. doi: 10.1021/jm300741f. Epub 2012 Sep 26.

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