Design of Bimodal Ligands of Neurotensin Receptor 1 for Positron Emission Tomography Imaging and Fluorescence-Guided Surgery of Pancreatic Cancer

J Med Chem. 2020 Mar 12;63(5):2426-2433. doi: 10.1021/acs.jmedchem.9b01407. Epub 2020 Jan 2.

Abstract

Neurotensin receptor 1 (NTSR1) is overexpressed in most human pancreatic ductal adenocarcinomas. It makes it an attractive target for the development of pancreatic cancer imaging agents. In this study, we sought to develop a bimodal positron emission tomography (PET)/fluorescent imaging agent capable of specifically targeting these receptors. Starting from the structure of a known NTSR1 agonist, a series of tracers were synthesized, radiometalated with gallium-68, and evaluated in vitro and in vivo, in mice bearing an AsPC-1 xenograft. PET imaging allowed us to identify the compound [68Ga]Ga-NODAGA-Lys(Cy5**)-AEEAc-[Me-Arg8,Tle12]-NT(7-13) as the one with the most promising biodistribution profile, characterized by high tumor uptake (2.56 ± 0.97%ID/g, 1 h post-injection) and rapid elimination from nontargeted organs, through urinary excretion. Fluorescence imaging gave similar results. On this basis, fluorescence-guided resection of tumor masses was successfully carried out on a preclinical model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / chemistry
  • Animals
  • Cell Line, Tumor
  • Female
  • Fluorescent Dyes / chemistry*
  • Gallium Radioisotopes / chemistry
  • Heterocyclic Compounds, 1-Ring / chemistry
  • Humans
  • Ligands
  • Mice
  • Optical Imaging / methods
  • Pancreas / diagnostic imaging
  • Pancreas / surgery
  • Pancreatic Neoplasms / diagnostic imaging
  • Pancreatic Neoplasms / surgery*
  • Positron-Emission Tomography / methods
  • Receptors, Neurotensin / analysis*
  • Surgery, Computer-Assisted / methods

Substances

  • 1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane
  • Acetates
  • Fluorescent Dyes
  • Gallium Radioisotopes
  • Heterocyclic Compounds, 1-Ring
  • Ligands
  • Receptors, Neurotensin
  • neurotensin type 1 receptor
  • Gallium-68