Positron Emission Tomography Imaging of Neurotensin Receptor-Positive Tumors with 68Ga-Labeled Antagonists: The Chelate Makes the Difference Again

J Med Chem. 2021 Jun 24;64(12):8564-8578. doi: 10.1021/acs.jmedchem.1c00523. Epub 2021 Jun 9.

Abstract

Neurotensin receptor 1 (NTS1) is involved in the development and progression of numerous cancers, which makes it an interesting target for the development of diagnostic and therapeutic agents. A small molecule NTS1 antagonist, named [177Lu]Lu-IPN01087, is currently evaluated in phase I/II clinical trials for the targeted therapy of neurotensin receptor-positive cancers. In this study, we synthesized seven compounds based on the structure of NTS1 antagonists, bearing different chelating agents, and radiolabeled them with gallium-68 for PET imaging. These compounds were evaluated in vitro and in vivo in mice bearing a HT-29 xenograft. The compound [68Ga]Ga-bisNODAGA-16 showed a promising biodistribution profile with mainly signal in tumor (4.917 ± 0.776%ID/g, 2 h post-injection). Its rapid clearance from healthy tissues led to high tumor-to-organ ratios, resulting in highly contrasted PET images. These results were confirmed on subcutaneous xenografts of AsPC-1 tumor cells, a model of NTS1-positive human pancreatic adenocarcinoma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Adamantane / analogs & derivatives*
  • Adamantane / chemical synthesis
  • Adamantane / chemistry
  • Adamantane / pharmacokinetics
  • Animals
  • Cell Line, Tumor
  • Chelating Agents / chemical synthesis
  • Chelating Agents / chemistry*
  • Chelating Agents / pharmacokinetics
  • Gallium Radioisotopes / chemistry
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry*
  • Imidazoles / pharmacokinetics
  • Mice
  • Neoplasms / diagnostic imaging*
  • Neoplasms / metabolism
  • Positron-Emission Tomography
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / chemistry*
  • Radiopharmaceuticals / pharmacokinetics
  • Receptors, Neurotensin / metabolism*

Substances

  • Chelating Agents
  • Gallium Radioisotopes
  • Imidazoles
  • Radiopharmaceuticals
  • Receptors, Neurotensin
  • SR 142948A
  • Gallium-68
  • Adamantane