PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the "Cancer Integrin" αvβ6 with Ga-68-Trivehexin

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Neil Gerard Quigley - , Technical University of Munich (Author)
  • Katja Steiger - , Technical University of Munich (Author)
  • Sebastian Hoberück - , Department of Nuclear Medicine, University Hospital Carl Gustav Carus Dresden (Author)
  • Norbert Czech - , Center of Nuclear Medicine and PET/CT Bremen (Author)
  • Maximilian Alexander Zierke - , Technical University of Munich (Author)
  • Susanne Kossatz - , Technical University of Munich (Author)
  • Marc Pretze - , Department of Nuclear Medicine, University Hospital Carl Gustav Carus Dresden (Author)
  • Frauke Richter - , Technical University of Munich (Author)
  • Wilko Weichert - , Technical University of Munich (Author)
  • Christian Pox - , Hospital St. Joseph-Stift Bremen (Author)
  • Jörg Kotzerke - , Department of Nuclear Medicine, University Hospital Carl Gustav Carus Dresden (Author)
  • Johannes Notni - , Technical University of Munich, University Hospital Essen (Author)

Abstract

PURPOSE: To develop a new probe for the αvβ6-integrin and assess its potential for PET imaging of carcinomas.

METHODS: Ga-68-Trivehexin was synthesized by trimerization of the optimized αvβ6-integrin selective cyclic nonapeptide Tyr2 (sequence: c[YRGDLAYp(NMe)K]) on the TRAP chelator core, followed by automated labeling with Ga-68. The tracer was characterized by ELISA for activities towards integrin subtypes αvβ6, αvβ8, αvβ3, and α5β1, as well as by cell binding assays on H2009 (αvβ6-positive) and MDA-MB-231 (αvβ6-negative) cells. SCID-mice bearing subcutaneous xenografts of the same cell lines were used for dynamic (90 min) and static (75 min p.i.) µPET imaging, as well as for biodistribution (90 min p.i.). Structure-activity-relationships were established by comparison with the predecessor compound Ga-68-TRAP(AvB6)3. Ga-68-Trivehexin was tested for in-human PET/CT imaging of HNSCC, parotideal adenocarcinoma, and metastatic PDAC.

RESULTS: Ga-68-Trivehexin showed a high αvβ6-integrin affinity (IC50 = 0.047 nM), selectivity over other subtypes (IC50-based factors: αvβ8, 131; αvβ3, 57; α5β1, 468), blockable uptake in H2009 cells, and negligible uptake in MDA-MB-231 cells. Biodistribution and preclinical PET imaging confirmed a high target-specific uptake in tumor and a low non-specific uptake in other organs and tissues except the excretory organs (kidneys and urinary bladder). Preclinical PET corresponded well to in-human results, showing high and persistent uptake in metastatic PDAC and HNSCC (SUVmax = 10-13) as well as in kidneys/urine. Ga-68-Trivehexin enabled PET/CT imaging of small PDAC metastases and showed high uptake in HNSCC but not in tumor-associated inflammation.

CONCLUSIONS: Ga-68-Trivehexin is a valuable probe for imaging of αvβ6-integrin expression in human cancers.

Details

Original languageEnglish
Pages (from-to)1136-1147
Number of pages12
JournalEuropean journal of nuclear medicine and molecular imaging
Volume49
Issue number4
Publication statusPublished - Mar 2022
Peer-reviewedYes

External IDs

PubMedCentral PMC8460406
Scopus 85115637466
ORCID /0000-0002-6432-5694/work/146644227

Keywords

Sustainable Development Goals

Keywords

  • Animals, Cell Line, Tumor, Gallium Radioisotopes, Head and Neck Neoplasms, Humans, Integrin alphaVbeta3/metabolism, Integrins/metabolism, Mice, Mice, SCID, Pancreatic Neoplasms/diagnostic imaging, Positron Emission Tomography Computed Tomography, Positron-Emission Tomography/methods, Squamous Cell Carcinoma of Head and Neck, Tissue Distribution

Library keywords