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

Purpose To develop a new probe for the alpha v beta 6-integrin and assess its potential for PET imaging of carcinomas. Methods Ga-68-Trivehexin was synthesized by trimerization of the optimized alpha v beta 6-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 alpha v beta 6, alpha v beta 8, alpha v beta 3, and alpha 5 beta 1, as well as by cell binding assays on H2009 (alpha v beta 6-positive) and MDA-MB-231 (alpha v beta 6-negative) cells. SCID-mice bearing subcutaneous xenografts of the same cell lines were used for dynamic (90 min) and static (75 min p.i.) mu PET 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 alpha v beta 6-integrin affinity (IC50 = 0.047 nM), selectivity over other subtypes (IC50-based factors: alpha v beta 8, 131; alpha v beta 3, 57; alpha 5 beta 1, 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 alpha v beta 6-integrin expression in human cancers.

Automated summary

Ga-68-Trivehexin is a valuable probe for imaging of alpha v beta 6-integrin expression in human cancers. It shows high target-specific uptake in tumors and low non-specific uptake in other organs and tissues except for the excretory organs. Preclinical and in-human PET imaging results confirm its potential for PET imaging of carcinomas.