# Exploring the theranostic potential of two metabolically stable GRPR-targeting peptides labelled with Ga-68 for PET imaging

## TL;DR

This study evaluates two GRPR-targeting peptides labeled with Ga-68 for PET imaging, showing high tumor uptake and potential as diagnostic tools for GRPR-positive tumors.

## Contribution

The study introduces two new Ga-68-labeled GRPR-targeting peptides with high diagnostic potential and compatibility for theranostic use with Lu-177.

## Key findings

- Both [68Ga]Ga-PKB2 and [68Ga]Ga-PKB3 showed high GRPR affinity and fast clearance with high tumor uptake in PC-3 xenografts.
- [68Ga]Ga-PKB3 had higher uptake in the pancreas and lower kidney uptake compared to [68Ga]Ga-PKB2.
- PET/CT images confirmed the biodistribution results, clearly showing tumor tissue.

## Abstract

Gastrin-releasing peptide receptor (GRPR) attracts increasing attention as a target for radiotheranostic applications. We previously developed a metabolically stable GRPR-targeting peptide, incorporating α-methyl-L-tryptophan within its sequence (PEG2-Pip-D-Phe6-Gln7-MetTrp8-Ala9-Val10-Sar11-His12-Sta13-Leu14-NH2) and coupled it to DOTAGA chelator (PKB2) and to DOTA (PKB3). When labelled with Lu-177, both peptide variants demonstrated promising properties for targeted radionuclide therapy.

In this study, we aimed to evaluate the diagnostic counterparts of PKB2 and PKB3 by radiolabelling them with Ga-68 for positron emission tomography (PET) imaging. [68Ga]Ga-PKB2 and [68Ga]Ga-PKB3 were produced with radiochemical yields over 99% and radiochemical purities over 97%. Both radiopeptides showed a high GRPR affinity with IC50 values in the low nanomolar range and a GRPR-mediated uptake in PC-3 cells with slow internalization. The labelled peptides [68Ga]Ga-PKB2 and [68Ga]Ga-PKB3 demonstrated fast clearance with activity concentration in blood below 0.5%IA/g at 2 pi, and a high tumour activity uptake in PC-3 xenografts (16 ± 3%IA/g and 17 ± 2%IA/g, respectively). [68Ga]Ga-PKB3 had a significantly higher activity uptake in the pancreas (GRPR-expressing organ) and lower uptake in the kidneys than [68Ga]Ga-PKB2. PET/CT images were concordant with the biodistribution results, clearly delineating tumour tissue.

[68Ga]Ga-PKB2 and [68Ga]Ga-PKB3 are promising PET tracers for imaging of GRPR-positive tumours and are potential diagnostic counterparts to their 177Lu-labelled analogues, supporting their use as a 177Lu/68Ga theranostic pair.

The online version contains supplementary material available at 10.1186/s41181-026-00431-5.