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

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.