Monomeric and Dimeric 68 Ga-Labeled Bombesin Analogues for Positron Emission Tomography (PET) Imaging of Tumors Expressing Gastrin-Releasing Peptide Receptors (GRPrs).

The GRPr, highly expressed in prostate PCa and breast cancer BCa, is a promising target for the development of new PET radiotracers. The chelator HBED-CC ( N, N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine- N, N'-diacetic acid) was coupled to the bombesin peptides: HBED-C-BN(2-14) 1, HBED-CC-PEG2 -[d-Tyr6 ,β-Ala11 ,Thi13 ,Nle14 ]-BN(6-14) 2, HBED-CC-Y-[d-Phe6 ,Sta13 ,Leu14 ]-BN(6-14) (Y = 4-amino-1-carboxymethylpiperidine) 3, and HBED-CC-{PEG2 -Y-[d-Phe6 ,Sta13 ,Leu14 ]-BN(6-14)}2 4 (homodimer). Compounds 1-4 presented high binding affinities for GRPr (T47D, 0.56-3.51 nM; PC-3, 2.12-4.68 nM). In PC-3 and T47D cells, agonists [68 Ga]1 and [68 Ga]2 were mainly internalized while antagonists [68 Ga]3 and [68 Ga]4 were surface bound. Cell-related radioactivity reached a maximum after 45 min, while tracer levels followed GRPr expression (PC-3 > T47D > LNCaP > MDA-MB-231). [68 Ga]4 showed the highest cell-bound radioactivity (PC-3 and T47D). In vivo, tumor (PC-3) targeting for [68 Ga]3 and [68 Ga]4 increased over time, with dynamic μPET showing clearer tumors images at later time points. [68 Ga]3 and [68 Ga]4 can be considered suitable PET tracers for imaging PCa and BCa expressing GRPr.