⁶⁸Ga-Labeled [Thz¹⁴]Bombesin(7-14) Analogs: Promising GRPR-Targeting Agonist PET Tracers with Low Pancreas Uptake

With overexpression in various cancers, the gastrin-releasing peptide receptor (GRPR) is a promising target for cancer imaging and therapy. However, the high pancreas uptake of reported GRPR-targeting radioligands limits their clinical application. Our goal was to develop ⁶⁸Ga-labeled agonist tracers for detecting GRPR-expressing tumors with positron emission tomography (PET), and compare them with the clinically validated agonist PET tracer, [⁶⁸Ga]Ga-AMBA. Ga-TacBOMB2, TacBOMB3, and TacBOMB4, derived from [Thz¹⁴]Bombesin(7-14), were confirmed to be GRPR agonists by a calcium mobilization study, and their binding affinities (K_i(GRPR)) were determined to be 7.62 ± 0.19, 6.02 ± 0.59, and 590 ± 36.5 nM, respectively, via in vitro competition binding assays. [⁶⁸Ga]Ga-TacBOMB2, [⁶⁸Ga]Ga-TacBOMB3, and [⁶⁸Ga]Ga-AMBA clearly visualized PC-3 tumor xenografts in a PET imaging study. [⁶⁸Ga]Ga-TacBOMB2 showed comparable tumor uptake but superior tumor-to-background contrast ratios when compared to [⁶⁸Ga]Ga-AMBA. Moreover, [⁶⁸Ga]Ga-TacBOMB2 and [⁶⁸Ga]Ga-TacBOMB3 showed a much lower rate of uptake in the pancreas (1.30 ± 0.14 and 2.41 ± 0.72%ID/g, respectively) than [⁶⁸Ga]Ga-AMBA (62.4 ± 4.26%ID/g). In conclusion, replacing Met¹⁴ in the GRPR-targeting sequence with Thz¹⁴ retains high GRPR-binding affinity and agonist properties. With good tumor uptake and tumor-to-background uptake ratios, [⁶⁸Ga]Ga-TacBOMB2 is promising for detecting GRPR-expressing tumors. The much lower pancreas uptake of [⁶⁸Ga]Ga-TacBOMB2 and [⁶⁸Ga]Ga-TacBOMB3 suggests that [Thz¹⁴]Bombesin(7-14) is a promising targeting vector for the design of GRPR-targeting radiopharmaceuticals, especially for radioligand therapy application.