68 Ga-Labeled [Leu 13 ψThz 14 ]Bombesin(7-14) Derivatives: Promising GRPR-Targeting PET Tracers with Low Pancreas Uptake.

The gastrin-releasing peptide receptor (GRPR) is a G-protein-coupled receptor that is overexpressed in many solid cancers and is a promising target for cancer imaging and therapy. However, high pancreas uptake is a major concern in the application of reported GRPR-targeting radiopharmaceuticals, particularly for targeted radioligand therapy. To lower pancreas uptake, we explored Ga-complexed TacsBOMB2, TacsBOMB3, TacsBOMB4, TacsBOMB5, and TacsBOMB6 derived from a potent GRPR antagonist sequence, [Leu 13 ψThz 14 ]Bombesin(7-14), and compared their potential for cancer imaging with [ 68 Ga]Ga-RM2. The K i (GRPR) values of Ga-TacsBOMB2, Ga-TacsBOMB3, Ga-TacsBOMB4, Ga-TacsBOMB5, Ga-TacsBOMB6, and Ga-RM2 were 7.08 ± 0.65, 4.29 ± 0.46, 458 ± 38.6, 6.09 ± 0.95, 5.12 ± 0.57, and 1.51 ± 0.24 nM, respectively. [ 68 Ga]Ga-TacsBOMB2, [ 68 Ga]Ga-TacsBOMB3, [ 68 Ga]Ga-TacsBOMB5, [ 68 Ga]Ga-TacsBOMB6, and [ 68 Ga]Ga-RM2 clearly show PC-3 tumor xenografts in positron emission tomography (PET) images, while [ 68 Ga]Ga-TacsBOMB5 shows the highest tumor uptake (15.7 ± 2.17 %ID/g) among them. Most importantly, the pancreas uptake values of [ 68 Ga]Ga-TacsBOMB2 (2.81 ± 0.78 %ID/g), [ 68 Ga]Ga-TacsBOMB3 (7.26 ± 1.00 %ID/g), [ 68 Ga]Ga-TacsBOMB5 (1.98 ± 0.10 %ID/g), and [ 68 Ga]Ga-TacsBOMB6 (6.50 ± 0.36 %ID/g) were much lower than the value of [ 68 Ga]Ga-RM2 (41.9 ± 10.1 %ID/g). Among the tested [Leu 13 ψThz 14 ]Bombesin(7-14) derivatives, [ 68 Ga]Ga-TacsBOMB5 has the highest tumor uptake and tumor-to-background contrast ratios, which is promising for clinical translation to detect GRPR-expressing tumors. Due to the low pancreas uptake of its derivatives, [Leu 13 ψThz 14 ]Bombesin(7-14) represents a promising pharmacophore for the design of GRPR-targeting radiopharmaceuticals, especially for targeted radioligand therapy application.