Synthesis\nand Evaluation of <sup>68</sup>Ga- and <sup>177</sup>Lu-Labeled [Pro<sup>14</sup>]bombesin(8–14) Derivatives\nfor Detection and Radioligand Therapy of Gastrin-Releasing Peptide\nReceptor-Expressing Cance

The gastrin-releasing peptide receptor (GRPR) is overexpressed\nin a variety of cancers and represents a promising target for diagnosis\nand therapy. However, the extremely high accumulation in the pancreas\nobserved for most of the clinically evaluated GRPR-targeted radiopharmaceuticals\ncould limit their applications. In this study, we synthesized one\nGRPR antagonist (ProBOMB5) and two GRPR agonists (LW02056 and LW02057)\nby replacing the 4-thiazolidinecarboxylic acid (Thz<sup>14</sup>)\nresidue in our previously reported GRPR-targeted tracers with Pro<sup>14</sup>. The <sup>68</sup>Ga and <sup>177</sup>Lu labeling were\nconducted in HEPES (2 M, pH 5.0) buffer and acetate (0.1 M, pH 4.5)\nbuffer, respectively, and the radiolabeled products were obtained\nin a 24–57% decay-corrected radiochemical yield and >92%\nradiochemical\npurity. The binding affinities (<i>K</i><sub>i</sub>) of\nGa-ProBOMB5, Ga-LW02056, Ga-LW02057, and Lu-ProBOMB5 were measured\nvia <i>in vitro</i> competition binding assays and were\n12.2 ± 1.89, 14.7 ± 4.81, 13.8 ± 2.24, and 13.6 ±\n0.25 nM, respectively. The PET imaging and <i>ex vivo</i> biodistribution studies were conducted in PC-3 tumor-bearing mice\nat 1 h post injection. [<sup>68</sup>Ga]Ga-ProBOMB5, [<sup>68</sup>Ga]Ga-LW02056, and [<sup>68</sup>Ga]Ga-LW02057 enabled clear tumor\nvisualization in PET images. The tumor uptake values of [<sup>68</sup>Ga]Ga-ProBOMB5, [<sup>68</sup>Ga]Ga-LW02056, and [<sup>68</sup>Ga]Ga-LW02057\nwere 12.4 ± 1.35, 8.93 ± 1.96, and 7.64 ± 0.55%ID/g,\nrespectively, and their average pancreas uptake values were minimal\n(0.60–1.37%ID/g). Longitudinal SPECT imaging and <i>ex\nvivo</i> biodistribution studies were also conducted for [<sup>177</sup>Lu]Lu-ProBOMB5 and clinically validated [<sup>177</sup>Lu]Lu-RM2.\nDespite comparable tumor uptake at 1 h post injection ([<sup>177</sup>Lu]Lu-ProBOMB5:8.09 ± 1.70%ID/g; [<sup>177</sup>Lu]Lu-RM2:7.73\n± 0.96%ID/g), a faster clearance from PC-3 tumor xenografts was\nobserved for [<sup>177</sup>Lu]Lu-ProBOMB5, leading to a lower radiation-absorbed\ndose delivered to tumors. Our data demonstrate that [<sup>68</sup>Ga]Ga-ProBOMB5 is a promising tracer for clinical translation for\ndetecting GRPR-expressing tumor lesions. However, further optimizations\nare needed for [<sup>177</sup>Lu]Lu-ProBOMB5 to prolong tumor retention\nfor therapeutic applications.