Synthesis and Evaluation of the First 68Ga-Labeled C-Terminal Hydroxamate-Derived Gastrin-Releasing Peptide Receptor-Targeted Tracers for Cancer Imaging with Positron Emission Tomography

Gastrin-releasing peptide receptor (GRPR), overexpressed in many solid tumors, is a promising imaging marker and therapeutic target. Most reported GRPR-targeted radioligands contain a C-terminal amide. Based on the reported potent antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH, we synthesized C-terminal hydroxamate-derived 68GaGa-LW02075 (68GaGa-DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH) and 68GaGa-LW02050 (68GaGa-DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH), and compared them with the closely related and clinically validated 68GaGa-SB3 (68GaGa-DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt). Binding affinities (Ki) of Ga-SB3, Ga-LW02075, and Ga-LW02050 were 1.20 ± 0.31, 1.39 ± 0.54, and 8.53 ± 1.52 nM, respectively. Both Ga-LW02075 and Ga-LW02050 were confirmed to be GRPR antagonists by calcium release assay. Imaging studies showed that PC-3 prostate cancer tumor xenografts were clearly visualized at 1 h post injection by 68GaGa-SB3 and 68GaGa-LW02050 in PET images, but not by 68GaGa-LW02075. Ex vivo biodistribution studies conducted at 1 h post injection showed that the tumor uptake of 68GaGa-LW02050 was comparable to that of 68GaGa-SB3 (5.38 ± 1.00 vs. 6.98 ± 1.36 %ID/g), followed by 68GaGa-LW02075 (3.97 ± 1.71 %ID/g). 68GaGa-SB3 had the highest pancreas uptake (37.3 ± 6.90 %ID/g) followed by 68GaGa-LW02075 (17.8 ± 5.24 %ID/g), while the pancreas uptake of 68GaGa-LW02050 was only 0.53 ± 0.11 %ID/g. Our data suggest that 68GaGa-LW02050 is a promising PET tracer for detecting GRPR-expressing cancer lesions.