A Radiotracer for Molecular Imaging and Therapy of Gastrin-Releasing Peptide Receptor–Positive Prostate Cancer
Ivica Bratanovic, Chengcheng Zhang, Zhengxing Zhang, Hsiou‐Ting Kuo, Nadine Colpo, Jutta Zeisler, Helen Merkens, Carlos Uribe, Kuo‐Shyan Lin, François Bénard
Abstract
The gastrin-releasing peptide receptor (GRPR) is overexpressed in many solid malignancies, particularly in prostate and breast cancers, among others. We synthesized ProBOMB2, a novel bombesin derivative radiolabeled with <sup>68</sup>Ga and <sup>177</sup>Lu, and evaluated its ability to target GRPR in a preclinical model of human prostate cancer. <b>Methods:</b> ProBOMB2 was synthesized in solid phase using fluorenylmethoxycarbonyl chemistry. The chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid was coupled to the <i>N</i> terminus and separated from the GRPR-targeting sequence by a cationic 4-amino-(1-carboxymethyl)-piperidine spacer. Binding affinity for both human and murine GRPR was determined using a cell-based competition assay, whereas a calcium efflux assay was used to measure the agonist and antagonist properties of the derivatives. ProBOMB2 was radiolabeled with <sup>177</sup>Lu and <sup>68</sup>Ga. SPECT and PET imaging and biodistribution studies were conducted using male immunocompromised mice bearing GRPR-positive PC-3 human prostate cancer xenografts. <b>Results:</b> Ga-ProBOMB2 and Lu-ProBOMB2 bound to PC-3 cells with an inhibition constant of 4.58 ± 0.67 and 7.29 ± 1.73 nM, respectively. <sup>68</sup>Ga-ProBOMB2 and <sup>177</sup>Lu-ProBOMB2 were radiolabeled with a radiochemical purity greater than 95%. Both radiotracers were excreted primarily via the renal pathway. PET images of PC-3 tumor xenografts were visualized with excellent contrast at 1 and 2 h after injection with <sup>68</sup>Ga-ProBOMB2, and there was very low off-target organ accumulation. <sup>177</sup>Lu-ProBOMB2 enabled clear visualization of PC-3 tumor xenografts by SPECT imaging at 1, 4, and 24 h after injection <sup>177</sup>Lu-ProBOMB2 displayed higher tumor uptake than <sup>68</sup>Ga-ProBOMB2 at 1 h after injection. <sup>177</sup>Lu-ProBOMB2 tumor uptake at 1, 4, and 24 h after injection was 14.9 ± 3.1, 4.8 ± 2.1, and 1.7 ± 0.3 percentage injected dose per gram of tissue, respectively. <b>Conclusion:</b><sup>68</sup>Ga-ProBOMB2 and <sup>177</sup>Lu-ProBOMB2 are promising radiotracers with limited pancreas uptake, good tumor uptake, and favorable pharmacokinetics for imaging and therapy of GRPR-expressing tumors.