A Novel Radiotracer for Molecular Imaging and Therapy of Gastrin-Releasing Peptide Receptor Positive Prostate Cancer.
2021
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 68Ga and 177Lu, and evaluated its ability to target GRPR in a preclinical model of human prostate cancer.
Methods: ProBOMB2 was synthesized on solid phase using Fmoc chemistry. The chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid was coupled to the N-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, while a calcium efflux assay was used to measure the agonist/antagonist properties of the derivatives. ProBOMB2 was radiolabeled with 177Lu and 68Ga. SPECT and PET imaging, and biodistribution studies were conducted using a preclinical prostate cancer model of male immunocompromised mice bearing GRPR-positive PC-3 human prostate cancer xenografts.
Results: Ga-ProBOMB2 and Lu-ProBOMB2 bound to PC-3 cells with a Ki of 4.58±0.67 and 7.29±1.73 nM, respectively. 68Ga-ProBOMB2 and 177Lu-ProBOMB2 were radiolabeled with a radiochemical purity greater than 95%. Both radiotracers were primarily excreted via the renal pathway. PET images of PC-3 tumor xenografts were visualized with excellent contrast at 1 h and 2 h post-injection (p.i.) with 68Ga-ProBOMB2, and very low off-target organ accumulation. 177Lu-ProBOMB2 enabled clear visualization of PC-3 tumor xenografts by SPECT imaging at 1 h, 4 h, and 24 h p.i. 177Lu-ProBOMB2 displayed higher tumor uptake than 68Ga-ProBOMB2 at 1 h p.i. 177Lu-ProBOMB2 tumor uptake at 1 h, 4 h, and 24 h p.i. was 14.9±3.1, 4.8±2.1, and 1.7±0.3 %ID/g, respectively.
Conclusion:68Ga-ProBOMB2 and 177Lu-ProBOMB2 are promising radiotracers with limited pancreas uptake, good tumor uptake, and favorable pharmacokinetics for imaging and therapy of GRPR-expressing tumors.
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