Theranostic Perspectives in Prostate Cancer with the Gastrin-Releasing Peptide Receptor Antagonist NeoBOMB1: Preclinical and First Clinical Results

We recently introduced the potent gastrin-releasing peptide receptor (GRPR) antagonist ⁶⁸Ga-SB3 (⁶⁸Ga-DOTA-p-aminomethylaniline-diglycolic acid-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt), showing excellent tumor localizing efficacy in animal models and in patients. By replacement of the C-terminal Leu¹³-Met¹⁴-NH₂ dipeptide of SB3 by Sta¹³-Leu¹⁴-NH₂, the novel GRPR antagonist NeoBOMB1 was generated and labeled with different radiometals for theranostic use. We herein report on the biologic profile of resulting ^67/68Ga-, ¹¹¹In-, and ¹⁷⁷Lu-NeoBOMB1 radioligands in GRPR-expressing cells and mouse models. The first evidence of prostate cancer lesion visualization in men using ⁶⁸Ga-NeoBOMB1 and PET/CT is also presented. Methods: NeoBOMB1 was radiolabeled with ^67/68Ga, ¹¹¹In, and ¹⁷⁷Lu according to published protocols. The respective metalated species ^natGa-, ^natIn-, and ^natLu-NeoBOMB1 were also synthesized and used in competition binding experiments against [¹²⁵I-Tyr⁴]BBN in GRPR-positive PC-3 cell membranes. Internalization of ⁶⁷Ga-, ¹¹¹In-, and ¹⁷⁷Lu-NeoBOMB1 radioligands was studied in PC-3 cells at 37°C, and their metabolic stability in peripheral mouse blood was determined by high-performance liquid chromatography analysis of blood samples. Biodistribution was performed by injecting a ⁶⁷Ga-, ¹¹¹In-, or ¹⁷⁷Lu-NeoBOMB1 bolus (74, 74, or 370 kBq, respectively, 100 μL, 10 pmol total peptide ± 40 nmol Tyr⁴-BBN: for in vivo GRPR blockade) in severe combined immunodeficiency mice bearing PC-3 xenografts. PET/CT images with ⁶⁸Ga-NeoBOMB1 were acquired in prostate cancer patients. Results: NeoBOMB1 and ^natGa-, ^natIn-, and ^natLu-NeoBOMB1 bound to GRPR with high affinity (half maximal inhibitory concentration, 1–2 nM). ⁶⁷Ga-, ¹¹¹In-, and ¹⁷⁷Lu-NeoBOMB1 specifically and strongly bound on the cell membrane of PC-3 cells displaying low internalization, as expected for receptor antagonists. They showed excellent metabolic stability in peripheral mouse blood (>95% intact at 5 min after injection). After injection in mice, all 3 (⁶⁷Ga-, ¹¹¹In-, and ¹⁷⁷Lu-NeoBOMB1) showed comparably high and GRPR-specific uptake in the PC-3 xenografts (e.g., 30.6 ± 3.9, 28.6 ± 6.0, and >35 percentage injected dose per gram at 4 h after injection, respectively), clearing from background predominantly via the kidneys. During a translational study in prostate cancer patients, ⁶⁸Ga-NeoBOMB1 rapidly localized in pathologic lesions, achieving high-contrast imaging. Conclusion: The GRPR antagonist radioligands ⁶⁷Ga-, ¹¹¹In-, and ¹⁷⁷Lu-NeoBOMB1, independent of the radiometal applied, have shown comparable behavior in prostate cancer models, in favor of future theranostic use in GRPR-positive cancer patients. Such translational prospects were further supported by the successful visualization of prostate cancer lesions in men using ⁶⁸Ga-NeoBOMB1 and PET/CT.