68Ga/177Lu-NeoBOMB1, a novel radiolabeled GRPR antagonist for theranostic use

Objectives Previous studies have demonstrated an overexpression of the gastrin releasing peptide receptor (GRPR) in a number of cancer types, including prostate and breast cancers. Targeting this receptor with radiolabeled peptide analogs for imaging and therapy should have a significant impact on the diagnosis and treatment of GRPR-expressing tumors. NeoBOMB1 is a novel DOTA-coupled GRPR antagonist generated by modification of the C-terminal Leu¹³-Met¹⁴-NH₂ of native bombesin(6-14). The ⁶⁸Ga-labelled peptide displays excellent GRPR affinity suitable for specific and rapid tumor localization in PC-3 xenografts in mice. The aim of our study was to explore the use of ¹⁷⁷Lu-NeoBOMB1 at two specific activities for theranostic purposes by comparing tumor and organ uptake in an in vivo mouse study. Biodistribution data was used to determine mouse dosimetry and to predict dosimetry in patients

Methods Balb c nu/nu male mice xenografted with the GRPR-expressing PC-3 cells were injected with 185 kBq ¹⁷⁷Lu-NeoBOMB1 associated with either 10 pmol or 200 pmol NeoBOMB1. Radioactivity uptake was quantified in targeted organs at 6 different time points (1 h, 4 h, 24 h, 48 h, 96 h and 7 d) post injection and the percentage injected dose per gram of tissue (%ID/g tissue) was determined for dosimetry calculations. To assess the specificity of peptide uptake, animals were injected with either 10 or 200 pmol ¹⁷⁷Lu-NeoBOMB1 with an excess of unlabeled peptide.

Results We found an average tumor uptake of 18.9±3.3 %ID/g tissue and 11.5±1.4 %ID/g tissue 4 h post injection of 200 pmol and 10 pmol NeoBOMB1/185 kBq ¹⁷⁷Lu, respectively (all data expressed as mean ± SD). This would lead to an absorbed dose per administered activity of 614 and 499 mGy/MBq (with 340±100 mm³ tumor volumes). When receptors were blocked by an excess of unlabeled peptide, the tumor uptake decreased to 0.88±0.04 and 0.56±0.09 %ID/g tissue. Next to the tumor, uptake in the GRPR-expressing pancreas was 21.0±7.5 and 78±14%ID/g tissue 4 h post injection of ¹⁷⁷Lu-NeoBOMB1 in 200 pmol and 10 pmol peptide dose, respectively, resulting in a meaningful increase in the absorbed dose ratio of pancreas over tumor with higher peptide concentration (1.9 vs. 0.5). Using the data to predict patient dosimetry, we found a kidney, pancreas and liver exposure of 0.10, 0.68 and 0.06 mGy/MBq, respectively.

Conclusions Our findings indicate that the GRPR antagonist ⁶⁸Ga/¹⁷⁷Lu-NeoBOMB1 is a very promising peptide with favorable biodistribution characteristics for peptide receptor scintigraphy and peptide receptor radionuclide therapy.