⁶⁸Ga/¹⁷⁷Lu-NeoBOMB1, a Novel Radiolabeled GRPR Antagonist for Theranostic Use in Oncology

Abstract

Because overexpression of the gastrin-releasing peptide receptor (GRPR) has been reported on various cancer types, for example, prostate cancer and breast cancer, targeting this receptor with radioligands might have a significant impact on staging and treatment of GRPR-expressing tumors. NeoBOMB1 is a novel DOTAcoupled GRPR antagonist with high affinity for GRPR and excellent in vivo stability. The purpose of this preclinical study was to further explore the use of NeoBOMB1 for theranostic application by determining the biodistribution of 68 Ga-NeoBOMB1 and 177 LuNeoBOMB1. Methods: PC-3 tumor-xenografted BALB/c nu/nu mice were injected with either approximately 13 MBq/250 pmol 68 GaNeoBOMB1 or a low (;1 MBq/200 pmol) versus high (;1 MBq/10 pmol) peptide amount of 177 Lu-NeoBOMB1, after which biodistribution and imaging studies were performed. At 6 time points (15,30, 60, 120, 240, and 360 min for 68 4,24, 48, 96, and 168 h for 177 Lu-NeoBOMB1) postinjection tumor and organ uptake was determined. To assess receptor specificity, additional groups of animals were coinjected with an excess of unlabeled NeoBOMB1. Results of the biodistribution studies were used to determine pharmacokinetics and dosimetry. Furthermore, PET/CT and SPECT/MRI were performed. Results: Injection of approximately 250 pmol 68 Ga-NeoBOMB1 resulted in a tumor and pancreas uptake of 12.4 6 2.3 and 22.7 6 3.3 percentage injected dose per gram (%ID/g) of tissue, respectively, at 120 min after injection. 177 Lu-NeoBOMB1 biodistribution studies revealed a higher tumor uptake (17.9 6 3.3 vs. 11.6 6 1.3 %ID/g of tissue at 240 min after injection) and a lower pancreatic uptake (19.8 6 6.9 vs. 105 6 13 %ID/g of tissue at 240 min after injection) with the higher peptide amount injected, leading to a significant increase in the absorbed dose to the tumor versus the pancreas (200 pmol, 570 vs. 265 mGy/ MBq; 10 pmol, 435 vs. 1393 mGy/MBq). Using these data to predict patient dosimetry, we found a kidney, pancreas, and liver exposure of 0.10, 0.65, and 0.06 mGy/MBq, respectively. Imaging studies resulted in good visualization of the tumor with both 68 Ga-NeoBOMB1 and 177 Lu-NeoBOMB1. Conclusion: Our findings indicate that 68 Ga-or 177 Lu-labeled NeoBOMB1 is a promising radiotracer with excellent tumor uptake and favorable pharmacokinetics for imaging and therapy of GRPR-expressing tumors.

Future cancer research priorities in the USA: a Lancet Oncology Commission

“…Other theranostic drugs labelled with 68 Ga or 177 Lu have been used to target chemokine receptor 4 ligands in myeloproliferative disorders and in cancers that overexpress gastrin-releasing peptide receptor. 316,317,328–330 With this rich historical context and recent major advances, theranostics should be considered a priority for further research and development for precision medicine.…”

Comparison of biological properties of [177Lu]Lu‐ProBOMB1 and [177Lu]Lu‐NeoBOMB1 for GRPR targeting

“…Stability of [ 177 Lu]Lu-ProBOMB1 at the 5 minutes in vivo plasma stability was 85.6 ± 5.3% (n = 3). 9 ProBOMB1, a BBN analogue derived from the RC-3950-II backbone, was synthesized and subsequently tested in an animal model of prostate cancer with promising imaging results. 19 The former radiometal can be used for diagnostic PET imaging and estimating dosimetry.…”

“…[1][2][3][4][5] BBN, a peptide isolated from the frog, Bombina bombina, has a mammalian ortholog named the gastrin-releasing peptide (GRP) and both bind GRPR. 7,[9][10][11][12] 13,14 In a previous article, we modified a sequence initially published by the Schally group, RC-3950-II, to adapt it for theranostic application yielding DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ψ-Pro-NH 2 (ProBOMB1), which we characterized after labeling with nat/68 Ga. 8,15 The radiotracer, [ 68 Ga]Ga-ProBOMB1, had excellent characteristics for imaging GRPR. In nuclear medicine, the use of peptides as delivery vectors is an effective strategy for targeting GPCRs (ie, somatostatin, CXC chemokine receptor 4, cholecystokinin-2, and substance P).…”

Will GRPR Compete with PSMA as a Target in Prostate Cancer?

“…They have a stable biodistribution in healthy volunteers (15) and mean effective doses comparable to those of other radiopharmaceuticals (16,17). Data are encouraging regarding their potential for the initial diagnosis of PCa (15)(16)(17)(18)(19), for the assessment of biochemical recurrence (15,16,(18)(19)(20)(21)(22)(23), and for the theranostic approach (24). The lack of salivary or lacrimal gland uptake and the low hepatobiliary clearance give them an advantage.…”

“…The lack of salivary or lacrimal gland uptake and the low hepatobiliary clearance give them an advantage. The high pancreatic uptake may be of concern to some; however, although initial uptake is high, it decreases rapidly whereas tumor radioactivity is retained longer (24). A comparison of 68 Ga-RM2 PET scans before and after treatment is shown in Figure 1, and comparisons of paired 68 Ga-PSMA-11 and 68 Ga-RM2 scans are shown in Figure 2.…”