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.

Recent advances in oncology involve the use of diagnostic/therapeutic radionuclide-carrier pairs that target cancer cells, offering exciting opportunities for personalized patient treatment. Theranostic gastrin-releasing peptide receptor (GRPR)-directed radiopeptides have been proposed for the management of GRPR-expressing prostate and breast cancers. We have recently introduced the PET tracer Ga-SB3 (SB3, DOTA- p-aminomethylaniline-diglycolic acid-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt), a receptor-radioantagonist that enables the visualization of GRPR-positive lesions in humans. Aiming to fully assess the theranostic potential of SB3, we herein report on the impact of switchingGa to In/Lu-label on the biological properties of resulting radiopeptides. Notably, the bioavailability of In/Lu-SB3 in mice drastically deteriorated compared with metabolically robust Ga-SB3, and as a result led to poorerIn/Lu-SB3 uptake in GRPR-positive PC-3 xenografts. The peptide cleavage sites were identified by chromatographic comparison of blood samples from mice intravenously receiving In/Lu-SB3 with each of newly synthesized In/Lu-SB3-fragments. Coinjection of the radioconjugates with the neprilysin (NEP)-inhibitor phosphoramidon led to full stabilization of In/Lu-SB3 in peripheral mouse blood and resulted in markedly enhanced radiolabel uptake in the PC-3 tumors. In conclusion, in situ NEP-inhibition led to indistinguishable Ga/In/Lu-SB3 profiles in mice emphasizing the theranostic prospects of SB3 for clinical use.

The gastrin releasing peptide receptor (GRPr) is overexpressed in prostate cancer (PCa) cells, making it an excellent tool for targeted imaging. The gallium-68 labeled GRPr antagonist SB3 ( 68 Ga-SB3) has shown excellent results in (pre)clinical studies and was selected for further clinical investigation. The aims of this phase I study were to investigate 68 Ga-SB3 PET/CT-imaging of primary PCa tumors and assess safety. More aims included biodistribution, dosimetry, comparison with pathology and GRPr expression.MATERIALS AND METHODS: Ten therapy-naive, biopsy-confirmed PCa patients planned for prostatectomy were included. A 3-hour extensive PET/CT-imaging protocol was performed, within 2 weeks prior to prostatectomy. Prostate tissue was evaluated for tumor localization, Gleason Score and in vitro autoradiography was performed to determine GRPr expression. Available MRI scans performed within 3 months prior to the study were matched. For dosimetry residence times were estimated and effective dose to the body as well as absorbed doses to organs were calculated using the IDAC dose 2.1 model. RESULTS: Administration of 68 Ga-SB3 (187.4 ± 40.0 MBq, 40±5 μg) was well tolerated, no significant changes in vital signs or laboratory results were observed. 68 Ga-SB3 PET/CT showed lesions in 8 out of 10 patients. Pathological analysis revealed a total of 16 tumor lesions of which PET/CT showed 14, resulting in a sensitivity of 88%. 68 Ga-SB3 PET/CT-imaging showed uptake in 2 large prostatic intraepithelial neoplasia foci, considered a precursor of PCa, resulting in an 88% specificity. Autoradiography of tumor lesions revealed heterogeneous GRPr expression and was negative in 4 patients. Both PET/CT-negative patients had a GRPr-negative tumor. In autoradiography-positive tumors, level of GRPr expression showed significant correlation to tracer uptake on PET/CT. Dosimetry calculations estimated the effective dose to be 0.0144 mSv/MBq, similar to other 68 Ga labeled radiopeptides. Highest absorbed dose was detected in the physiological GRPr-expressing pancreas (0.198 mGy/MBq), followed by bladder wall and kidneys. CONCLUSION: 68 Ga-SB3 PET/CT is a safe imaging method and a promising tool for early PCa imaging.