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The gastrin-releasing peptide receptor (GRPr) is overexpressed in prostate cancer (PCa) cells, making it an excellent tool for targeted imaging. The 68 Ga-labeled GRPr antagonist SB3 has shown excellent results in preclinical and 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 an investigation of biodistribution and dosimetry and a comparison with pathology and GRPr expression. Methods: Ten therapy-naïve, biopsy-confirmed PCa patients planned for prostatectomy were included. A 3-h extensive PET/CT imaging protocol was performed within 2 wk before prostatectomy. Prostate tissue was evaluated for tumor localization and Gleason score, and in vitro autoradiography was performed to determine GRPr expression. Available MRI scans performed within 3 mo before 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 model, version 2.1. 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 of 10 patients. Pathologic 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 to 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, the level of GRPr expression showed a 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. The highest absorbed dose was detected in the physiologic GRPr-expressing pancreas (0.198 mGy/MBq), followed by the bladder wall and kidneys. Conclusion: 68 Ga-SB3 PET/CT is a safe imaging method and a promising tool for early PCa imaging., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

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 DOTA-coupled 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 Lu-NeoBOMB1., Methods: PC-3 tumor-xenografted BALB/c nu/nu mice were injected with either approximately 13 MBq/250 pmol 68 Ga-NeoBOMB1 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 Ga-NeoBOMB1 and 1, 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 ± 2.3 and 22.7 ± 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 ± 3.3 vs. 11.6 ± 1.3 %ID/g of tissue at 240 min after injection) and a lower pancreatic uptake (19.8 ± 6.9 vs. 105 ± 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., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Unlabelled: Peptide receptor scintigraphy and peptide receptor radionuclide therapy using radiolabeled somatostatin receptor (SSTR) agonists are successfully used in the clinic for imaging and treatment of neuroendocrine tumors. Contrary to the paradigm that internalization and the resulting accumulation of radiotracers in cells is necessary for efficient tumor targeting, recent studies have demonstrated the superiority of radiolabeled SSTR antagonists for imaging purposes, despite little to no internalization in cells. However, studies comparing the therapeutic antitumor effects of radiolabeled SSTR agonists versus antagonists are lacking. The aim of this study was to directly compare the therapeutic effect of (177)Lu-DOTA-octreotate, an SSTR agonist, and (177)Lu-DOTA-JR11, an SSTR antagonist., Methods: We analyzed radiotracer uptake (both membrane-bound and internalized fractions) and the produced DNA double-strand breaks, by determining the number of p53 binding protein 1 foci, after incubating SSTR2-positive cells with (177)Lu-diethylene triamine pentaacetic acid, (177)Lu-DOTA-octreotate, or (177)Lu-DOTA-JR11. Also, biodistribution studies were performed in tumor-xenografted mice to determine the optimal dose for therapy experiments. Afterward, in vivo therapy experiments comparing the effect of (177)Lu-DOTA-octreotate and (177)Lu-DOTA-JR11 were performed in this same animal model., Results: We found a 5-times-higher uptake of (177)Lu-DOTA-JR11 than of (177)Lu-DOTA-octreotate. The major part (88% ± 1%) of the antagonist uptake was membrane-bound, whereas 74% ± 3% of the total receptor agonist uptake was internalized. Cells treated with (177)Lu-DOTA-JR11 showed 2 times more p53-binding protein 1 foci than cells treated with (177)Lu-DOTA-octreotate. Biodistribution studies with (177)Lu-DOTA-JR11 (0.5 μg/30 MBq) resulted in the highest tumor radiation dose of 1.8 ± 0.7 Gy/MBq, 4.4 times higher than the highest tumor radiation dose found for (177)Lu-DOTA-octreotate. In vivo therapy studies with (177)Lu-DOTA-octreotate and (177)Lu-DOTA-JR11 resulted in a tumor growth delay time of 18 ± 5 and 26 ± 7 d, respectively. Median survival rates were 43.5, 61, and 71 d for the control group, (177)Lu-DOTA-octreotate group, and the (177)Lu-DOTA-JR11-treated group, respectively., Conclusion: On the basis of these results, we concluded that the use of radiolabeled SSTR antagonists such as JR11 might enhance peptide receptor scintigraphy and peptide receptor radionuclide therapy of neuroendocrine tumors and provide successful imaging and therapeutic strategies for cancer types with relatively low SSTR expression., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)