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A comparative study of radiolabeled bombesin analogs for the PET imaging of prostate cancer.

ABSTRACT: Radiolabeled bombesin (BBN) analogs that bind to the gastrin-releasing peptide receptor (GRPR) represent a topic of active investigation for the development of molecular probes for PET or SPECT of prostate cancer (PCa). RM1 and AMBA have been identified as the 2 most promising BBN peptides for GRPR-targeted cancer imaging and therapy. In this study, to develop a clinically translatable BBN-based PET probe, we synthesized and evaluated (18)F-AlF- (aluminum-fluoride) and (64)Cu-radiolabeled RM1 and AMBA analogs for their potential application in PET imaging of PCa.1,4,7-triazacyclononane, 1-glutaric acid-4,7 acetic acid (NODAGA)-conjugated RM1 and AMBA were synthesized and tested for their GRPR-binding affinities. The NODAGA-RM1 and NODAGA-AMBA probes were further radiolabeled with (64)Cu or (18)F-AlF and then evaluated in a subcutaneous PCa xenograft model (PC3) by small-animal PET imaging and biodistribution studies.NODAGA-RM1 and NODAGA-AMBA can be successfully synthesized and radiolabeled with (64)Cu and (18)F-AlF. (64)Cu- and (18)F-AlF-labeled NODAGA-RM1 demonstrated excellent serum stability and tumor-imaging properties in the in vitro stability assays and in vivo imaging studies. (64)Cu-NODAGA-RM1 exhibited tumor uptake values of 3.3 ± 0.38, 3.0 ± 0.76, and 3.5 ± 1.0 percentage injected dose per gram of tissue (%ID/g) at 0.5, 1.5, and 4 h after injection, respectively. (18)F-AlF-NODAGA-RM1 exhibited tumor uptake values of 4.6 ± 1.5, 4.0 ± 0.87, and 3.9 ± 0.48 %ID/g at 0.5, 1, and 2 h, respectively.The high-stability, efficient tumor uptake and optimal pharmacokinetic properties highlight (18)F-AlF-NODAGA-RM1 as a probe with great potential and clinical application for the PET imaging of prostate cancer.

SUBMITTER: Liu Y

PROVIDER: S-EPMC4215198 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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A comparative study of radiolabeled bombesin analogs for the PET imaging of prostate cancer.

Liu Yang Y Hu Xiang X Liu Hongguang H Bu Lihong L Ma Xiaowei X Cheng Kai K Li Jinbo J Tian Mei M Zhang Hong H Cheng Zhen Z

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20131106 12

<h4>Unlabelled</h4>Radiolabeled bombesin (BBN) analogs that bind to the gastrin-releasing peptide receptor (GRPR) represent a topic of active investigation for the development of molecular probes for PET or SPECT of prostate cancer (PCa). RM1 and AMBA have been identified as the 2 most promising BBN peptides for GRPR-targeted cancer imaging and therapy. In this study, to develop a clinically translatable BBN-based PET probe, we synthesized and evaluated (18)F-AlF- (aluminum-fluoride) and (64)Cu- ...[more]

PMID: 24198391

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Project description:BACKGROUND:Among the many peptide receptor systems, gastrin-releasing-peptide (GRP) receptors, the mammalian equivalent of bombesin (BN) receptors, are potential targets for diagnosis and therapy of breast tumors due to their overexpression in various frequently occurring human cancers. The aim of this study was to synthesize and comparative evaluation of 99mTc-labeled new BN peptide analogs. Four new BN analogs, HYNIC-Asp[PheNle]BN(7-14)NH2, BN1; HYNIC-Pro-Asp[TyrMet]BN(7-14)NH2, BN2; HYNIC-Asp-Asn[Lys-CHAla-Nle]BN(7-14)NH2, BN3; and DOMA-GABA[Pro-Tyr-Nle]BN(7-14)NH2, BN4 were synthesized and biologically evaluated for targeted imaging of GRP receptor-positive breast-tumors. METHODS:Solid-phase synthesis using Fmoc-chemistry was adopted for the synthesis of peptides. BN1-BN4 analogs were better over the standard Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (BNS). Lipophilicity, serum stability, internalization, and binding affinity studies were carried out using 99mTc-labeled analogs. Biodistribution and imaging analyses were performed on MDA-MB-231 cell-induced tumor-bearing mice. BN-analogs induced angiogenesis; tumor formation and GRP-receptor-expression were confirmed by histology and immunohistochemistry analyses of tumor sections and important tissue sections. RESULTS:All the analogs displayed ≥ 97% purity after the HPLC purification. BN-peptide-conjugates exhibited high serum stability and significant binding affinity to GRP-positive tumor; rapid internalization/externalization in/from MDA-MB-231 cells were noticed for the BN analogs. BN4 and BN3 exhibited higher binding affinity, stability than BN1 and BN2. Highly specific in vivo uptakes to the tumor were clearly visualized by scintigraphy; rapid excretion from non-target tissues via kidneys suggests a higher tumor-to-background ratio. BN4, among all the analogs, stimulates the expression of angiogenic markers to a maximum. CONCLUSION:Considering its most improved pharmacological characteristics, BN4 is thus considered as most promising probes for early non-invasive diagnosis of GRP receptor-positive breast tumors.

Project description:Receptor-targeted agents, such as gastrin-releasing peptide receptor (BB2r)-targeted peptides, have been investigated extensively in preclinical and clinical studies. In an attempt to increase the effectiveness of diagnostic or radiotherapeutic agents, we have begun to explore the incorporation of the hypoxia-selective prodrug 2-nitroimidazole into receptor-targeted peptides. Hypoxia is a well-known characteristic of many solid tumors, including breast, prostate, and pancreatic cancers. The aim of this approach is to use the hypoxia-trapping capability of 2-nitroimidazoles to increase the retention of the agent in hypoxic, BB2r-positive tumors. We have demonstrated that incorporation of one or more 2-nitroimidazoles into the BB2r-targeted peptide significantly increases the in vitro retention of the agent in hypoxic prostate cancer cells. The study described herein represents our first investigation of the in vivo properties of these hypoxia-enhanced BB2r-targeted agents in a PC-3 xenograft mouse model.Four (111)In-labeled BB2r-targeted conjugates--(111) IN-1, (111) IN-2, (111) IN-3, and (111) IN-4, composed of 2-nitroimidazole moieties of 0, 1, 2, and 3, respectively--were synthesized, labeled, and purified. The BB2r binding affinities, externalization, and protein-association properties of these radioconjugates were assessed using the BB2r-positive PC-3 human prostate cancer cell line under hypoxic and normoxic environments. The in vivo biodistribution and micro-SPECT/CT imaging of the (111) IN-1, (111) IN-2, and (111) IN-4 radioconjugates were investigated in PC-3 tumor-bearing severely combined immunodeficient mice.All conjugates and (nat)In-conjugates demonstrated nanomolar binding affinities. (111) IN-1, (111) IN-2, (111) IN-3, and (111) IN-4 demonstrated 41.4%, 60.7%, 69.1%, and 69.4% retention, correspondingly, of internalized radioactivity under hypoxic conditions relative to 34.8%, 35.3%, 33.2%, and 29.7% retention, respectively, under normoxic conditions. Protein-association studies showed significantly higher levels of association under hypoxic conditions for 2-nitroimidazole-containing BB2r-targeted radioconjugates than for controls. On the basis of the initial 1-h uptake in the PC-3 tumors, (111) IN-1, (111) IN-2, and (111) IN-4 demonstrated tumor retentions of 1.5%, 6.7%, and 21.0%, respectively, by 72 h after injection. Micro-SPECT/CT imaging studies of (111) IN-1, (111) IN-2, and (111) IN-4 radioconjugates resulted in clear delineation of the tumors.On the basis of the in vitro and in vivo studies, the BB2r-targeted agents that incorporated 2-nitroimidazole moieties demonstrated improved retention. These results indicate that further exploration into the potential of hypoxia-selective trapping agents for BB2r-targeted agents, as well as other targeted compounds, is warranted.

Project description:BACKGROUND:Current imaging techniques may not detect all prostate cancer (PCa) lesions. OBJECTIVE:To evaluate positron emission tomography (PET)/computed tomography (CT) using the radiolabeled GRPR antagonist probe BAY86-7548 (68Ga-RM2) for localization of newly diagnosed PCa in comparison with multiparametric magnetic resonance imaging (mpMRI), histopathology, and immunohistochemistry (IHC). DESIGN, SETTING, AND PARTICIPANTS:This was a prospective study of 16 men with biopsy-proven PCa (2 low, 8 intermediate, and 6 high risk). 68Ga-RM2 PET/CT was performed within 4 wk after mpMRI and within 2 wk before radical prostatectomy and extended bilateral pelvic lymph node dissection. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:The presence of cancer was evaluated by blinded specialists using a 5-point Likert scale, with lesions scoring 4 or 5 considered positive, on 68Ga-RM2 PET/CT, mpMRI, and 68Ga-RM2 PET/CT-mpMRI fused images for each of 12 anatomic areas of the prostate. Whole-mount, step-section pathology served as the reference standard. Expression of GRPR and prostate-specific membrane antigen (PSMA) was analyzed via IHC of tumor paraffin sections. RESULTS AND LIMITATIONS:Of 192 areas analyzed, 128 contained cancer. The sensitivity, specificity, and accuracy of 68Ga-RM2 PET/CT imaging and mpMRI did not differ significantly; fusing the images maximized the sensitivity and accuracy (85.2% and 83.9%, respectively) and averaged the specificity (81.3%). The area under the receiver operating characteristic curve was 0.76 for PET visual analysis, 0.72 for PET quantitative analysis, 0.76 for mpMRI, and 0.85 for combined PET/CT and mpMRI analysis. 68Ga-RM2 uptake did not correlate with Gleason score. IHC analysis revealed weaker staining for GRPR than for PSMA, and the expression of these markers was not correlated (r=0.3882). The major limitation is the small sample size. CONCLUSIONS:68Ga-RM2 PET/CT is promising for detection and localization of primary PCa, and complements mpMRI. GRPR expression appears to be independent from PSMA expression, suggesting that GRPR- and PSMA-targeted PET imaging may be complementary. PATIENT SUMMARY:This pilot prospective study shows that a positron emission tomography probe that binds to a marker of prostate cancer, GRPR, improves the ability of magnetic resonance imaging to detect prostate cancer.

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A comparative study of radiolabeled bombesin analogs for the PET imaging of prostate cancer.

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A comparative study of radiolabeled bombesin analogs for the PET imaging of prostate cancer.

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