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F-Labeled GRPR Agonists and Antagonists: A Comparative Study in Prostate Cancer Imaging.

ABSTRACT: Radiolabeled bombesin analogs are promising probes for cancer imaging of gastrin-releasing peptide receptor (GRPR). In this study, we developed (18)F-labeled GRPR agonists and antagonists for positron emission tomography (PET) imaging of prostate cancer. GRPR antagonists ATBBN (D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHCH(2)CH(3)) and MATBBN (Gly-Gly-Gly-Arg-Asp-Asn-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHCH(2)CH(3)), and agonists AGBBN (Gln-Trp-Ala-Val-Gly-His-Leu-MetNH(2)) and MAGBBN (Gly-Gly-Gly-Arg-Asp-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-MetNH(2)) were radiolabeled with (18)F via 4-nitrophenyl 2-(18)F-fluoropropionate. The in vitro receptor binding, cell uptake, and efflux properties of the radiotracers were studied on PC-3 cells. An in vivo PET study was performed on mice bearing PC-3 tumors. Direct (18)F-labeling of known GRPR antagonist ATBBN and agonist AGBBN did not result in good tumor targeting or appropriate pharmacokinetics. Modification was made by introducing a highly hydrophilic linker Gly-Gly-Gly-Arg-Asp-Asn. Higher receptor binding affinity, much higher cell uptake and slower washout were observed for the agonist (18)F-FP-MAGBBN over the antagonist (18)F-FP-MATBBN. Both tracers showed good tumor/background contrast, with the agonist (18)F-FP-MAGBBN having significantly higher tumor uptake than the antagonist (18)F-FP-MATBBN (P < 0.01). In conclusion, Gly-Gly-Gly-Arg-Asp-Asn linker significantly improved the pharmacokinetics of the otherwise hydrophobic BBN radiotracers. (18)F-labeled BBN peptide agonists may be the probes of choice for prostate cancer imaging due to their relatively high tumor uptake and retention as compared with the antagonist counterparts.

SUBMITTER: Yang M

PROVIDER: S-EPMC3086613 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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F-Labeled GRPR Agonists and Antagonists: A Comparative Study in Prostate Cancer Imaging.

Yang Min M Gao Haokao H Zhou Yaru Y Ma Ying Y Quan Qimeng Q Lang Lixin L Chen Kai K Niu Gang G Yan Yongjun Y Chen Xiaoyuan X

Theranostics 20110101

Radiolabeled bombesin analogs are promising probes for cancer imaging of gastrin-releasing peptide receptor (GRPR). In this study, we developed (18)F-labeled GRPR agonists and antagonists for positron emission tomography (PET) imaging of prostate cancer. GRPR antagonists ATBBN (D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHCH(2)CH(3)) and MATBBN (Gly-Gly-Gly-Arg-Asp-Asn-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHCH(2)CH(3)), and agonists AGBBN (Gln-Trp-Ala-Val-Gly-His-Leu-MetNH(2)) and MAGBBN (Gly-Gly-Gly-Arg-As ...[more]

PMID: 21544226

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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.

Project description:Ace-1 canine prostate cancer cells grow orthotopically in cyclosporine immunosuppressed laboratory beagles. We previously transfected (human Gastrin-Releasing Peptide Receptor, huGRPr) into Ace-1 cells and demonstrated receptor-targeted NIRF imaging with IR800-G-Abz4-t-BBN, an agonist to huGRPr. Herein, we used the new cell line to develop the first canine prostate cancer model expressing a human growth factor receptor. Dogs were immunosuppressed with cyclosporine, azathioprine, prednisolone, and methylprednisolone. Their prostate glands were implanted with Ace-1huGRPr cells. The implantation wounds were sealed with a cyanoacrylic adhesive to prevent extraprostatic tumor growth. Intraprostatic tumors grew in 4-5 week. A lobar prostatic artery was then catheterized via the carotid artery and 25-100 nmol IR800-Abz4-t-BBN was infused in 2 mL followed by euthanasia in dogs 1-2, and recovery for 24 h before euthanasia in dogs 3-6. Excised tissues were imaged optically imaged, and histopathology performed. Dog1 grew no tumors with cyclosporine alone. Using the four drug protocol, Dogs 2-6 grew abundant 1-2 mm intracapsular and 1-2 cm intraglandular tumors. Tumors grew >5 cm when the prostate cancer cells became extracapsular. Dogs 4-6 with sealed prostatic capsule implantation sites had growth of intracapsular and intraglandular tumors and LN metastases at 5 weeks. High tumor to background BPH signal in the NIRF images of sectioned prostate glands resulted from the 100 nmol dose (∼8 nmol/kg) in dogs 2-4 and 50 nmol dose in dog 5, but not from the 25 nmol dose in Dog 6. Imaging of mouse Ace-1huGRPr tumors required an intravenous dose of 500 nmol/kg body wt. A lymph node that drained the prostate gland was detectable in Dog 4. Histologic findings confirmed the imaging data. Ace-1huGRPr cells created viable, huGRPr-expressing tumors when implanted orthotopically into immune-suppressed dogs. Local delivery of an imaging agent through the prostatic artery allowed a very low imaging dose, suggesting that therapeutic agents could be used safely for treatment of early localized intraglandular prostate cancer as adjuvant therapy for active surveillance or focal ablation therapies, or for treating multifocal intraglandular disease where focal ablation therapies are not indicated or ineffective.

Project description:A novel recombinant disintegrin, vicrostatin (VCN), displays high binding affinity to a broad range of human integrins in substantial competitive biological advantage over other integrin-based antagonists. In this study, we synthesized a new 64Cu-labeled VCN probe and evaluated its imaging properties for prostate cancer in PC-3 tumor-bearing mice. Macrocyclic chelating agent 1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosine (DiAmSar) was conjugated with PEG unit and followed by coupling with VCN. The precursor was then radiolabeled with positron emitter 64Cu (t1/2 = 12.7 h) in ammonium acetate buffer to provide 64Cu-Sar-PEG-VCN, which was subsequently subjected to in vitro studies, small animal PET, and biodistribution studies. The PC-3 tumor-targeting efficacy of 64Cu-Sar-PEG-VCN was compared to a cyclic RGD peptide-based PET probe (64Cu-Sar-RGD). 64Cu labeling was achieved in 75% decay-corrected yield with radiochemical purity of > 98%. The specific activity of 64Cu-Sar-PEG-VCN was estimated to be 37 MBq/nmol. MicroPET imaging results showed that 64Cu-Sar-PEG-VCN has preferential tumor uptake and good tumor retention in PC-3 tumor xenografts. As compared to 64Cu-Sar-RGD, 64Cu-Sar-PEG-VCN produces higher tumor-to-muscle (T/M) imaging contrast ratios at 2 h (4.66 ± 0.34 vs. 2.88 ± 0.46) and 24 h (4.98 ± 0.80 vs. 3.22 ± 0.30) post-injection (pi) and similar tumor-to-liver ratios at 2 h (0.43 ± 0.09 vs. 0.37 ± 0.04) and 24 h (0.57 ± 0.13 vs. 0.52 ± 0.07) pi. The biodistribution results were consistent with the quantitative analysis of microPET imaging, demonstrating good T/M ratio (2.73 ± 0.36) of 64Cu-Sar-PEG-VCN at 48 h pi in PC-3 tumor xenografts. For both microPET and biodistribution studies at 48 h pi, the PC-3 tumor uptake of 64Cu-Sar-PEG-VCN is lower than that of 64Cu-Sar-RGD. 64Cu-Sar-PEG-VCN has the potential for in vivo imaging of prostate cancer with PET, which may provide a unique non-invasive method to quantitatively localize and characterize prostate cancer.

Project description:A versatile drug screening system was developed to simplify early targeted drug discovery in mice and then translate readily from mice to a dog prostate cancer model that more fully replicates the features of human prostate cancer.We stably transfected human cDNA of the GRPr bombesin (BBN) receptor subtype to canine Ace-1 prostate cancer cells (Ace-1(huGRPr) ). Expression was examined by (125) I-Tyr(4) -BBN competition, calcium stimulation assay, and fluorescent microscopy. A dual tumor nude mouse xenograft model was developed from Ace-1(CMV) (vector transfected Ace-1) and Ace-1(huGRPr) cells. The model was used to explore the in vivo behavior of two new IRDye800-labeled GRPr binding optical imaging agents: 800-G-Abz4-t-BBN, from a GRPr agonist peptide, and 800-G-Abz4-STAT, from a GRPr antagonist peptide, by imaging the tumor mice and dissected organs.Both agents bound Ace-1(huGRPr) and PC-3, a known GRPr-expressing human prostate cancer cell line, with 4-13?nM IC50 against (125) I-Tyr(4) -BBN, but did not bind Ace-1(CMV) cells (vector transfected). Binding was blocked by bombesin. Ca(2+) activation assays demonstrated that Ace-1(huGPRr) expressed biologically active GRPr. Both Ace-1 cell lines grew in the flanks of 100% of the nude mice and formed tumors of ?0.5?cm diameter in 1 week. In vivo imaging of the mice at 800?nm emission showed GRPr+: GRPr- tumor signal brighter by a factor of two at 24?h post IV administration of 10?nmol of the imaging agents. Blood retention (4-8% ID at 1?h) was greater by a factor >10 and cumulative urine accumulation (28-30% at 4?h) was less by a factor 2 compared to a radioactive analog of the t-BBN containing agent, (177) LuAMBA, probably due to binding to blood albumin, which we confirmed in a mouse serum assay.The dual tumor Ace-1(CMV) /Ace-1(huGRPr) model system provides a rapid test of specific to nonspecific binding of new GRPr avid agents in a model that will extend logically to the known Ace-1 orthotopic canine prostate cancer model. Prostate 76:783-795, 2016. © 2016 Wiley Periodicals, Inc.

Dataset Information

F-Labeled GRPR Agonists and Antagonists: A Comparative Study in Prostate Cancer Imaging.

Publications

F-Labeled GRPR Agonists and Antagonists: A Comparative Study in Prostate Cancer Imaging.

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