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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:The gastrin-releasing peptide receptor (GRPr) is overexpressed in prostate cancer (PCa) cells, making it an excellent tool for targeted imaging. The 68Ga-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 68Ga-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 68Ga-SB3 (187.4 ± 40.0 MBq, 40 ± 5 μg) was well tolerated; no significant changes in vital signs or laboratory results were observed. 68Ga-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%. 68Ga-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 68Ga-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: 68Ga-SB3 PET/CT is a safe imaging method and a promising tool for early PCa imaging.

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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