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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Evaluation of A Novel GLP-1R Ligand for PET Imaging of Prostate Cancer

Author(s): Yuanyuan Yue, Yuping Xu, Lirong Huang, Donghui Pan, Zhicheng Bai, Lizhen Wang, Runlin Yang, Junjie Yan, Huizhu Song*, Xiaotian Li* and Min Yang*

Volume 19, Issue 4, 2019

Page: [509 - 514] Pages: 6

DOI: 10.2174/1871520618666180801101730

Price: $65


Background: Glucagon-like peptide 1 receptor (GLP-1R) is an important biomarker for diagnosis and therapy of the endocrine cancers due to overexpression. Recently, in human prostate cancer cell lines the receptor was also observed, therefore it may be a potential target for the disease. 18F-Al-NOTA-MAL-Cys39- exendin-4 holds great promise for GLP-1R. Therefore, the feasibility of the 18F-labeled exendin-4 analog for prostate cancer imaging was investigated.

Methods: New probe 18F-Al-NOTA-MAL-Cys39-exendin-4 was made through one-step fluorination. Prostate cancer PC3 cell xenograft model mice were established to primarily evaluate the imaging properties of the tracer via small animal PET studies in vivo. Pathological studies and Western Blots were also performed.

Results: PC-3 prostate xenografts were clearly imaged under baseline conditions. At 30 and 60 min postinjection, the tumor uptakes were 2.90±0.41%ID/g and 2.26±0.32 %ID/g respectively. The presence of cys39-exendin-4 significantly reduced the tumor uptake to 0.82±0.10 %ID/g at 60 min p.i. Findings of ex vivo biodistribution studies were similar to those of in vivo PET imaging. The tumors to blood and muscles were significantly improved with the increase of time due to rapid clearance of the tracer from normal organs. Low levels of radioactivity were also detected in the GLP-1R positive tumor and normal organs after coinjection with excessive unlabeled peptides. Immunohistochemistry and Western Blots results confirmed that GLP-1R was widely expressed in PC-3 prostate cancers.

Conclusion: 18F-Al labeled exendin-4 analog might be a promising tracer for in vivo detecting GLP-1R positive prostate cancer with the advantage of facile synthesis and favorable pharmacokinetics. It may be useful in differential diagnosis, molecularly targeted therapy and prognosis of the cancers.

Keywords: GLP-1R, prostate cancer, micro PET, PET imaging, endocrine cancers, molecularly targeted therapy.

Graphical Abstract
Okarvi, S.M. Peptide-based radiopharmaceuticals: Future tools for diagnostic imaging of cancers and other diseases. Med. Res. Rev., 2004, 24(5), 685-686.
Reubi, J.C.; Maecke, H.R. Peptide-based probes for cancer imaging. J. Nucl. Med., 2008, 49(11), 1735-1738.
Chen, K.; Conti, P.S. Target-specific delivery of peptide-based probes for PET imaging. Adv. Drug Deliv. Rev., 2010, 62(11), 1005-1022.
Fani, M.; Maecke, H.R.; Okarvi, S.M. Radiolabeled peptides: Valuable tools for the detection and treatment of cancer. Theranostics, 2012, 2(5), 481-501.
Rybalov, M.; Ananias, H.J.K.; Hoving, H.D.; Van-Der-Poel, H.G.; Rosati, S.; De-Jong, I.J. PSMA, EpCAM, VEGF and GRPR as imaging targets in locally recurrent prostate cancer after radiotherapy. Int. J. Mol. Sci., 2014, 15(4), 6046-6061.
Yao, V.; Berkman, C.E.; Choi, J.K.; O’Keefe, D.S.; Bacich, D.J. Expression of Prostate-Specific Membrane Antigen (PSMA), increases cell folate uptake and proliferation and suggests a novel role for PSMA in the uptake of the non-polyglutamated folate, folic acid. Prostate, 2010, 70(3), 305-316.
Wang, X.; Ma, D.; Olson, W.C.; Heston, W.D.W. In vitro and in vivo responses of advanced prostate tumors to PSMA ADC, an auristatin-conjugated antibody to prostate-specific membrane antigen. Mol. Cancer Ther., 2011, 10(9), 1728-1739.
Mannweiler, S.; Amersdorfer, P.; Trajanoski, S.; Terrett, J.; King, D.; Mehes, G. Heterogeneity of Prostate-Specific Membrane Antigen (PSMA) expression in prostate carcinoma with distant metastasis. Pathol. Oncol. Res., 2009, 15(2), 167-172.
Lagerstrom, M.C.; Schioth, H.B. Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat. Rev. Drug Discov., 2008, 7(4), 339-357.
Klabunde, T.; Hessler, G. Drug design strategies for targeting G-protein-coupled receptors. ChemBioChem, 2002, 3(10), 928-944.
Selvaraju, R.K.; Velikyan, I.; Asplund, V.; Johansson, L.; Wu, Z.; Todorov, I.; Shively, J.; Kandeel, F.; Eriksson, B.; Korsgren, O.; Eriksson, O. Pre-clinical evaluation of [68 Ga] Ga-DO3A-VS-Cys 40-Exendin-4 for imaging of insulinoma. Nucl. Med. Biol., 2014, 41(6), 471-476.
Gao, H.; Kiesewetter, D.O.; Zhang, X. PET of glucagonlike peptide receptor upregulation after myocardial ischemia or reperfusion injury. J. Nucl. Med., 2012, 53(12), 1960-1968.
Wang, P.; Yoo, B.; Yang, J. GLP-1R–targeting magnetic nanoparticles for pancreatic islet imaging. Diabetes, 2014, 63(5), 1465-1474.
Brand, C.; Abdel-Atti, D.; Zhang, Y.; Carlin, S.; Clardy, S.M.; Keliher, E.J.; Weber, W.A.; Lewis, J.S.; Reiner, T. In vivo imaging of GLP-1R with a targeted bimodal PET/fluorescence imaging agent. Bioconjug. Chem., 2014, 25(7), 1323-1330.
Tornehave, D.; Kristensen, P.; Rømer, J.; Knudsen, L.B.; Heller, R.S. Expression of the GLP-1 receptor in mouse, rat, and human pancreas. J. Histochem. Cytochem., 2008, 56(9), 841-851.
Ahrén, B. Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes. Nat. Rev. Drug Discov., 2009, 8(5), 369-385.
Körner, M.; Stöckli, M.; Waser, B.; Reubi, J.C. GLP-1 receptor expression in human tumors and human normal tissues: Potential for in vivo targeting. J. Nucl. Med., 2007, 48(5), 736-743.
Christ, E.; Wild, D.; Forrer, F.; Brandle, M.; Sahli, R.; Clerici, T.; Gloor, B.; Martius, F.; Maecke, H.; Reubi, J.C. Glucagon-like peptide-1 receptor imaging for localization of insulinomas. J. Clin. Endocrinol. Metab., 2009, 94(11), 4398-4405.
Pattou, F.; Kerr-Conte, J.; Wild, D. 18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma. Eur. J. Nucl. Med. Mol. Imaging, 2012, 39(3), 463-473.
Brom, M.; Joosten, L.; Oyen, W.J.; Gotthardt, M.; Boerman, O.C. Radiolabelled GLP‐1 analogues for in vivo targeting of insulinomas. Contr. Med. Mol. Imag., 2012, 7(2), 160-166.
Yue, X.; Yan, X.; Wu, C.; Niu, G.; Ma, Y.; Jacobson, O.; Shen, B.; Kiesewetter, D.O.; Chen, X. One-pot two-step radiosynthesis of a new F-18-labeled thiol reactive prosthetic group and its conjugate for insulinoma imaging. Mol. Pharm., 2014, 11(11), 3875-3884.
Wu, Z.; Liu, S.; Nair, I.; Omori, K.; Scott, S.; Todorov, I.; Shively, J.E.; Conti, P.S.; Li, Z.; Kandeel, F. 64Cu Labeled sarcophagine exendin-4 for microPET imaging of glucagon like peptide-1 receptor expression. J. Nucl. Med., 2014, 4(8), 770-777.
Nomiyama, T.; Kawanami, T.; Irie, S.; Hamaguchi, Y.; Terawaki, Y.; Murase, K.; Tsutsumi, Y.; Nagaishi, R.; Tanabe, M.; Morinaga, H.; Tanaka, T. Exendin-4, a GLP-1 receptor agonist, attenuates prostate cancer growth. Diabetes, 2014, 3(11), 3891-3905.
Gao, H.; Niu, G.; Yang, M.; Quan, Q.; Ma, Y.; Murage, E.N.; Ahn, J.M.; Kiesewetter, D.O.; Chen, X. PET of insulinoma using F-18-FBEM-EM3106B, a new GLP-1 analogue. Mol. Pharm., 2011, 8(5), 1775-1782.
Xu, Y.; Pan, D.; Xu, Q.; Zhu, C.; Wang, L.; Chen, F.; Yang, R.; Luo, S.; Yang, M. Insulinoma imaging with glucagon-like peptide-1 receptor targeting probe F-18-FBEM–Cys39-exendin-4. J. Cancer Res. Clin. Oncol., 2014, 140(9), 1479-1488.
Jiang, Z.; Woda, B.A.; Rock, K.L.; Xu, Y.; Savas, L.; Khan, A.; Pihan, G.; Cai, F.; Babcook, J.S.; Rathanaswami, P.; Reed, S.G. P504S: A new molecular marker for the detection of prostate carcinoma. Am. J. Surg. Pathol., 2001, 25, 1397-1404.
Pan, D.; Yan, Y.; Yang, R.; Xu, Y.P.; Chen, F.; Wang, L.; Luo, S.; Yang, M. PET imaging of prostate tumors with 18F‐Al‐NOTA‐ MATBBN. Contr. Med. Mol. Imag., 2014, 9(5), 342-348.
Xu, Y.; Pan, D.; Zhu, C.; Xu, Q.; Wang, L.; Chen, F.; Yang, R.; Luo, S.; Yang, M.; Yan, Y. Pilot study of a novel 18F-labeled FSHR probe for tumor imaging. Mol. Imaging Biol., 2014, 16(4), 578-585.
Wan, W.; Guo, N.; Pan, D.; Yu, C.; Weng, Y.; Luo, S.; Ding, H.; Xu, Y.; Wang, L.; Lang, L.; Xie, Q. First experience of 18F-alfatide in lung cancer patients using a new lyophilized kit for rapid radiofluorination. J. Nucl. Med., 2013, 54(5), 691-698.
Goldenberg, D.M.; Sharkey, R.M.; McBride, W.J.; Boerman-Otto, C. (AlF)-F-18: A new standard for radiofluorination. J. Nucl. Med., 2013, 54(7), 1170-1170.
McBride, W.J.; Sharkey, R.M.; Goldenberg, D.M. Radiofluorination using aluminum-fluoride (Al (18) F). EJNMMI Res., 2013, 3(1), 36.
Xu, Q.; Zhu, C.; Xu, Y.; Pan, D.; Liu, P.; Yang, R.; Wang, L.; Chen, F.; Sun, X.; Luo, S.; Yang, M. Preliminary evaluation of [18F] AlF-NOTA-MAL-Cys39-exendin-4 in insulinoma with PET. J. Drug Target., 2015, 23(9), 813-820.
Bauman, A.; Valverde, I.E.; Fischer, C.A.; Vomstein, S.; Mindt, T.L. Development of Ga-68-and Zr-89-labeled exendin-4 as potential radiotracers for the imaging of insulinomas by PET. J. Nucl. Med., 2015, 56(10), 1569-1574.
Cardinale, J.; Schäfer, M.; Benešová, M.; Bauder-Wüst, U.; Leotta, K.; Eder, M.; Neels, O.C.; Haberkorn, U.; Giesel, F.L.; Kopka, K. Preclinical evaluation of 18F-PSMA-1007, a new prostate-specific membrane antigen ligand for prostate cancer imaging. J. Nucl. Med., 2017, 58, 425-431.
Kiesewetter, D.O.; Guo, N.; Guo, J.; Gao, H.; Zhu, L.; Ma, Y.; Niu, G.; Chen, X. Evaluation of an [F-18] AlF-NOTA analog of exendin-4 for imaging of GLP-1 receptor in insulinoma. Theranostics, 2012, 2(10), 999-1009.

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