Nilantha Bandara1, Alex Zheleznyak1, Kaavya Cherukuri1, David A Griffith2, Chris Limberakis3, David A Tess4, Chen Jianqing5, Rikki Waterhouse5, Suzanne E Lapi6. 1. Department of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA. 2. Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA, 02139, USA. 3. Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT, 06340, USA. 4. Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Cambridge, MA, 02139, USA. 5. Clinical and Translational Imaging, Pfizer Worldwide Research and Development, Cambridge, MA, 02139, USA. 6. Department of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA. lapis@mir.wustl.edu.
Abstract
PURPOSE: Copper-64 (Cu-64) and Galium-68 (Ga-68) radiolabeled DO3A and NODA conjugates of exendin-4 were used for preclinical imaging of pancreatic β cells via targeting of glucagon-like peptide-1 receptor (GLP-1R). PROCEDURES: DO3A-VS- and NODA-VS-tagged Cys(40)exendin-4 (DO3A-VS-Cys(40)-exendin-4 and NODA-VS-Cys(40)-exendin-4, respectively) were labeled with Cu-64 and Ga-68 using standard techniques. Biodistribution and dynamic positron emission tomography (PET) were carried out in normal Sprague-Dawley (SD) rats. Ex vivo autoradiography imaging was conducted with freshly frozen pancreatic thin sections. RESULTS: DO3A-VS- and NODA-VS-Cys(40)-exendin-4 analogues were labeled with Cu-64 and Ga-68 to a specific activity of 518.7 ± 3.7 Ci/mmol (19.19 ± 0.14 TBq/mmol) and radiochemical yield above 98 %. Biodistribution data demonstrated pancreatic uptake of 0.11 ± 0.02 %ID/g for [(64)Cu]DO3A-VS-, 0.14 ± 0.02 %ID/g for [(64)Cu]NODA-VS-, 0.11 ± 0.03 for [(68)Ga]DO3A-VS-, and 0.26 ± 0.03 for [(68)Ga]NODA-VS-Cys(40)-exendin-4. Excess exendin-4 and exendin-(9-39)-amide displaced all four Cu-64 and Ga-68 labeled exendin-4 derivatives in blocking studies. CONCLUSIONS: [(64)Cu]/[(68)Ga]DO3A-VS-Cys(40)- and [(64)Cu]/[(68)Ga]NODA-VS-Cys(40)-exendin-4 can be used as PET imaging agents specific for GLP-1R expressed on β cells. Here, we report the first evidence of pancreatic uptake visualized with exendin-4 derivative in a rat animal model via in vivo dynamic PET imaging.
PURPOSE:Copper-64 (Cu-64) and Galium-68 (Ga-68) radiolabeled DO3A and NODA conjugates of exendin-4 were used for preclinical imaging of pancreatic β cells via targeting of glucagon-like peptide-1 receptor (GLP-1R). PROCEDURES: DO3A-VS- and NODA-VS-tagged Cys(40)exendin-4 (DO3A-VS-Cys(40)-exendin-4 and NODA-VS-Cys(40)-exendin-4, respectively) were labeled with Cu-64 and Ga-68 using standard techniques. Biodistribution and dynamic positron emission tomography (PET) were carried out in normal Sprague-Dawley (SD) rats. Ex vivo autoradiography imaging was conducted with freshly frozen pancreatic thin sections. RESULTS:DO3A-VS- and NODA-VS-Cys(40)-exendin-4 analogues were labeled with Cu-64 and Ga-68 to a specific activity of 518.7 ± 3.7 Ci/mmol (19.19 ± 0.14 TBq/mmol) and radiochemical yield above 98 %. Biodistribution data demonstrated pancreatic uptake of 0.11 ± 0.02 %ID/g for [(64)Cu]DO3A-VS-, 0.14 ± 0.02 %ID/g for [(64)Cu]NODA-VS-, 0.11 ± 0.03 for [(68)Ga]DO3A-VS-, and 0.26 ± 0.03 for [(68)Ga]NODA-VS-Cys(40)-exendin-4. Excess exendin-4 and exendin-(9-39)-amide displaced all four Cu-64 and Ga-68 labeled exendin-4 derivatives in blocking studies. CONCLUSIONS: [(64)Cu]/[(68)Ga]DO3A-VS-Cys(40)- and [(64)Cu]/[(68)Ga]NODA-VS-Cys(40)-exendin-4 can be used as PET imaging agents specific for GLP-1R expressed on β cells. Here, we report the first evidence of pancreatic uptake visualized with exendin-4 derivative in a rat animal model via in vivo dynamic PET imaging.
Authors: Huy N Hoang; Kun Song; Timothy A Hill; David R Derksen; David J Edmonds; W Mei Kok; Chris Limberakis; Spiros Liras; Paula M Loria; Vincent Mascitti; Alan M Mathiowetz; Justin M Mitchell; David W Piotrowski; David A Price; Robert V Stanton; Jacky Y Suen; Jane M Withka; David A Griffith; David P Fairlie Journal: J Med Chem Date: 2015-04-16 Impact factor: 7.446
Authors: Martin Gotthardt; Georg Lalyko; Julliëtte van Eerd-Vismale; Boris Keil; Tino Schurrat; Michael Hower; Peter Laverman; Thomas M Behr; Otto C Boerman; Burkhard Göke; Martin Béhé Journal: Regul Pept Date: 2006-08-22
Authors: Ahmed Abbas; Christine Beamish; Rebecca McGirr; John Demarco; Neil Cockburn; Dawid Krokowski; Ting-Yim Lee; Michael Kovacs; Maria Hatzoglou; Savita Dhanvantari Journal: F1000Res Date: 2016-07-27
Authors: Reinier Hernandez; Stephen A Graves; Trillian Gregg; Halena R VanDeusen; Rachel J Fenske; Haley N Wienkes; Christopher G England; Hector F Valdovinos; Justin J Jeffery; Todd E Barnhart; Gregory W Severin; Robert J Nickles; Michelle E Kimple; Matthew J Merrins; Weibo Cai Journal: Diabetes Date: 2017-05-17 Impact factor: 9.461
Authors: Tolulope A Aweda; Zumrut F B Muftuler; Adriana V F Massicano; Dhruval Gadhia; Kelly A McCarthy; Stacy Queern; Anupam Bandyopadhyay; Jianmin Gao; Suzanne E Lapi Journal: Contrast Media Mol Imaging Date: 2019-10-29 Impact factor: 3.161