|
1
|
Zhang T, Ma X, Xu M, Cai J, Cai J, Cao Y, Zhang Z, Ji X, He J, Cabrera GOF, Wu X, Zhao W, Wu Z, Xie J, Li Z. Chelator boosted tumor-retention and pharmacokinetic properties: development of 64Cu labeled radiopharmaceuticals targeting neurotensin receptor. Eur J Nucl Med Mol Imaging 2024; 51:3322-3333. [PMID: 38771516 PMCID: PMC11368631 DOI: 10.1007/s00259-024-06754-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 05/05/2024] [Indexed: 05/22/2024]
Abstract
PURPOSE Accumulating evidence suggests that neurotensin (NTS) and neurotensin receptors (NTSRs) play key roles in lung cancer progression by triggering multiple oncogenic signaling pathways. This study aims to develop Cu-labeled neurotensin receptor 1 (NTSR1)-targeting agents with the potential for both imaging and therapeutic applications. METHOD A series of neurotensin receptor antagonists (NRAs) with variable propylamine (PA) linker length and different chelators were synthesized, including [64Cu]Cu-CB-TE2A-iPA-NRA ([64Cu]Cu-4a-c, i = 1, 2, 3), [64Cu]Cu-NOTA-2PA-NRA ([64Cu]Cu-4d), [64Cu]Cu-DOTA-2PA-NRA ([64Cu]Cu-4e, also known as [64Cu]Cu-3BP-227), and [64Cu]Cu-DOTA-VS-2PA-NRA ([64Cu]Cu-4f). The series of small animal PET/CT were conducted in H1299 lung cancer model. The expression profile of NTSR1 was also confirmed by IHC using patient tissue samples. RESULTS For most of the compounds studied, PET/CT showed prominent tumor uptake and high tumor-to-background contrast, but the tumor retention was strongly influenced by the chelators used. For previously reported 4e, [64Cu]Cu-labeled derivative showed initial high tumor uptake accompanied by rapid tumor washout at 24 h. The newly developed [64Cu]Cu-4d and [64Cu]Cu-4f demonstrated good tumor uptake and tumor-to-background contrast at early time points, but were less promising in tumor retention. In contrast, our lead compound [64Cu]Cu-4b demonstrated 9.57 ± 1.35, 9.44 ± 2.38 and 9.72 ± 4.89%ID/g tumor uptake at 4, 24, and 48 h p.i., respectively. Moderate liver uptake (11.97 ± 3.85, 9.80 ± 3.63, and 7.72 ± 4.68%ID/g at 4, 24, and 48 h p.i.) was observed with low uptake in most other organs. The PA linker was found to have a significant effect on drug distribution. Compared to [64Cu]Cu-4b, [64Cu]Cu-4a had a lower background, including a greatly reduced liver uptake, while the tumor uptake was only moderately reduced. Meanwhile, [64Cu]Cu-4c showed increased uptake in both the tumor and the liver. The clinical relevance of NTSR1 was also demonstrated by the elevated tumor expression in patient tissue samples. CONCLUSIONS Through the side-by-side comparison, [64Cu]Cu-4b was identified as the lead agent for further evaluation based on its high and sustained tumor uptake and moderate liver uptake. It can not only be used to efficiently detect NTSR1 expression in lung cancer (for diagnosis, patient screening, and treatment monitoring), but also has the great potential to treat NTSR-positive lesions once chelating to the beta emitter 67Cu.
Collapse
Affiliation(s)
- Tao Zhang
- Department of Radiology, Biomedical Research Imaging Center, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , 27599, USA.
- Department of Radiopharmaceuticals, Nuclear Medicine Clinical Transformation Center, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
- Department of Nuclear Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.
| | - Xinrui Ma
- Department of Radiology, Biomedical Research Imaging Center, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , 27599, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, Raleigh, NC, North Carolina State University, NC 27599, USA
| | - Muyun Xu
- Department of Radiology, Biomedical Research Imaging Center, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , 27599, USA
| | - Jinghua Cai
- Department of Radiology, Biomedical Research Imaging Center, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , 27599, USA
| | - Jianhua Cai
- Department of Radiology, Biomedical Research Imaging Center, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , 27599, USA
| | - Yanguang Cao
- Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Zhihao Zhang
- Department of Radiopharmaceuticals, Nuclear Medicine Clinical Transformation Center, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
| | - Xin Ji
- Department of Radiopharmaceuticals, Nuclear Medicine Clinical Transformation Center, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
| | - Jian He
- Department of Nuclear Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - German Oscar Fonseca Cabrera
- Department of Radiology, Biomedical Research Imaging Center, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , 27599, USA
| | - Xuedan Wu
- Department of Radiology, Biomedical Research Imaging Center, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , 27599, USA
| | - Weiling Zhao
- Department of Radiology, Biomedical Research Imaging Center, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , 27599, USA
| | - Zhanhong Wu
- Department of Radiology, Biomedical Research Imaging Center, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , 27599, USA
| | - Jin Xie
- Department of Chemistry, University of Georgia, 302 East Campus Road, Athens, GA, 30602, USA.
| | - Zibo Li
- Department of Radiology, Biomedical Research Imaging Center, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina , 27599, USA.
| |
Collapse
|
|
2
|
Xie Y, Wang Y, Pei W, Chen Y. Theranostic in GLP-1R molecular imaging: challenges and emerging opportunities. Front Mol Biosci 2023; 10:1210347. [PMID: 37780209 PMCID: PMC10540701 DOI: 10.3389/fmolb.2023.1210347] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Accepted: 09/06/2023] [Indexed: 10/03/2023] Open
Abstract
Theranostic in nuclear medicine combines diagnostic imaging and internal irradiation therapy using different therapeutic nuclear probes for visual diagnosis and precise treatment. GLP-1R is a popular receptor target in endocrine diseases, non-alcoholic steatohepatitis, tumors, and other areas. Likewise, it has also made breakthroughs in the development of molecular imaging. It was recognized that GLP-1R imaging originated from the study of insulinoma and afterwards was expanded in application including islet transplantation, pancreatic β-cell mass measurement, and ATP-dependent potassium channel-related endocrine diseases. Fortunately, GLP-1R molecular imaging has been involved in ischemic cardiomyocytes and neurodegenerative diseases. These signs illustrate the power of GLP-1R molecular imaging in the development of medicine. However, it is still limited to imaging diagnosis research in the current molecular imaging environment. The lack of molecular-targeted therapeutics related report hinders its radiology theranostic. In this article, the current research status, challenges, and emerging opportunities for GLP-1R molecular imaging are discussed in order to open a new path for theranostics and to promote the evolution of molecular medicine.
Collapse
Affiliation(s)
- Yang Xie
- Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, China
- Academician (Expert) Workstation of Sichuan Province, Luzhou, Sichuan, China
| | - Yudi Wang
- Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, China
- Academician (Expert) Workstation of Sichuan Province, Luzhou, Sichuan, China
| | - Wenjie Pei
- Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, China
- Academician (Expert) Workstation of Sichuan Province, Luzhou, Sichuan, China
| | - Yue Chen
- Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, China
- Academician (Expert) Workstation of Sichuan Province, Luzhou, Sichuan, China
| |
Collapse
|
|
3
|
Ye X, Xiong L, Fu Q, Wang B, Wang Y, Zhang K, Yang J, Kantawong F, Kumsaiyai W, Zhou J, Lan C, Wu J, Zeng J. Chemical characterization and DPP-IV inhibitory activity evaluation of tripeptides from Gynura divaricata (L.) DC. JOURNAL OF ETHNOPHARMACOLOGY 2022; 292:115203. [PMID: 35304277 DOI: 10.1016/j.jep.2022.115203] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 03/08/2022] [Accepted: 03/11/2022] [Indexed: 02/05/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Gynura divaricata (L.) DC. (GD), a herbal medicine, has been used for the prevention and treatment of hyperglycemia in China. However, hypoglycemic ingredients within GD have not yet been well studied. AIM OF THE STUDY The aim of this study was to explore undiscovered compounds with dipeptidyl peptidase IV (DPP-IV) inhibitory activity within GD. MATERIALS AND METHODS A four-step strategy was developed to explore undiscovered DPP-IV inhibitors within GD. First, the components were preliminarily characterized using UHPLC-HRMS combined with a library search. Second, preliminarily characterized compounds were searched for potential bioactivity. Third, a mixture of these preliminarily characterized compounds was isolated and thoroughly characterized based on fragmentation patterns associated with molecular networking. Fourth, the activities of these compounds were verified using DPP-IV inhibitory assay and molecular docking. RESULTS Diprotin A, a tripeptide inhibitor against DPP-IV, was identified. Thereafter, a mixture of twenty-five diprotin A analogs was isolated and characterized, which exhibited IC50 of 0.40 mg/mL for DPP-IV. Molecular docking results also confirmed the interactions between the tripeptide analogs and DPP-IV mainly via H-bonds and hydrophobic interactions. CONCLUSIONS This is the first report of DPP-IV inhibitors within GD. These findings demonstrate that the extract of GD might be beneficial for the treatment of type 2 diabetes mellitus, and is expected to promote further development and utilization of GD in herbal medicine.
Collapse
Affiliation(s)
- Xinyuan Ye
- School of Pharmacy, Southwest Medical University, Luzhou, China.
| | - Ling Xiong
- School of Pharmacy, Southwest Medical University, Luzhou, China.
| | - Qifeng Fu
- School of Pharmacy, Southwest Medical University, Luzhou, China.
| | - Binyou Wang
- School of Pharmacy, Southwest Medical University, Luzhou, China.
| | - Yiwei Wang
- School of Pharmacy, Southwest Medical University, Luzhou, China; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
| | - Kailian Zhang
- School of Pharmacy, Southwest Medical University, Luzhou, China.
| | - Jie Yang
- School of Pharmacy, Southwest Medical University, Luzhou, China; Faculty Associated Medical Sciences, Department of Medical Technology, Chiang Mai University, Chiang Mai, Thailand.
| | - Fahsai Kantawong
- Faculty Associated Medical Sciences, Department of Medical Technology, Chiang Mai University, Chiang Mai, Thailand.
| | - Warunee Kumsaiyai
- Faculty Associated Medical Sciences, Department of Medical Technology, Chiang Mai University, Chiang Mai, Thailand.
| | - Jie Zhou
- School of Pharmacy, Southwest Medical University, Luzhou, China; Education Ministry Key Laboratory of Medical Electrophysiology, Luzhou, China; Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou, China; Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, China.
| | - Cai Lan
- School of Pharmacy, Southwest Medical University, Luzhou, China; Education Ministry Key Laboratory of Medical Electrophysiology, Luzhou, China; Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou, China; Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, China.
| | - Jianming Wu
- School of Pharmacy, Southwest Medical University, Luzhou, China; Education Ministry Key Laboratory of Medical Electrophysiology, Luzhou, China; Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou, China; Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, China.
| | - Jing Zeng
- School of Pharmacy, Southwest Medical University, Luzhou, China.
| |
Collapse
|
|
4
|
Development of novel 67/68Ga-labeled pyridyl benzofuran derivatives as islet amyloid imaging probes. Nucl Med Biol 2022; 106-107:72-79. [DOI: 10.1016/j.nucmedbio.2022.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 12/20/2021] [Accepted: 01/07/2022] [Indexed: 11/18/2022]
|
|
5
|
Luo Y, Chen X. Imaging of Insulinoma by Targeting Glucagonlike Peptide-1 Receptor. PET Clin 2021; 16:205-217. [PMID: 33589387 DOI: 10.1016/j.cpet.2020.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
"Glucagonlike peptide-1 (GLP-1) receptor imaging, using radiolabeled exendin-4, was recently established for detecting insulinoma in patients with hyperinsulinemic hypoglycemia. It has proven to be a sensitive and specific method for preoperative localization of insulinoma. This review introduces the development, clinical research, and perspective of GLP-1 receptor imaging mainly in insulinoma.
Collapse
Affiliation(s)
- Yaping Luo
- Department of Nuclear Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College Hospital, #1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing 100730, P. R. China; Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine
| | - Xiaoyuan Chen
- Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore 117597, Singapore.
| |
Collapse
|
|
6
|
Kondo N, Oishi A, Hirata M, Temma T. Indirectly radioiodinated exendin-4 as an analytical tool for in vivo detection of glucagon-like peptide-1 receptor in a disease setting. Ann Nucl Med 2021; 35:83-91. [PMID: 33067731 DOI: 10.1007/s12149-020-01540-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 10/07/2020] [Indexed: 10/23/2022]
Abstract
OBJECTIVE Glucagon-like peptide-1 receptor agonist (GLP-1RA) has been reported to have therapeutic effects on diabetes and various diseases. Precise detection of GLP-1 receptor (GLP-1R) can be useful to diagnose and elucidate the mechanism of such diseases. Here we aimed to develop an imaging probe based on GLP-1RA that has high molar activity and sensitivity for detection of low-level GLP-1R expression in non-pancreatic diseases. METHODS We selected the agonist exenatide (Ex4) as the parent peptide of a GLP-1R targeting probe and prepared Cys-Ex4 by addition of an N-terminal Cys residue and labeling with the prosthetic agent N-(3-[125I]iodophenyl)maleimide ([125I]IPM) to generate [125I]Ex4ipm. We evaluated the affinity of [125I]Ex4ipm for GLP-1R, as well as cellular binding profiles in insulinoma and prostate cancer cell lines, and in vivo biodistributions in normal and tumor-bearing mice to assess GLP-1R-dependent accumulation of radioactivity in tissues. RESULTS [125I]Ex4ipm was easily synthesized with high radiochemical yield (73%), radiochemical purity (> 99%), and molar activity (81 GBq/µmol) via a thiol/maleimide reaction. Following administration to mice, [125I]Ex4ipm accumulated to high levels in the pancreas (23.3% ID/g), with radioactivity co-localizing in areas having insulin-positive β cells. High amounts of radioactivity also accumulated in insulinomas that overexpressed GLP-1R (27.5% ID/g). In contrast, low amounts of [125I]Ex4ipm accumulation, corresponding to low expression levels of GLP-1R, were observed in prostate cancer cells and xenografts used as a model of non-pancreatic applications. CONCLUSION Our results suggested that [123I]Ex4ipm could be valuable for GLP-1R imaging in diabetes, insulinomas, and various diseases related to GLP-1R.
Collapse
Affiliation(s)
- Naoya Kondo
- Department of Biofunctional Analysis, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan
| | - Ayaka Oishi
- Department of Biofunctional Analysis, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan
| | - Masahiko Hirata
- Department of Biofunctional Analysis, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan
| | - Takashi Temma
- Department of Biofunctional Analysis, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan.
| |
Collapse
|
|
7
|
Murakami T, Fujimoto H, Inagaki N. Non-invasive Beta-cell Imaging: Visualization, Quantification, and Beyond. Front Endocrinol (Lausanne) 2021; 12:714348. [PMID: 34248856 PMCID: PMC8270651 DOI: 10.3389/fendo.2021.714348] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 06/14/2021] [Indexed: 01/07/2023] Open
Abstract
Pancreatic beta (β)-cell dysfunction and reduced mass play a central role in the development and progression of diabetes mellitus. Conventional histological β-cell mass (BCM) analysis is invasive and limited to cross-sectional observations in a restricted sampling area. However, the non-invasive evaluation of BCM remains elusive, and practical in vivo and clinical techniques for β-cell-specific imaging are yet to be established. The lack of such techniques hampers a deeper understanding of the pathophysiological role of BCM in diabetes, the implementation of personalized BCM-based diabetes management, and the development of antidiabetic therapies targeting BCM preservation and restoration. Nuclear medical techniques have recently triggered a major leap in this field. In particular, radioisotope-labeled probes using exendin peptides that include glucagon-like peptide-1 receptor (GLP-1R) agonist and antagonist have been employed in positron emission tomography and single-photon emission computed tomography. These probes have demonstrated high specificity to β cells and provide clear images accurately showing uptake in the pancreas and transplanted islets in preclinical in vivo and clinical studies. One of these probes, 111indium-labeled exendin-4 derivative ([Lys12(111In-BnDTPA-Ahx)]exendin-4), has captured the longitudinal changes in BCM during the development and progression of diabetes and under antidiabetic therapies in various mouse models of type 1 and type 2 diabetes mellitus. GLP-1R-targeted imaging is therefore a promising tool for non-invasive BCM evaluation. This review focuses on recent advances in non-invasive in vivo β-cell imaging for BCM evaluation in the field of diabetes; in particular, the exendin-based GLP-1R-targeted nuclear medicine techniques.
Collapse
Affiliation(s)
- Takaaki Murakami
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hiroyuki Fujimoto
- Radioisotope Research Center, Agency of Health, Safety and Environment, Kyoto University, Kyoto, Japan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan
- *Correspondence: Nobuya Inagaki,
| |
Collapse
|
|
8
|
Kelly JM, Ponnala S, Amor-Coarasa A, Zia NA, Nikolopoulou A, Williams C, Schlyer DJ, DiMagno SG, Donnelly PS, Babich JW. Preclinical Evaluation of a High-Affinity Sarcophagine-Containing PSMA Ligand for 64Cu/ 67Cu-Based Theranostics in Prostate Cancer. Mol Pharm 2020; 17:1954-1962. [PMID: 32286841 DOI: 10.1021/acs.molpharmaceut.0c00060] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
The application of small molecules targeting prostate-specific membrane antigen (PSMA) has emerged as a highly promising clinical strategy for visualization and treatment of prostate cancer. Ligands that integrate the ability to both quantify the distribution of radioactivity and treat disease through the use of a matched pair of radionuclides have particular value in clinical and regulatory settings. In this study, we describe the development and preclinical evaluation of RPS-085, a ligand that binds PSMA and serum albumin and exploits the 64/67Cu radionuclide pair for prostate cancer theranostics. RPS-085 was synthesized by conjugation of a PSMA-targeting moiety, an Nε-(2-(4-iodophenyl)acetyl)lysine albumin binding group, and a bifunctionalized MeCOSar chelator. The IC50 of the metal-free RPS-085 was determined in a competitive binding assay. The affinity for human serum albumin of the radiolabeled compound was determined by high-performance affinity chromatography. Radiolabeling was performed in NH4OAc buffer at 25 °C. The stability of the radiolabeled compounds was assessed in vitro and in vivo. The biodistribution of [64/67Cu]Cu-RPS-085 was determined following intravenous administration to male BALB/c mice bearing LNCaP tumor xenografts. The radiochemical yields of [64/67Cu]Cu-RPS-085 were nearly quantitative after 20 min. The metal-free complex is a potent inhibitor of PSMA (IC50 = 29 ± 2 nM), and the radiolabeled compound has moderate affinity for human serum albumin (Kd = 9.9 ± 1.7 μM). Accumulation of the tracer in mice was primarily evident in tumor and kidneys. Activity in all other tissues, including blood, was negligible, and the radiolabeled compounds demonstrated high stability in vitro and in vivo. Tumor activity reached a maximum at 4 h post injection (p.i.) and cleared gradually over a period of 96 h. By contrast, activity in the kidney cleared rapidly from 4 to 24 h p.i. As a consequence, by 24 h p.i., the tumor-to-kidney ratio exceeds 2, and the predicted dose to tumors is significantly greater than the dose to kidneys. [64Cu]Cu-RPS-085 combines rapid tissue distribution and clearance with prolonged retention in LNCaP tumor xenografts. The pharmacokinetics should enable radioligand therapy using [67Cu]Cu-RPS-085. By virtue of its rapid kidney clearance, the therapeutic index of [67Cu]Cu-RPS-085 likely compares favorably to its parent structure, [177Lu]Lu-RPS-063, a highly avid PSMA-targeting compound. On this basis, [64/67Cu]Cu-RPS-085 show great promise as PSMA-targeting theranostic ligands for prostate cancer imaging and therapy.
Collapse
Affiliation(s)
- James M Kelly
- Division of Radiopharmaceutical Sciences and MI3 Institute, Department of Radiology, Weill Cornell Medicine, New York, New York 10021, United States
| | - Shashikanth Ponnala
- Division of Radiopharmaceutical Sciences and MI3 Institute, Department of Radiology, Weill Cornell Medicine, New York, New York 10021, United States
| | - Alejandro Amor-Coarasa
- Division of Radiopharmaceutical Sciences and MI3 Institute, Department of Radiology, Weill Cornell Medicine, New York, New York 10021, United States
| | - Nicholas A Zia
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3010, Australia
| | - Anastasia Nikolopoulou
- Division of Radiopharmaceutical Sciences and MI3 Institute, Department of Radiology, Weill Cornell Medicine, New York, New York 10021, United States.,Citigroup Biomedical Imaging Center, Weill Cornell Medicine, New York, New York 10021, United States
| | - Clarence Williams
- Division of Radiopharmaceutical Sciences and MI3 Institute, Department of Radiology, Weill Cornell Medicine, New York, New York 10021, United States
| | - David J Schlyer
- Brookhaven National Laboratory, Upton, New York 11973, United States.,Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York 11794, United States
| | - Stephen G DiMagno
- College of Pharmacy, University of Illinois-Chicago, Chicago, Illinois 60612, United States
| | - Paul S Donnelly
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria 3010, Australia
| | - John W Babich
- Division of Radiopharmaceutical Sciences and MI3 Institute, Department of Radiology, Weill Cornell Medicine, New York, New York 10021, United States.,Citigroup Biomedical Imaging Center, Weill Cornell Medicine, New York, New York 10021, United States.,Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10065, United States
| |
Collapse
|
|
9
|
Senica K, Tomazic A, Skvarca A, Kolenc Peitl P, Mikolajczak R, Hubalewska-Dydejczyk A, Lezaic L. Superior Diagnostic Performance of the GLP-1 Receptor Agonist [Lys 40(AhxHYNIC-[ 99mTc]/EDDA)NH 2]-Exendin-4 over Conventional Imaging Modalities for Localization of Insulinoma. Mol Imaging Biol 2020; 22:165-172. [PMID: 31098984 DOI: 10.1007/s11307-019-01372-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE Insulinomas are the most common functioning neuroendocrine neoplasms of the pancreas, typically diagnosed due to characteristic symptoms. In the vast majority, the treatment is surgical and curative, requiring accurate localization of the tumour; conventional imaging, including somatostatin receptor molecular imaging, is negative in up to 10 % of cases. Recently, labelled glucagon-like peptide receptor (GLP-1R) analogues were introduced as a sensitive diagnostic method for localization of insulinomas. The aim of this study was to assess the diagnostic accuracy of a Tc-99m-labelled GLP-1R agonist [Lys40(AhxHYNIC-[99mTc]EDDA)NH2]-exendin-4 for localization of occult insulinoma. PROCEDURES Eight patients (all females; age range 35-75 years) with biochemically proven insulinoma and with negative or inconclusive conventional imaging (consisting of somatostatin receptor scintigraphy, computed tomography, endoscopic ultrasound and magnetic resonance imaging) were enrolled. Whole-body single-photon emission tomography/computed tomography (SPECT/CT) imaging was performed 4 h post-injection of 740 MBq of [Lys40(AhxHYNIC-[99mTc]EDDA)NH2]-exendin-4. Surgical treatment was performed based on imaging findings. Histology of the removed lesions and biochemical and clinical symptom resolution was considered as the gold standard for analysis of the imaging results. RESULTS Focal uptake of [Lys40(AhxHYNIC-[99mTc]EDDA)NH2]-exendin-4 was found in all patients, leading to successful removal of the offending lesion and complete biochemical and symptomatic resolution. Histological analysis confirmed insulinoma in all included patients. CONCLUSIONS [Lys40(AhxHYNIC-[99mTc]EDDA)NH2]-exendin-4 SPECT/CT appears to be an excellent molecular imaging method for preoperative localization of an occult insulinoma, surpassing conventional imaging methods. If routinely available, it could be considered as a method of choice due to its favorable combination of imaging characteristics.
Collapse
Affiliation(s)
- Katra Senica
- Department of Nuclear Medicine, University Medical Centre Ljubljana, Zaloska 7, 1525, Ljubljana, Slovenia
| | - Ales Tomazic
- Department of Abdominal Surgery, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Ales Skvarca
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Petra Kolenc Peitl
- Department of Nuclear Medicine, University Medical Centre Ljubljana, Zaloska 7, 1525, Ljubljana, Slovenia
| | - Renata Mikolajczak
- Radioisotope Centre POLATOM, National Centre for Nuclear Research, Otwock, Poland
| | | | - Luka Lezaic
- Department of Nuclear Medicine, University Medical Centre Ljubljana, Zaloska 7, 1525, Ljubljana, Slovenia.
| |
Collapse
|
|
10
|
Velikyan I, Eriksson O. Advances in GLP-1 receptor targeting radiolabeled agent development and prospective of theranostics. Theranostics 2020; 10:437-461. [PMID: 31903131 PMCID: PMC6929622 DOI: 10.7150/thno.38366] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 09/10/2019] [Indexed: 12/15/2022] Open
Abstract
In the light of theranostics/radiotheranostics and prospective of personalized medicine in diabetes and oncology, this review presents prior and current advances in the development of radiolabeled imaging and radiotherapeutic exendin-based agents targeting glucagon-like peptide-1 receptor. The review covers chemistry, preclinical, and clinical evaluation. Such critical aspects as structure-activity-relationship, stability, physiological potency, kidney uptake, and dosimetry are discussed.
Collapse
Affiliation(s)
- Irina Velikyan
- Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
| | - Olof Eriksson
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
| |
Collapse
|
|
11
|
Evaluation of [ 68Ga]DO3A-VS-Cys 40-Exendin-4 as a PET Probe for Imaging Human Transplanted Islets in the Liver. Sci Rep 2019; 9:5705. [PMID: 30952975 PMCID: PMC6450933 DOI: 10.1038/s41598-019-42172-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 03/22/2019] [Indexed: 11/15/2022] Open
Abstract
[68Ga]DO3A-VS-Cys40-Exendin-4, a glucagon-like peptide 1 receptor agonist, was evaluated as a potential PET tracer for the quantitation of human islets transplanted to the liver. The short-lived PET radionuclide 68Ga, available on a regular basis from a 68Ge/68Ga generator, is an attractive choice. Human C-peptide was measured to evaluate human islet function post-transplantation and prior to microPET imaging. [68Ga]DO3A-VS-Cys40-Exendin-4 was radiosynthesized and evaluated for PET imaging of transplanted human islets in the liver of healthy NOD/SCID mice. The biodistribution of the tracer was evaluated to determine the uptake into various organs, and qPCR of liver samples was conducted to confirm engrafted islet numbers after PET imaging. Measurement of human C-peptide indicated that higher engrafted islet mass resulted in higher human C-peptide levels in post-transplantation. The microPET imaging yielded high resolution images of liver-engrafted islets and also showed significant retention in mouse livers at 8 weeks post-transplantation. Biodistribution studies in mice revealed that liver uptake of [68Ga]DO3A-VS-Cys40-Exendin-4 was approximately 6-fold higher in mice that received 1000 islet equivalent (IEQ) than in non-transplanted mice. qPCR analysis of insulin expression suggested that islet engraftment numbers were close to 1000 IEQ transplanted. In conclusion, human islets transplanted into the livers of mice exhibited significant uptake of [68Ga]DO3A-VS-Cys40-Exendin-4 compared to the livers of untreated mice; and imaging of the mice using PET showed the human islets clearly with high contrast against liver tissue, enabling accurate quantitation of islet mass. Further validation of [68Ga]DO3A-VS-Cys40-Exendin-4 as an islet imaging probe for future clinical application is ongoing.
Collapse
|
|
12
|
Wei W, Ehlerding EB, Lan X, Luo QY, Cai W. Molecular imaging of β-cells: diabetes and beyond. Adv Drug Deliv Rev 2019; 139:16-31. [PMID: 31378283 DOI: 10.1016/j.addr.2018.06.022] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 04/27/2018] [Accepted: 06/26/2018] [Indexed: 02/09/2023]
Abstract
Since diabetes is becoming a global epidemic, there is a great need to develop early β-cell specific diagnostic techniques for this disorder. There are two types of diabetes (i.e., type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM)). In T1DM, the destruction of pancreatic β-cells leads to reduced insulin production or even absolute insulin deficiency, which consequently results in hyperglycemia. Actually, a central issue in the pathophysiology of all types of diabetes is the relative reduction of β-cell mass (BCM) and/or impairment of the function of individual β-cells. In the past two decades, scientists have been trying to develop imaging techniques for noninvasive measurement of the viability and mass of pancreatic β-cells. Despite intense scientific efforts, only two tracers for positron emission tomography (PET) and one contrast agent for magnetic resonance (MR) imaging are currently under clinical evaluation. β-cell specific imaging probes may also allow us to precisely and specifically visualize transplanted β-cells and to improve transplantation outcomes, as transplantation of pancreatic islets has shown promise in treating T1DM. In addition, some of these probes can be applied to the preoperative detection of hidden insulinomas as well. In the present review, we primarily summarize potential tracers under development for imaging β-cells with a focus on tracers for PET, SPECT, MRI, and optical imaging. We will discuss the advantages and limitations of the various imaging probes and extend an outlook on future developments in the field.
Collapse
|
|
13
|
Jahan M, Johnström P, Selvaraju RK, Svedberg M, Winzell MS, Bernström J, Kingston L, Schou M, Jia Z, Skrtic S, Johansson L, Korsgren O, Farde L, Halldin C, Eriksson O. The development of a GPR44 targeting radioligand [ 11C]AZ12204657 for in vivo assessment of beta cell mass. EJNMMI Res 2018; 8:113. [PMID: 30588560 PMCID: PMC6306373 DOI: 10.1186/s13550-018-0465-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 12/05/2018] [Indexed: 12/28/2022] Open
Abstract
Background The G-protein-coupled receptor 44 (GPR44) is a beta cell-restricted target that may serve as a marker for beta cell mass (BCM) given the development of a suitable PET ligand. Methods The binding characteristics of the selected candidate, AZ12204657, at human GPR44 were determined using in vitro ligand binding assays. AZ12204657 was radiolabeled using 11C- or 3H-labeled methyl iodide ([11C/3H]CH3I) in one step, and the conversion of [11C/3H]CH3I to the radiolabeled product [11C/3H]AZ12204657 was quantitative. The specificity of radioligand binding to GPR44 and the selectivity for beta cells were evaluated by in vitro binding studies on pancreatic sections from human and non-human primates as well as on homogenates from endocrine and exocrine pancreatic compartments. Results The radiochemical purity of the resulting radioligand [11C]AZ12204657 was > 98%, with high molar activity (MA), 1351 ± 575 GBq/μmol (n = 18). The radiochemical purity of [3H]AZ12204657 was > 99% with MA of 2 GBq/μmol. Pancreatic binding of [11C/3H]AZ12204657 was co-localized with insulin-positive islets of Langerhans in non-diabetic individuals and individuals with type 2 diabetes (T2D). The binding of [11C]AZ12204657 to GPR44 was > 10 times higher in islet homogenates compared to exocrine homogenates. In human islets of Langerhans GPR44 was co-expressed with insulin, but not glucagon as assessed by co-staining and confocal microscopy. Conclusion We radiolabeled [11C]AZ12204657, a potential PET radioligand for the beta cell-restricted protein GPR44. In vitro evaluation demonstrated that [3H]AZ12204657 and [11C]AZ12204657 selectively target pancreatic beta cells. [11C]AZ12204657 has promising properties as a marker for human BCM.
Collapse
Affiliation(s)
- Mahabuba Jahan
- Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
| | - Peter Johnström
- Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.,PET Science Centre, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Karolinska Institutet, Stockholm, Sweden
| | - Ram K Selvaraju
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
| | - Marie Svedberg
- Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden
| | - Maria Sörhede Winzell
- Bioscience, Cardiovascular Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
| | - Jenny Bernström
- Discovery Biology, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
| | - Lee Kingston
- Early Chemical Development, Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
| | - Magnus Schou
- Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.,PET Science Centre, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Karolinska Institutet, Stockholm, Sweden
| | - Zhisheng Jia
- Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden
| | - Stanko Skrtic
- Innovation Strategies & External Liaison, Pharmaceutical Technology & Development, AstraZeneca, Gothenburg, Sweden
| | - Lars Johansson
- GMED Diabetes, Global Medicines Development, AstraZeneca, Gothenburg, Sweden.,Present address: Antaros Medical, Mölndal, Sweden
| | - Olle Korsgren
- Department of Immunology, Genetics and Pathology, Division of Immunology, Uppsala University, Uppsala, Sweden
| | - Lars Farde
- Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.,PET Science Centre, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Karolinska Institutet, Stockholm, Sweden
| | - Christer Halldin
- Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.,Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Olof Eriksson
- Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
| |
Collapse
|
|
14
|
Garousi J, Lindbo S, Borin J, von Witting E, Vorobyeva A, Oroujeni M, Mitran B, Orlova A, Buijs J, Tolmachev V, Hober S. Comparative evaluation of dimeric and monomeric forms of ADAPT scaffold protein for targeting of HER2-expressing tumours. Eur J Pharm Biopharm 2018; 134:37-48. [PMID: 30408518 DOI: 10.1016/j.ejpb.2018.11.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 10/19/2018] [Accepted: 11/04/2018] [Indexed: 12/23/2022]
Abstract
ADAPTs are small engineered non-immunoglobulin scaffold proteins, which have demonstrated very promising features as vectors for radionuclide tumour targeting. Radionuclide imaging of human epidermal growth factor 2 (HER2) expression in vivo might be used for stratification of patients for HER2-targeting therapies. ADAPT6, which specifically binds to HER2, has earlier been shown to have very promising features for in vivo targeting of HER2 expressing tumours. In this study we tested the hypothesis that dimerization of ADAPT6 would increase the apparent affinity to HER2 and accordingly improve tumour targeting. To find an optimal molecular design of dimers, a series of ADAPT dimers with different linkers, -SSSG- (DiADAPT6L1), -(SSSG)2- (DiADAPT6L2), and -(SSSG)3- (DiADAPT6L3) was evaluated. Dimers in combination with optimal linker lengths demonstrated increased apparent affinity to HER2. The best variants, DiADAPT6L2 and DiADAPT6L3 were site-specifically labelled with 111In and 125I, and compared with a monomeric ADAPT6 in mice bearing HER2-expressing tumours. Despite higher affinity, both dimers had lower tumour uptake and lower tumour-to-organ ratios compared to the monomer. We conclude that improved affinity of a dimeric form of ADAPT does not compensate the disadvantage of increased size. Therefore, increase of affinity should be obtained by affinity maturation and not by dimerization.
Collapse
Affiliation(s)
- Javad Garousi
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-75185 Uppsala, Sweden
| | - Sarah Lindbo
- Department of Protein Technology, KTH - Royal Institute of Technology, SE-10691 Stockholm, Sweden
| | - Jesper Borin
- Department of Protein Technology, KTH - Royal Institute of Technology, SE-10691 Stockholm, Sweden
| | - Emma von Witting
- Department of Protein Technology, KTH - Royal Institute of Technology, SE-10691 Stockholm, Sweden
| | - Anzhelika Vorobyeva
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-75185 Uppsala, Sweden
| | - Maryam Oroujeni
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-75185 Uppsala, Sweden
| | - Bogdan Mitran
- Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
| | - Anna Orlova
- Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
| | - Jos Buijs
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-75185 Uppsala, Sweden
| | - Vladimir Tolmachev
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-75185 Uppsala, Sweden.
| | - Sophia Hober
- Department of Protein Technology, KTH - Royal Institute of Technology, SE-10691 Stockholm, Sweden
| |
Collapse
|
|
15
|
Ahmedova A, Todorov B, Burdzhiev N, Goze C. Copper radiopharmaceuticals for theranostic applications. Eur J Med Chem 2018; 157:1406-1425. [DOI: 10.1016/j.ejmech.2018.08.051] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 08/15/2018] [Accepted: 08/18/2018] [Indexed: 12/12/2022]
|
|
16
|
Deng H, Wang H, Zhang H, Wang M, Giglio B, Ma X, Jiang G, Yuan H, Wu Z, Li Z. Imaging Neurotensin Receptor in Prostate Cancer With 64Cu-Labeled Neurotensin Analogs. Mol Imaging 2018; 16:1536012117711369. [PMID: 28849698 PMCID: PMC6081756 DOI: 10.1177/1536012117711369] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
INTRODUCTION Neurotensin receptor 1 (NTR-1) is expressed and activated in prostate cancer cells. In this study, we explore the NTR expression in normal mouse tissues and study the positron emission tomography (PET) imaging of NTR in prostate cancer models. MATERIALS AND METHODS Three 64Cu chelators (1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid [DOTA], 1,4,7-triazacyclononane-N,N',N″-triacetic acid [NOTA], or AmBaSar) were conjugated to an NT analog. Neurotensin receptor binding affinity was evaluated using cell binding assay. The imaging profile of radiolabeled probes was compared in well-established NTR+ HT-29 tumor model. Stability of the probes was tested. The selected agents were further evaluated in human prostate cancer PC3 xenografts. RESULTS All 3 NT conjugates retained the majority of NTR binding affinity. In HT-29 tumor, all agents demonstrated prominent tumor uptake. Although comparable stability was observed, 64Cu-NOTA-NT and 64Cu-AmBaSar-NT demonstrated improved tumor to background contrast compared with 64Cu-DOTA-NT. Positron emission tomography/computed tomography imaging of the NTR expression in PC-3 xenografts showed high tumor uptake of the probes, correlating with the in vitro Western blot results. Blocking experiments further confirmed receptor specificity. CONCLUSIONS Our results demonstrated that 64Cu-labeled neurotensin analogs are promising imaging agents for NTR-positive tumors. These agents may help us identify NTR-positive lesions and predict which patients and individual tumors are likely to respond to novel interventions targeting NTR-1.
Collapse
Affiliation(s)
- Huaifu Deng
- 1 Department of Radiology, Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,2 PET/CT Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Hui Wang
- 1 Department of Radiology, Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - He Zhang
- 1 Department of Radiology, Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,3 Department of Radiology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Mengzhe Wang
- 1 Department of Radiology, Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Ben Giglio
- 1 Department of Radiology, Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Xiaofen Ma
- 1 Department of Radiology, Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,4 Department of Medical Imaging, Provincial People's Hospital, Guangzhou, China
| | - Guihua Jiang
- 4 Department of Medical Imaging, Provincial People's Hospital, Guangzhou, China
| | - Hong Yuan
- 1 Department of Radiology, Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Zhanhong Wu
- 1 Department of Radiology, Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Zibo Li
- 1 Department of Radiology, Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| |
Collapse
|
|
17
|
Yang CT, Ghosh KK, Padmanabhan P, Langer O, Liu J, Halldin C, Gulyás BZ. PET probes for imaging pancreatic islet cells. Clin Transl Imaging 2017. [DOI: 10.1007/s40336-017-0251-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
18
|
Seo D, Faintuch BL, Aparecida de Oliveira E, Faintuch J. Pancreas and liver uptake of new radiolabeled incretins (GLP-1 and Exendin-4) in models of diet-induced and diet-restricted obesity. Nucl Med Biol 2017; 49:57-64. [DOI: 10.1016/j.nucmedbio.2017.03.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 02/02/2017] [Accepted: 03/15/2017] [Indexed: 01/19/2023]
|
|
19
|
Fani M, Peitl PK, Velikyan I. Current Status of Radiopharmaceuticals for the Theranostics of Neuroendocrine Neoplasms. Pharmaceuticals (Basel) 2017; 10:E30. [PMID: 28295000 PMCID: PMC5374434 DOI: 10.3390/ph10010030] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 03/08/2017] [Accepted: 03/09/2017] [Indexed: 02/06/2023] Open
Abstract
Nuclear medicine plays a pivotal role in the management of patients affected by neuroendocrine neoplasms (NENs). Radiolabeled somatostatin receptor analogs are by far the most advanced radiopharmaceuticals for diagnosis and therapy (radiotheranostics) of NENs. Their clinical success emerged receptor-targeted radiolabeled peptides as an important class of radiopharmaceuticals and it paved the way for the investigation of other radioligand-receptor systems. Besides the somatostatin receptors (sstr), other receptors have also been linked to NENs and quite a number of potential radiolabeled peptides have been derived from them. The Glucagon-Like Peptide-1 Receptor (GLP-1R) is highly expressed in benign insulinomas, the Cholecystokinin 2 (CCK2)/Gastrin receptor is expressed in different NENs, in particular medullary thyroid cancer, and the Glucose-dependent Insulinotropic Polypeptide (GIP) receptor was found to be expressed in gastrointestinal and bronchial NENs, where interestingly, it is present in most of the sstr-negative and GLP-1R-negative NENs. Also in the field of sstr targeting new discoveries brought into light an alternative approach with the use of radiolabeled somatostatin receptor antagonists, instead of the clinically used agonists. The purpose of this review is to present the current status and the most innovative strategies for the diagnosis and treatment (theranostics) of neuroendocrine neoplasms using a cadre of radiolabeled regulatory peptides targeting their receptors.
Collapse
Affiliation(s)
- Melpomeni Fani
- Division of Radiopharmaceutical Chemistry, University Hospital of Basel, 4031 Basel, Switzerland.
| | - Petra Kolenc Peitl
- Department of Nuclear Medicine, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia.
| | - Irina Velikyan
- Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden.
| |
Collapse
|
|
20
|
Läppchen T, Tönnesmann R, Eersels J, Meyer PT, Maecke HR, Rylova SN. Radioiodinated Exendin-4 Is Superior to the Radiometal-Labelled Glucagon-Like Peptide-1 Receptor Probes Overcoming Their High Kidney Uptake. PLoS One 2017; 12:e0170435. [PMID: 28103285 PMCID: PMC5245897 DOI: 10.1371/journal.pone.0170435] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 01/04/2017] [Indexed: 11/19/2022] Open
Abstract
GLP-1 receptors are ideal targets for preoperative imaging of benign insulinoma and for quantifying the beta cell mass. The existing clinical tracers targeting GLP-1R are all agonists with low specific activity and very high kidney uptake. In order to solve those issues we evaluated GLP-1R agonist Ex-4 and antagonist Ex(9-39) radioiodinated at Tyr40 side by side with [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]Ex-4 (68Ga-Ex-4) used in the clinic. The Kd, Bmax, internalization and binding kinetics of [Nle14,125I-Tyr40-NH2]Ex-4 and [Nle14,125I-Tyr40-NH2]Ex(9-39) were studied in vitro using Ins-1E cells. Biodistribution and imaging studies were performed in nude mice bearing Ins-1E xenografts. In vitro evaluation demonstrated high affinity binding of the [Nle14,125I-Tyr40-NH2]Ex-4 agonist to the Ins-1E cells with fast internalization kinetics reaching a plateau after 30 min. The antagonist [Nle14,125I-Tyr40-NH2]Ex(9-39) did not internalize and had a 4-fold higher Kd value compared to the agonist. In contrast to [Nle14,125I-Tyr40-NH2]Ex(9-39), which showed low and transient tumor uptake, [Nle14,125I-Tyr40-NH2]Ex-4 demonstrated excellent in vivo binding properties with tumor uptake identical to that of 68Ga-Ex-4, but substantially lower kidney uptake resulting in a tumor-to-kidney ratio of 9.7 at 1 h compared to 0.3 with 68Ga-Ex-4. Accumulation of activity in thyroid and stomach for both peptides, which was effectively blocked by irenat, confirms that in vivo deiodination is the mechanism behind the low kidney retention of iodinated peptides. The 124I congener of [Nle14,125I-Tyr40-NH2]Ex-4 demonstrated a similar favourable biodistribution profile in the PET imaging studies in contrast to the typical biodistribution pattern of [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]Ex-4. Our results demonstrate that iodinated Ex-4 is a very promising tracer for imaging of benign insulinomas. It solves the problem of high kidney uptake of the radiometal-labelled tracers by improving the tumor-to-kidney ratio measured for [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]Ex-4 by 32 fold.
Collapse
Affiliation(s)
- Tilman Läppchen
- Department of Nuclear Medicine, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
- Department of Nuclear Medicine, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
| | - Roswitha Tönnesmann
- Department of Nuclear Medicine, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
| | - Jos Eersels
- Department of Radiology and Nuclear Medicine, VU University Medical Centre, Amsterdam, The Netherlands
| | - Philipp T. Meyer
- Department of Nuclear Medicine, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Helmut R. Maecke
- Department of Nuclear Medicine, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Svetlana N. Rylova
- Department of Nuclear Medicine, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- * E-mail:
| |
Collapse
|
|
21
|
Template synthesis and X-ray structure of the tris-glyoximate iron(II) clathrochelates with terminal reactive groups. Inorganica Chim Acta 2016. [DOI: 10.1016/j.ica.2016.08.019] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
|
|
22
|
Li J, Karunananthan J, Pelham B, Kandeel F. Imaging pancreatic islet cells by positron emission tomography. World J Radiol 2016; 8:764-774. [PMID: 27721939 PMCID: PMC5039672 DOI: 10.4329/wjr.v8.i9.764] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Revised: 04/15/2016] [Accepted: 08/08/2016] [Indexed: 02/06/2023] Open
Abstract
It was estimated that every year more than 30000 persons in the United States - approximately 80 people per day - are diagnosed with type 1 diabetes (T1D). T1D is caused by autoimmune destruction of the pancreatic islet (β cells) cells. Islet transplantation has become a promising therapy option for T1D patients, while the lack of suitable tools is difficult to directly evaluate of the viability of the grafted islet over time. Positron emission tomography (PET) as an important non-invasive methodology providing high sensitivity and good resolution, is able to accurate detection of the disturbed biochemical processes and physiological abnormality in living organism. The successful PET imaging of islets would be able to localize the specific site where transplanted islets engraft in the liver, and to quantify the level of islets remain alive and functional over time. This information would be vital to establishing and evaluating the efficiency of pancreatic islet transplantation. Many novel imaging agents have been developed to improve the sensitivity and specificity of PET islet imaging. In this article, we summarize the latest developments in carbon-11, fluorine-18, copper-64, and gallium-68 labeled radioligands for the PET imaging of pancreatic islet cells.
Collapse
|
|
23
|
Rylova SN, Waser B, Del Pozzo L, Tönnesmann R, Mansi R, Meyer PT, Reubi JC, Maecke HR. Approaches to Improve the Pharmacokinetics of Radiolabeled Glucagon-Like Peptide-1 Receptor Ligands Using Antagonistic Tracers. J Nucl Med 2016; 57:1282-8. [DOI: 10.2967/jnumed.115.168948] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 03/21/2016] [Indexed: 01/14/2023] Open
|
|
24
|
|
|
25
|
Xu YP, Yang M. Advancement in treatment and diagnosis of pancreatic cancer with radiopharmaceuticals. World J Gastrointest Oncol 2016; 8:165-172. [PMID: 26909131 PMCID: PMC4753167 DOI: 10.4251/wjgo.v8.i2.165] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 09/30/2015] [Accepted: 12/18/2015] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer (PC) is a major health problem. Conventional imaging modalities show limited accuracy for reliable assessment of the tumor. Recent researches suggest that molecular imaging techniques with tracers provide more biologically relevant information and are benefit for the diagnosis of the cancer. In addition, radiopharmaceuticals also play more important roles in treatment of the disease. This review summaries the advancement of the radiolabeled compounds in the theranostics of PC.
Collapse
|
|
26
|
Zhang H, Liu Y, Guan S, Qu D, Wang L, Wang X, Li X, Zhou S, Zhou Y, Wang N, Meng J, Ma X. An Orally Active Allosteric GLP-1 Receptor Agonist Is Neuroprotective in Cellular and Rodent Models of Stroke. PLoS One 2016; 11:e0148827. [PMID: 26863436 PMCID: PMC4749391 DOI: 10.1371/journal.pone.0148827] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 01/21/2016] [Indexed: 12/25/2022] Open
Abstract
Diabetes is a major risk factor for the development of stroke. Glucagon-like peptide-1 receptor (GLP-1R) agonists have been in clinical use for the treatment of diabetes and also been reported to be neuroprotective in ischemic stroke. The quinoxaline 6,7-dichloro-2-methylsulfonyl-3-N-tert- butylaminoquinoxaline (DMB) is an agonist and allosteric modulator of the GLP-1R with the potential to increase the affinity of GLP-1 for its receptor. The aim of this study was to evaluate the neuroprotective effects of DMB on transient focal cerebral ischemia. In cultured cortical neurons, DMB activated the GLP-1R, leading to increased intracellular cAMP levels with an EC50 value about 100 fold that of exendin-4. Pretreatment of neurons with DMB protected against necrotic and apoptotic cell death was induced by oxygen-glucose deprivation (OGD). The neuroprotective effects of DMB were blocked by GLP-1R knockdown with shRNA but not by GLP-1R antagonism. In C57BL/6 mice, DMB was orally administered 30 min prior to middle cerebral artery occlusion (MCAO) surgery. DMB markedly reduced the cerebral infarct size and neurological deficits caused by MCAO and reperfusion. The neuroprotective effects were mediated by activation of the GLP-1R through the cAMP-PKA-CREB signaling pathway. DMB exhibited anti-apoptotic effects by modulating Bcl-2 family members. These results provide evidence that DMB, a small molecular GLP-1R agonist, attenuates transient focal cerebral ischemia injury and inhibits neuronal apoptosis induced by MCAO. Taken together, these data suggest that DMB is a potential neuroprotective agent against cerebral ischemia.
Collapse
Affiliation(s)
- Huinan Zhang
- Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi’an, China
| | - Yunhan Liu
- School of Nurse, the Fourth Military Medical University, Xi’an, China
| | - Shaoyu Guan
- Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi’an, China
| | - Di Qu
- Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi’an, China
| | - Ling Wang
- Department of Health Statistics, Faculty of Preventative Medicine, the Fourth Military Medical University, Xi’an, China
| | - Xinshang Wang
- Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi’an, China
| | - Xubo Li
- Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi’an, China
| | - Shimeng Zhou
- Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi’an, China
| | - Ying Zhou
- Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi’an, China
| | - Ning Wang
- Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi’an, China
| | - Jingru Meng
- Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi’an, China
- * E-mail: . (XM); (JM)
| | - Xue Ma
- Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi’an, China
- * E-mail: . (XM); (JM)
| |
Collapse
|
|
27
|
Paterson BM, Donnelly PS. Macrocyclic Bifunctional Chelators and Conjugation Strategies for Copper-64 Radiopharmaceuticals. ADVANCES IN INORGANIC CHEMISTRY 2016. [DOI: 10.1016/bs.adioch.2015.09.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
|
|
28
|
Synthesis, structure and reactivity of iron(II) clathrochelates with terminal formyl (acetal) groups. Inorganica Chim Acta 2016. [DOI: 10.1016/j.ica.2015.11.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
|
|
29
|
Bauman A, Valverde IE, Fischer CA, Vomstein S, Mindt TL. Development of 68Ga- and 89Zr-Labeled Exendin-4 as Potential Radiotracers for the Imaging of Insulinomas by PET. J Nucl Med 2015; 56:1569-74. [PMID: 26251418 DOI: 10.2967/jnumed.115.159186] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 07/27/2015] [Indexed: 12/25/2022] Open
Abstract
UNLABELLED Clinical studies have demonstrated the potential of radiometallated exendin-4 derivatives for the imaging of glucagonlike peptide-1 receptor-overexpressing insulinomas. Recently investigated exendin-4 derivatives were radiolabeled with the SPECT isotopes 99mTc or 111In. Despite promising results, the low spatial resolution associated with SPECT and the occasional need to perform imaging several days after injection for the demarcation of insulinomas from the kidneys represent current limitations. The aim of this work was the development of exendin-4 derivatives for the imaging of insulinomas by high-resolution PET at early or late time points after injection of the radiotracer. METHODS An exendin-4 derivative conjugated to desferrioxamine (DFO) was used for radiolabeling with the PET isotopes 68Ga and 89Zr. Both radiotracers were evaluated in vitro with RIN-m5F cells for their cell internalization properties as well as affinities and specificities toward the glucagonlike peptide-1 receptor. Serum stabilities of the radiopeptides were assessed in blood serum, and their distribution coefficient was determined by the shake-flask method. Biodistribution experiments were performed with nude mice bearing RIN-m5F xenografts. For all experiments, clinically evaluated [Lys40-(AHX-DTPA-111In)NH2]exendin-4 was used as a reference compound. RESULTS [Lys40-(AHX-DFO)NH2]exendin-4 was labeled with 89Zr and 68Ga in high radiochemical yield and purity. In vitro experiments showed favorable cell uptake and receptor affinity for [Lys40-(AHX-DFO-68Ga)NH2]exendin-4, and [Lys40-(AHX-DFO-89Zr)NH2]exendin-4 and [Lys40-(AHX-DTPA-111In)NH2]exendin-4 performed similarly well. In biodistribution experiments, [Lys40-(AHX-DFO-68Ga)NH2]exendin-4 exhibited a significantly enhanced tumor uptake 1 h after injection in comparison to the other 2 radiotracers. Tumor uptake of [Lys40-(AHX-DFO-89Zr)NH2]exendin-4 was comparable to that of [Lys40-(AHX-DTPA-111In)NH2]exendin-4 at 1-48 h after injection. All compounds showed a fast blood clearance and low accumulation in receptor-negative organs and tissue with the exception of the kidneys, a known characteristic for exendin-4-based radiotracers. CONCLUSION 68Ga- and 89Zr-radiolabeled [Lys40-(AHX-DFO)NH2]exendin-4 exhibit characteristics comparable or superior to the clinically tested reference compound [Lys40-(AHX-DTPA-111In)NH2]exendin-4 and, thus, represent potential new tracers for the imaging of insulinomas by PET.
Collapse
Affiliation(s)
- Andreas Bauman
- Division of Radiopharmaceutical Chemistry, University of Basel Hospital, Basel, Switzerland
| | - Ibai E Valverde
- Division of Radiopharmaceutical Chemistry, University of Basel Hospital, Basel, Switzerland
| | - Christiane A Fischer
- Division of Radiopharmaceutical Chemistry, University of Basel Hospital, Basel, Switzerland
| | - Sandra Vomstein
- Division of Radiopharmaceutical Chemistry, University of Basel Hospital, Basel, Switzerland
| | - Thomas L Mindt
- Division of Radiopharmaceutical Chemistry, University of Basel Hospital, Basel, Switzerland
| |
Collapse
|
|
30
|
Abstract
The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, (18)F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in positron emission tomography.
Collapse
Affiliation(s)
- Eric P Gillis
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Kyle J Eastman
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - Matthew D Hill
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States
| | - David J Donnelly
- Discovery Chemistry Platforms, PET Radiochemical Synthesis, Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States
| | - Nicholas A Meanwell
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States
| |
Collapse
|
|
31
|
Li D, Huang Z, Chen S, Hu Z, Li WH. GLP-1 Receptor Mediated Targeting of a Fluorescent Zn(2+) Sensor to Beta Cell Surface for Imaging Insulin/Zn(2+) Release. Bioconjug Chem 2015; 26:1443-50. [PMID: 26121325 DOI: 10.1021/acs.bioconjchem.5b00332] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The pancreatic islet beta cell plays an essential role in maintaining the normal blood glucose level by releasing insulin. Loss of functional beta cell mass leads to diabetes—a disease affecting ∼9% of the population worldwide. There has been great interest and intense effort in developing imaging probes for monitoring islet beta cells, and glucagon-like peptide-1 receptor (GLP-1R) has emerged as a valuable biomarker for targeting beta cells. However, efforts thus far in GLP-1R mediated beta cell labeling and imaging has largely, if not exclusively, focused on developing imaging probes for monitoring beta cell mass, and few studies have investigated imaging beta cell function (insulin release) through GLP-1R. We now report the design and synthesis of a bioconjugate, ZIMIR-Ex4(9-39), that consists of a fluorescent Zn(2+) sensor and a truncated exendin 4 peptide for imaging insulin/Zn(2+) release in islet beta cells. In vitro, the conjugate bound to Zn(2+) with high affinity and displayed a robust fluorescence enhancement upon Zn(2+) chelation. When added to beta cells at submicromolar concentration, ZIMIR-Ex4(9-39) rapidly labeled cell surface in minutes to report the dynamics of insulin/Zn(2+) release with high spatiotemporal resolution. Future explorations of this approach may lead to probes for tracking beta cell function using different imaging modalities.
Collapse
Affiliation(s)
- Daliang Li
- †Departments of Cell Biology and of Biochemistry, ‡Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, Texas 75390-9039, United States
| | - ZhiJiang Huang
- †Departments of Cell Biology and of Biochemistry, ‡Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, Texas 75390-9039, United States
| | - Shiuhwei Chen
- †Departments of Cell Biology and of Biochemistry, ‡Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, Texas 75390-9039, United States
| | - Zeping Hu
- †Departments of Cell Biology and of Biochemistry, ‡Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, Texas 75390-9039, United States
| | - Wen-hong Li
- †Departments of Cell Biology and of Biochemistry, ‡Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, Texas 75390-9039, United States
| |
Collapse
|
|
32
|
Voloshin YZ, Novikov VV, Nelyubina YV. Recent advances in biological applications of cage metal complexes. RSC Adv 2015. [DOI: 10.1039/c5ra10949c] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
This review highlights advances in biochemical and medical applications of cage metal complexes (clathrochelates) and related polyhedral compounds.
Collapse
Affiliation(s)
- Yan Z. Voloshin
- Nesmeyanov Institute of the Organoelement Compounds
- Russian Academy of Sciences
- Moscow
- Russia
| | - Valentin V. Novikov
- Nesmeyanov Institute of the Organoelement Compounds
- Russian Academy of Sciences
- Moscow
- Russia
| | - Yulia V. Nelyubina
- Nesmeyanov Institute of the Organoelement Compounds
- Russian Academy of Sciences
- Moscow
- Russia
| |
Collapse
|