A Synthetic Heterobivalent Ligand Composed of Glucagon-Like Peptide 1 and Yohimbine Specifically Targets β Cells Within the Pancreas

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• 作者：Leah V. Steyn ; Kameswari Ananthakrishnan…
• 关键词：GLP ; 1 ; β Cell mass ; Imaging ; Adrenergic receptor ; Multivalency
• 刊名：Molecular Imaging and Biology
• 出版年：2015
• 出版时间：August 2015
• 年：2015
• 卷：17
• 期：4
• 页码：461-470
• 全文大小：1,570 KB
• 参考文献：1.Singhal T, Ding YS, Weinzimmer D et al (2011) Pancreatic beta cell mass PET imaging and quantification with 11C-DTBZ and 18F-FP-(+)-DTBZ in rodent models of diabetes. Mol Imaging Biol 13:973-84PubMed Central PubMed View Article
  2.Mukai E, Toyoda K, Kimura H et al (2009) GLP-1 receptor antagonist as a potential probe for pancreatic β-cell imaging. Biochem Biophys Res Commun 389:523-26PubMed View Article
  3.Moore A, Bonner-Weir S, Weissleder R (2001) Noninvasive in vivo measurement of β-cell mass in mouse model of diabetes. Diabetes 50:2231-236PubMed View Article
  4.Hampe CS, Wallen AR, Schlosser M et al (2005) Quantitative evaluation of a monoclonal antibody and its fragment as potential markers for pancreatic beta cell mass. Exp Clin Endocrinol Diabetes 113:381-87PubMed View Article
  5.Sweet IR, Cook DL, Lernmark ? et al (2004) Systematic screening of potential β-cell imaging agents. Biochem Biophys Res Commun 314:976-83PubMed View Article
  6.Souza F, Freeby M, Hultman K et al (2006) Current progress in non-invasive imaging of beta cell mass of the endocrine pancreas. Curr Med Chem 13:2761-773PubMed View Article
  7.Schneider S, Feilen P, Schreckenberger M et al (2005) In vitro and in vivo evaluation of novel glibenclamide derivatives as imaging agents for the non-invasive assessment of the pancreatic islet cell mass in animals and humans. Exp Clin Endocrinol Diabetes 113:388-95PubMed View Article
  8.Normandin MD, Petersen KF, Ding YS et al (2012) In vivo imaging of endogenous pancreatic beta cell mass in healthy and type 1 diabetic subjects using 18F-fluoropropyl-dihydrotetrabenazine and PET. J Nucl Med 53:908-16PubMed Central PubMed View Article
  9.Brom M, Woliner-van der Weg W, Joosten L et al (2014) Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin. Diabetologia 57:950-59PubMed View Article
  10.Mikkola K, Yim C, Fagerholm V et al (2014) 64Cu- and 68Ga-labelled [Nle14, Lys40 (Ahx-NODAGA) NH2]-exendin-4 for pancreatic beta cell imaging in rats. Mol Imaging Biol 16:255-63PubMed View Article
  11.Yim CB, Mikkola K, Fagerholm V et al (2013) Synthesis and preclinical characterization of [Cu-64] NODAGA-MAL-exendin-4 with a N-epsilon-maleoyl-l-lysyl-glycine linkage. Nucl Med Biol 40:1006-012PubMed View Article
  12.Wild D, Behe M, Wicki A et al (2006) [Lys40 (Ahx-DTPA-111In) NH2] exendin-4, a very promising ligand for glucagon-like peptide-1 (GLP-1) receptor targeting. J Nucl Med 47:2025-033PubMed
  13.Wild D, Wicki A, Mansi R et al (2010) Exendin-4-based radiopharmaceuticals for glucagonlike peptide-1 receptor PET/CT and SPECT/CT. J Nucl Med 51:1059-067PubMed View Article
  14.Hart NJ, Chung WJ, Ananthakrishnan K et al (2013) Heterobivalent GLP-1/Glibenclamide for targeting pancreatic b-cells. ChemBioChem 15:135-5PubMed Central PubMed View Article
  15.Xu L, Josan JS, Vagner J et al (2012) Heterobivalent ligands target cell-surface receptor combinations in vivo. Proc Natl Acad Sci U S A 109:21295-1300PubMed Central PubMed View Article
  16.Josan JS, Handl HL, Sankaranarayanan R et al (2011) Cell-specific targeting by heterovalent ligands. Bioconjug Chem 22:1270-278PubMed Central PubMed View Article
  17.Brabez N, Lynch RM, Xu L et al (2011) Design, synthesis, and biological studies of efficient multivalent melanotropin ligands: tools toward melanoma diagnosis and treatment. J Med Chem 54:7375-384PubMed Central PubMed View Article
  18.Handl HL, Sankaranarayanan R, Josan JS et al (2007) Synthesis and evaluation of bivalent NDP-alpha-MSH (7) peptide ligands for binding to the human melanocortin receptor 4 (hMC4R). Bioconjug Chem 18:1101-109PubMed Central PubMed View Article
  19.Caplan MR, Rosca EV (2005) Targeting drugs to combinations of receptors: a modeling analysis of potential specificity. Ann Biomed Eng 33:1113-124PubMed View Article
  20.Uttenthal LO, Blazquez E (1990) Characterization of high-affinity receptors for truncated glucagon-like peptide-1 in rat gastric glands. FEBS Lett 262:139-41PubMed View Article
  21.K?rner M, St?ckli M, Waser B, Reubi JC (2007) GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J Nucl Med 48:743View Article
  22.Kelly AC, Steyn LV, Kitzmann JP et al (2014) Function and expression of sulfonylurea, adrenergic, and glucagon-like peptide 1 receptors in isolated porcine islets. Xenotransplantation 21:385-91PubMed Central PubMed View Article
  23.Tornehave D, Kristensen P, Romer J et al (2008) Expression of the GLP-1 receptor in mouse, rat, and human pancreas. J Histochem Cytochem 56:841-51PubMed Central PubMed View Article
  24.Pyke C, Heller RS, Kirk RK et al (2014) GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology 155:1280-290PubMed View Article
  25.Gotthardt M, Lalyko G, van Eerd-Vismale J et al (2006) A new tec
• 作者单位：Leah V. Steyn (1)
  Kameswari Ananthakrishnan (2)
  Miranda J. Anderson (1)
  Renata Patek (3)
  Amy Kelly (1)
  Josef Vagner (3)
  Ronald M. Lynch (2) (3)
  Sean W. Limesand (1) (3)
  
  1. School of Animal and Comparative Biomedical Sciences, William J. Parker Agricultural Research Center, The University of Arizona, 4101 N Campbell Ave, Tucson, AZ, 85719, USA
  2. Department of Physiology, Arizona Health Sciences Center, 1501 N. Campbell, Tucson, AZ, 85724, USA
  3. BIO5 Institute, The University of Arizona, 1657 E. Helen Street, Tucson, AZ, 85721, USA
  
• 刊物主题：Imaging / Radiology;
• 出版者：Springer US
• ISSN：1860-2002

文摘

Purpose β Cell specificity for a heterobivalent ligand composed of glucagon-like peptide-1 (GLP-1) linked to yohimbine (GLP-1/Yhb) was evaluated to determine its utility as a noninvasive imaging agent. Procedures Competition binding assays were performed on βTC3 cells and isolated rat islets. Immunostaining for insulin was used to co-localized intravenously injected Cy5-labeled GLP-1/Yhb in β cells of Sprague–Dawley rats. Rats were intravenously injected with In-111-labeled GLP-1/Yhb to determine clearance rates and tissue biodistribution. Tissue-specific binding was confirmed by competition with pre-administration of unlabeled GLP-1/Yhb and in Streptozotocin-induced diabetic rats. Results In βTC3 cells, high affinity binding of GLP-1/Yhb required interactions with both receptors because monovalent competition or receptor knockdown with RNAi lowered specificity and avidity of the heterobivalent ligand. Binding specificity for isolated islets was 2.6-fold greater than that of acinar tissue or islets pre-incubated with excess unlabeled GLP-1/Yhb. Immunofluorescent localization of Cy5-labeled GLP-1/Yhb was restricted to pancreatic islets. Within 30?min, ~90?% of the In-111-labeled GLP-1/Yhb was cleared from blood. Tissue-specific accumulation of radiolabeled ligand was apparent in the pancreas, but not in other tissues within the abdominal imaging field. Pancreas specificity was lost in Streptozotocin-induced diabetic rats. Conclusions The GLP-1/Yhb exhibits high specificity for β cells, rapid blood clearance rates, and low non-specific uptake by other tissues within the abdominal imaging field. These characteristics of GLP-1/Yhb are desirable for application to β cell imaging in vivo and provide a basis for developing additional multivalent β cell-specific targeting agents to aid in the management of type 1 diabetes.