title: A Synthetic Heterobivalent Ligand Composed of Glucagon-Like Peptide 1 and Yohimbine Specifically Targets β Cells Within the Pancreas.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: 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.
authors.forename: Leah V
authors.initials: LV
authors.lastname: Steyn
authors.forename: Kameswari
authors.initials: K
authors.lastname: Ananthakrishnan
authors.forename: Miranda J
authors.initials: MJ
authors.lastname: Anderson
authors.forename: Renata
authors.initials: R
authors.lastname: Patek
authors.forename: Amy
authors.initials: A
authors.lastname: Kelly
authors.forename: Josef
authors.initials: J
authors.lastname: Vagner
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Lynch
authors.forename: Sean W
authors.initials: SW
authors.lastname: Limesand
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003287:Contrast Media / Q000737:chemistry* / Q000493:pharmacokinetics; D003921:Diabetes Mellitus, Experimental; D016503:Drug Delivery Systems; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry* / Q000493:pharmacokinetics; D007205:Indium Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D057054:Molecular Imaging; D010179:Pancreas / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D015016:Yohimbine / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D003287:Contrast Media; D007205:Indium Radioisotopes; D015016:Yohimbine; D052216:Glucagon-Like Peptide 1