title: Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging.
abstract: OBJECTIVE
  Quantitative molecular imaging of beta cell mass (BCM) would enable early detection and treatment monitoring of type 1 diabetes. The glucagon-like peptide-1 (GLP-1) receptor is an attractive target due to its beta cell specificity and cell surface location. We quantitatively investigated the impact of plasma clearance and receptor internalization on targeting efficiency in healthy B6 mice.
  
  
  METHODS
  Four exenatide-based probes were synthesized that varied in molecular weight, binding affinity, and plasma clearance. The GLP-1 receptor internalization rate and in vivo receptor expression were quantified.
  
  
  RESULTS
  Receptor internalization (54,000 receptors/cell in vivo) decreased significantly within minutes, reducing the benefit of a slower-clearing agent. The multimers and albumin binding probes had higher kidney and liver uptake, respectively.
  
  
  CONCLUSIONS
  Slow plasma clearance is beneficial for GLP-1 receptor peptide therapeutics. However, for exendin-based imaging of islets, down-regulation of the GLP-1 receptor and non-specific background uptake result in a higher target-to-background ratio for fast-clearing agents.
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA. gthurber@umich.edu.|Department of Biomedical Engineering, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI, 48109, USA. gthurber@umich.edu.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Thurber
mesh_terms: D000818:Animals; D001557:Benzenesulfonates / Q000737:chemistry; D015536:Down-Regulation / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor / Q000097:blood* / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000737:chemistry; D008810:Mice, Inbred C57BL; D057054:Molecular Imaging / Q000379:methods*; D010455:Peptides / Q000494:pharmacology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014688:Venoms / Q000494:pharmacology
chemical_list: D001557:Benzenesulfonates; D000067757:Glucagon-Like Peptide-1 Receptor; C562366:IRDye 800CW; D007211:Indoles; D010455:Peptides; D014688:Venoms; D049452:Green Fluorescent Proteins; D000077270:Exenatide
keywords: Exendin; Glucagon-like peptide-1 receptor; Type 1 diabetes imaging