title: Assessment of islet specificity of dihydrotetrabenazine radiotracer binding in rat pancreas and human pancreas.
abstract: Vesicular monoamine transporter 2 (VMAT2) is a putative molecular target for the quantitative imaging of pancreatic beta-cell mass by PET. The VMAT2 PET tracer (11)C-dihydrotetrabenazine ((11)C-DTBZ) exhibits high pancreatic uptake that is reduced in type 1 diabetes. The aim of this study was to assess the islet and VMAT2 specificity of DTBZ binding in the pancreas.
  
  
  METHODS
  The biodistribution of (11)C-DTBZ in rats was determined 10 and 60 min after injection. The localization of DTBZ radioactivity in rat and human pancreatic tissue sections was investigated by autoradiography. Saturation and competition binding assays were performed with (3)H-DTBZ and sections of rat pancreatic and control tissues. The binding of (11)C-DTBZ in pancreatic sections from rats with streptozotocin-induced diabetes was compared with that in control rats.
  
  
  RESULTS
  The values for the pancreatic uptake of (11)C-DTBZ (percentage injected dose per gram of tissue) were 3.0 at 10 min and 2.7 at 60 min. At 10 min, pancreatic radioactivity was heterogeneously distributed, with higher levels toward the head of the pancreas (head-to-tail ratio, 1.7). No such gradient was observed in pancreatic sections incubated with (11)C-DTBZ and (3)H-DTBZ in vitro. In rats, (11)C-DTBZ and (3)H-DTBZ binding in pancreatic islets did not exceed binding in the exocrine pancreas. Saturable (3)H-DTBZ binding was observed in the rat brain striatum (dissociation constant [K(d)], 1.3 nM) and the bovine adrenal medulla (K(d), 3.3 nM), whereas in the rat pancreas, (3)H-DTBZ binding was nonsaturable. Competition binding with (3)H-DTBZ and VMAT2 antagonists also indicated that DTBZ binding in the rat pancreas was nonspecific and did not represent binding to VMAT2. Nonspecific pancreatic (11)C-DTBZ binding was lower in rats with streptozotocin-induced diabetes than in control rats. In sections of human pancreas, a subset of pancreatic islets were weakly but VMAT2-specifically labeled with (3)H-DTBZ.
  
  
  CONCLUSIONS
  The results showed that the pancreatic uptake of (11)C-DTBZ is mainly due to nonspecific binding in the exocrine pancreas and suggested that the reduction in pancreatic (11)C-DTBZ binding observed in type 1 diabetes is not specific for the loss of beta-cell mass.
authors: Turku PET Centre, University of Turku, Turku, Finland. veronica.fagerholm@utu.fi
authors: Veronica
authors: V
authors: Fagerholm
authors: Kirsi K
authors: KK
authors: Mikkola
authors: Tamiko
authors: T
authors: Ishizu
authors: Eveliina
authors: E
authors: Arponen
authors: Saila
authors: S
authors: Kauhanen
authors: Kjell
authors: K
authors: Någren
authors: Olof
authors: O
authors: Solin
authors: Pirjo
authors: P
authors: Nuutila
authors: Merja
authors: M
authors: Haaparanta
mesh_terms: D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D002417:Cattle; D003920:Diabetes Mellitus / Q000378:metabolism; D005260:Female; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009928:Organ Specificity; D011485:Protein Binding; D011849:Radioactive Tracers; D051381:Rats; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
chemical_list: D011849:Radioactive Tracers; D050493:Vesicular Monoamine Transport Proteins; C032811:dihydrotetrabenazine; D013747:Tetrabenazine