title: Sigma receptor binding of tetrabenazine series tracers targeting VMAT2 in rat pancreas.
abstract: The vesicular monoamine transporter type II (VMAT2) is highly expressed in pancreatic β-cells and thus has been proposed to be a potential target for measuring β-cell mass (BCM) by molecular imaging. Several tracers based on the TBZ backbone, including 9-fluoropropyl-(+)-dihydrotetrabenazine ([(18)F]AV-133), have shown some promising results as potential biomarkers for BCM despite a relatively high background signal in the pancreas. In the present study, we explore the background binding characteristics of [(18)F]AV-133 in rat pancreas.
  
  
  METHODS
  Pancreatic exocrine cells and islet cells were isolated and purified from Sprague-Dawley rats. Membrane homogenates, prepared from both pancreatic exocrine and islet cells as well as from brain striatum regions, were used for in vitro binding studies of [(18)F]AV-133 under a selective masking condition. 1,3-Di-o-tolylguanidine (DTG), displaying high and roughly equal affinity for both sigma-1 and sigma-2 receptors, was chosen at 5 μM concentration for the masking/blocking studies.
  
  
  RESULTS
  [(18)F]AV-133 binding to rat striatum homogenates was not significantly altered by the presence of DTG. In contrast, [(18)F]AV-133 showed significant competition with DTG for binding sites in rat pancreatic exocrine homogenates as well as in rat islet cell homogenates. Importantly, in the presence of DTG, [(18)F]AV-133 showed a single high-affinity binding site on islet cell homogenates with a K(d) value of 3.8 nM which is consistent with the affinity reported previously for VMAT2 sites in rat pancreas.
  
  
  CONCLUSIONS
  [(18)F]AV-133, in addition to a high-affinity VMAT2 binding site, binds with low affinity (but high capacity) to sigma components that are present in the rat pancreas. Identification of the cause of background binding of [(18)F]AV-133 to rat pancreatic tissue may lead to improved methods for quantification.
authors: Department of Nuclear Medicine, Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
authors: Hsin-Hsin
authors: HH
authors: Tsao
authors: Daniel M
authors: DM
authors: Skovronsky
authors: Kun-Ju
authors: KJ
authors: Lin
authors: Tzu-Chen
authors: TC
authors: Yen
authors: Shiaw-Pyng
authors: SP
authors: Wey
authors: Mei-Ping
authors: MP
authors: Kung
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D005462:Fluorine Radioisotopes; D006146:Guanidines / Q000378:metabolism; D008297:Male; D017072:Neostriatum / Q000378:metabolism; D020799:Pancrelipase / Q000378:metabolism*; D011485:Protein Binding; D011849:Radioactive Tracers; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism*; D013379:Substrate Specificity; D013747:Tetrabenazine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
chemical_list: D005462:Fluorine Radioisotopes; D006146:Guanidines; D011849:Radioactive Tracers; D017480:Receptors, sigma; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; C032811:dihydrotetrabenazine; D020799:Pancrelipase; C549477:florbenazine F 18; C050232:1,3-ditolylguanidine; D013747:Tetrabenazine