Sigma receptor binding of tetrabenazine series tracers targeting VMAT2 in rat pancreas

The vesicular monoamine transporter type II (VMAT2) is highly expressed in pancreatic beta-cells and thus has been proposed to be a potential target for measuring beta-cell mass (BCM) by molecular imaging. Several tracers based on the TBZ backbone, including 9-fluoropropyl-(+)-dihydrotetrabenazine ([F-18]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 [F-18]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 [F-18]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 mu M concentration for the masking/blocking studies. Results: [F-18]AV-133 binding to rat striatum homogenates was not significantly altered by the presence of DIG. In contrast, [F-18]AV-133 showed significant competition with DIG for binding sites in rat pancreatic exocrine homogenates as well as in rat islet cell homogenates. Importantly, in the presence of DTG, [F-18]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: [F-18]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 [F-18]AV-133 to rat pancreatic tissue may lead to improved methods for quantification. (C) 2011 Elsevier Inc. All rights reserved.